INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MOKSIFTOR 400 (MOXIFTOR 400)

Composition:

Active substance: moxifloxacin;

One tablet contains 400 mg of moxifloxacin hydrochloride calculated as moxifloxacin;

Excipients: lactose monohydrate, colloidal anhydrous silicon dioxide, povidone, sodium croscarmellose, magnesium stearate;
coating: talc, titanium dioxide (E 171), hypromellose, colloidal anhydrous silicon dioxide, polyethylene glycol 6000, iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: capsule-shaped, light pink, biconvex, film-coated tablets with a break line on one side.

Pharmacotherapeutic group.

Antimicrobial agents for systemic use. Antibacterial agents of the quinolone group.

ATC code J01M A14.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Moxifloxacin is an 8-methoxyfluoroquinolone agent with a broad spectrum of bactericidal activity. In vitro, moxifloxacin is active 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 effect of moxifloxacin is due to inhibition of both type II topoisomerases (DNA gyrase and topoisomerase IV), which are essential for replication, transcription, and repair of bacterial DNA.

The C8-methoxy substituent is believed to enhance activity and reduce the selection of resistant mutants in 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.

Moxifloxacin exhibits concentration-dependent bactericidal activity. Minimal bactericidal concentrations (MBC) are generally equivalent to minimal inhibitory concentrations (MIC).

Effect on human intestinal flora

In two studies involving healthy volunteers, the following changes in intestinal flora were observed after oral administration of moxifloxacin. The numbers of E. coli, Bacillus spp., Enterococcus, and Klebsiella spp., as well as anaerobes Bacteroides vulgatus, Bifidobacterium spp., Eubacterium, and Peptostreptococcus, were reduced. An increase in Bacteroides fragilis was observed.

The numbers of the above-mentioned microorganisms returned to normal levels within two weeks.

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

Clinical breakpoints

Table 1.

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

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

Microbiological susceptibility

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

Expert advice on antimicrobial resistance should be sought if local resistance prevalence is so high that the efficacy of a particular medicinal product against at least some infectious pathogens is questionable.

Susceptible species

Aerobic Gram-positive microorganisms

Gardnerella vaginalis

Staphylococcus aureus * (methicillin-susceptible)

Streptococcus agalactiae (Group B)

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

Streptococcus pneumoniae *

Streptococcus pyogenes * (Group A)

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

Aerobic Gram-negative microorganisms

Acinetobacter baumannii

Haemophilus influenzae *

Haemophilus parainfluenzae *

Legionella pneumophila

Moraxella (Branhamella) catarrhalis *

Anaerobic microorganisms

Fusobacterium spp.

Prevotella spp.

Other microorganisms

Chlamydophila (Chlamydia) pneumoniae *

Chlamydia trachomatis*

Coxiella burnetii

Mycoplasma genitalium

Mycoplasma hominis

Mycoplasma pneumoniae *

Species with possible acquired resistance

Aerobic Gram-positive microorganisms

Enterococcus faecalis**

Enterococcus faecium**

Staphylococcus aureus (methicillin-resistant)+

Aerobic Gram-negative microorganisms

Enterobacter cloacae**

Escherichia coli*#*

Klebsiella pneumoniae*#*

Klebsiella oxytoca

Neisseria gonorrhoeae*+*

Proteus mirabilis**

Anaerobic microorganisms

Bacteroides fragilis**

Peptostreptococcus spp.**

Resistant species

Aerobic Gram-negative microorganisms

Pseudomonas aeruginosa

* Adequate activity against susceptible strains has been demonstrated in clinical trials 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 erythrocytes 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. Cases of neurotoxicity (CNS effects – 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. No signs of genotoxicity were detected in in vivo tests, despite the use 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 indicate the absence of phototoxic and photogenotoxic properties of moxifloxacin when tested within a comprehensive program during in vitro and in vivo studies. Under the same conditions, other quinolones demonstrated these effects.

At high concentrations, moxifloxacin acts as an inhibitor of the rapid component of the cardiac slow delayed rectifier potassium current and may therefore lead to QT interval prolongation. Toxicological studies conducted 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 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 body weight of 50 kg), calculated on the basis of dose/body weight ratio (mg/kg), with plasma concentrations 2 to 3 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 signs of risk to the visual organs. In dog studies, only high oral doses (≥ 60 mg/kg) resulted in plasma concentrations ≥ 20 mg/L, leading 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 conducted in rats (with oral and intravenous administration of moxifloxacin) and monkeys (with oral administration of moxifloxacin) did not reveal teratogenic effects of moxifloxacin or effects on fertility. Skeletal malformations were observed in rabbits after intravenous administration of moxifloxacin at a dose of 20 mg/kg. Increased abortion rates were observed in monkeys and rabbits when moxifloxacin was administered at therapeutic doses. 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 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. Steady state is achieved within 3 days. After an oral dose of 400 mg, 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.

Distribution

Moxifloxacin rapidly distributes into the extravascular space; after a 400 mg dose, AUC is 35 µg/L. The volume of distribution at steady state is 2 L/kg. As determined in in vitro and ex vivo experiments, protein binding in blood is approximately 40–42% and is independent of drug concentration.

Table 2.

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

* Intravenous administration of a single 400 mg dose.

1 10 hours after administration.

2 Free concentration.

3 From 3 hours to 36 hours after dose administration.

4 At the end of infusion.

Metabolism

Moxifloxacin undergoes phase II biotransformation and is excreted via the kidneys as well as in feces/bile, both in unchanged form and as inactive sulfate metabolites (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 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 a 400 mg dose, urinary excretion (approximately 19% unchanged drug, approximately 2.5% as M1, and approximately 14% as M2) and fecal excretion (approximately 25% 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 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 levels 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 bacterial infections listed below, caused by microorganisms sensitive to the drug (see sections "Special precautions", "Adverse reactions", "Pharmacological properties"), in patients aged 18 years and older. Moxifloxacin should be prescribed only when use of antibacterial agents typically recommended for initial treatment of the infections listed below is inappropriate or when such treatment has been ineffective.

• Acute bacterial sinusitis (diagnosed with high probability).
• Acute exacerbation of chronic bronchitis (diagnosed with high probability).
• Community-acquired pneumonia, excluding community-acquired pneumonia with severe course.
• Moderate to severe pelvic inflammatory diseases (including infectious involvement of the upper genital tract in women, such as salpingitis and endometritis), not associated with tubo-ovarian abscess or pelvic abscesses. The tablet form of Moxiflor 400 is not recommended for use as monotherapy in moderate to severe pelvic inflammatory diseases, but may be used in combination with other appropriate antibacterial agents (e.g., cephalosporins) due to increasing resistance of moxifloxacin to Neisseria gonorrhoeae (except for moxifloxacin-resistant strains of N. gonorrhoeae) (see sections "Special precautions", "Pharmacological properties").

The tablet form of Moxiflor 400 may be used to complete a treatment course in which initial parenteral therapy with moxifloxacin was effective and indicated for the following conditions:

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

The tablet form of Moxiflor 400 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 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").
• Patients with history of tendon disorders related to quinolone therapy.

During preclinical and clinical studies following administration of moxifloxacin, changes in cardiac electrophysiology were observed, manifested as 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 types of interactions").

Due to limited clinical data on drug use, it 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, 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, vincamine IV, bepridil, difemalil).

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

An interval of approximately 6 hours is required between 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 oral administration of activated charcoal and 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% at steady state was observed, without affecting AUC (area under the concentration-time curve) or trough levels. Therefore, no precautionary measures are required when digoxin is co-administered.

In studies involving volunteers and diabetic patients, 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 levels, insulin levels). Thus, no clinically relevant interaction between moxifloxacin and glyburide was detected.

In patients receiving oral anticoagulants in combination with antibacterial agents, including fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and certain cephalosporins, numerous cases of increased anticoagulant activity have been reported. Risk factors include infectious diseases (and associated inflammatory processes), age, and the patient's general condition. Due to these circumstances, it is difficult to assess whether infection or treatment causes deviations in INR values. As a precautionary measure, more frequent INR monitoring 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 on 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). Therefore, moxifloxacin can be administered independently of food intake.

Special precautions for use

There have been reports of hypersensitivity and allergic reactions to fluoroquinolones, including moxifloxacin, following the first dose. Anaphylactic reactions may progress to life-threatening anaphylactic shock even after the first administration. In such cases, the drug should be discontinued immediately and appropriate treatment initiated (e.g., shock therapy).

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

Moxifloxacin should be prescribed with caution to patients with ongoing 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 higher drug concentrations. Therefore, the recommended dose should not be exceeded.

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

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

Cases of fulminant hepatitis potentially leading to hepatic failure (including fatal outcomes) have been reported with moxifloxacin (see section "Adverse reactions"). Patients should be advised to consult a physician before continuing treatment if symptoms suggestive of fulminant hepatitis develop, such as jaundice-associated asthenia, rapidly progressing fatigue, dark urine, bleeding tendency, or hepatic encephalopathy.

If signs of liver dysfunction occur, liver function tests and examinations should be performed.

Bullous skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, have been reported during moxifloxacin use (see section "Adverse reactions"). If skin and/or mucosal reactions occur, patients should be advised to seek immediate medical advice before continuing treatment.

It is known that quinolones may provoke seizures. Moxifloxacin should be used with caution in patients with CNS disorders or other risk factors that may predispose to seizures or lower the seizure threshold. If seizures occur, moxifloxacin should be discontinued and appropriate measures taken.

Sensory or sensorimotor polyneuropathy, leading to paresthesia, hyposthesia, dysesthesia, or weakness, has been reported in patients receiving quinolones, including moxifloxacin. If neuropathy symptoms such as pain, burning, tingling, numbness, or weakness develop, patients receiving moxifloxacin should inform their physician before continuing treatment (see section "Adverse reactions").

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

Due to the use of broad-spectrum antibiotics, including moxifloxacin, antibiotic-associated diarrhea (AAD) and antibiotic-associated colitis (AAC), including Clostridium difficile-associated diarrhea and pseudomembranous colitis, have been reported. The severity ranges from mild diarrhea to fatal colitis. It is therefore important to consider this diagnosis in patients who develop severe diarrhea during or after moxifloxacin treatment. If AAD or AAC is suspected or confirmed, antibacterial therapy, including moxifloxacin, should be discontinued immediately and appropriate therapeutic measures initiated. In addition, appropriate hygiene and epidemiological measures should be taken to reduce the risk of transmission. Antiperistaltic agents are contraindicated in patients with severe diarrhea.

Moxifloxacin should be used with caution in patients with myasthenia gravis due to the potential for symptom exacerbation.

Tendon inflammation and rupture (especially of the Achilles tendon), sometimes bilateral, may occur during treatment with quinolones, including moxifloxacin, even within the first 48 hours of therapy. Cases have also been reported several months after discontinuation of treatment. During therapy with quinolones, including moxifloxacin, there is an increased risk of tendon inflammation and rupture, particularly in elderly patients and those receiving concomitant corticosteroid therapy.

At the first signs of pain or inflammation, patients should discontinue moxifloxacin, rest the affected limb(s), and seek immediate medical advice for appropriate management (e.g., splinting) of the affected tendon (see sections "Contraindications", "Adverse reactions").

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

If visual disturbances or other ocular effects occur, patients should seek immediate ophthalmological evaluation (see sections "Ability to influence reaction rate when driving or operating machinery", "Adverse reactions").

Photosensitivity reactions have been reported with quinolone use. However, studies have shown that moxifloxacin has a lower risk of photosensitivity. Nevertheless, patients should be advised to avoid both ultraviolet radiation and prolonged and/or intense exposure to sunlight during moxifloxacin therapy.

Patients with a family or personal history of glucose-6-phosphate dehydrogenase (G6PD) deficiency may be prone to hemolytic reactions during quinolone therapy. Therefore, moxifloxacin should be used with caution in such patients.

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medication.

Moxifloxacin tablets 400 mg are not recommended for patients with complicated pelvic inflammatory disease (e.g., associated with tubo-ovarian abscess or pelvic abscess) for whom intravenous therapy is considered necessary.

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.

Moxifloxacin causes cartilage damage in young animals; therefore, its use in children (under 18 years of age) is contraindicated.

Moxifloxacin is not recommended for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In cases of suspected or confirmed MRSA infection, appropriate antibacterial therapy should be initiated (see section "Pharmacological properties").

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

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

Animal studies have not shown impairment of fertility (see section "Pharmacological properties").

Hypoglycemia and hyperglycemia

As with other fluoroquinolones, glucose level disturbances, including hypoglycemia and hyperglycemia, may occur during moxifloxacin therapy. Dysglycemia may occur predominantly in elderly patients with diabetes who are receiving concomitant therapy with oral hypoglycemic agents (e.g., sulfonylureas) or insulin. Close monitoring of blood glucose levels is recommended in diabetic patients (see section "Adverse 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 to humans is not known.

Due to the risk of fluoroquinolone-induced damage to weight-bearing joints in young animals (based on experimental data) and reversible joint damage reported in children treated with certain fluoroquinolones, moxifloxacin should 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").

Ability to influence reaction rate when driving or operating machinery

No studies have been conducted on the effect of moxifloxacin on the ability to drive or operate machinery. However, fluoroquinolones, including moxifloxacin, may impair the ability to drive or operate machinery due to central nervous system effects (e.g., dizziness, transient acute vision loss — see section "Adverse reactions") or acute transient 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

Adults

The recommended dose is one tablet (400 mg) of moxifloxacin once daily.

The tablets should be swallowed whole with sufficient fluid. The drug may be taken regardless of food intake.

Treatment Duration

The duration of therapy with the tablet form of Moksiftor 400 depends on the type of infection and is as follows:

• Exacerbation of chronic bronchitis – 5–10 days;
• Community-acquired pneumonia – 10 days;
• Acute bacterial sinusitis – 7 days;
• Moderate to moderate-severe pelvic inflammatory disease – 14 days.

It is known that the treatment duration with the tablet form of Moksiftor 400 was up to 14 days.

Stepwise (intravenous to oral) therapy

During clinical studies of stepwise 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 treatment with 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.

Elderly patients / patients with low body weight

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

Hepatic impairment

Dose adjustment is not required in patients with hepatic impairment (see also section "Special Warnings").

Renal impairment

Dose adjustment is not required in patients with mild to moderate renal impairment (including creatinine clearance < 30 mL/min/1.73 m²), as well as in patients undergoing continuous hemodialysis or long-term ambulatory peritoneal dialysis (see section "Pharmacological Properties").

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, treatment should be based on clinical presentation and include symptomatic and supportive therapy, along with ECG monitoring due to the potential for QT interval prolongation.

Concomitant administration of activated charcoal with a 400 mg oral dose of moxifloxacin reduces systemic availability of the drug by more than 80%. In cases of overdose following oral intake of the drug, administration of activated charcoal at the early stage of absorption may be effective in preventing increased systemic exposure to moxifloxacin.

Adverse reactions.

Listed below are adverse effects reported from all clinical trials using moxifloxacin 400 mg (oral and sequential therapy) and their frequency. The adverse reactions listed under the column "frequent" were observed at a rate 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, <1/1000), very rare (<1/10,000).

Table 3.

In rare cases following treatment with other fluoroquinolones, the following adverse reactions have been reported, which might possibly also occur during moxifloxacin use: hypernatraemia, hypercalcaemia, haemolytic anaemia, rhabdomyolysis, photosensitisation reactions (see section "Special precautions").

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging.

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

Prescription category. Prescription only.

Manufacturer.

TORRENT PHARMACEUTICALS LTD.

Manufacturer's address and location of operations.

Indrad Plant, Village Indrad, Taluka-Kadi, District-Mehsana, Gujarat 382721, India.