Moximac

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MOXIMAC (MOXIMAC)

Composition:

Active substance: moxifloxacin;

1 tablet contains moxifloxacin hydrochloride equivalent to moxifloxacin 400 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, povidone, magnesium stearate, coating Instacoat universal pink A05G11785: hydroxypropylmethylcellulose, polyethylene glycol 400, polyethylene glycol 6000, titanium dioxide (E 171), iron oxide red (E 172).

Medicinal form. Film-coated tablets.

Main physico-chemical properties: biconvex capsule-shaped film-coated tablets of pink color, with "T 75" embossed on one side and smooth on the other.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Antibacterial agents of the quinolone group. ATC code J01MA14.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

In vitro, moxifloxacin is active against many Gram-positive and Gram-negative microorganisms. The bactericidal effect of moxifloxacin is caused by 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 the selection of resistant mutants among Gram-positive bacteria compared to the C8-H substituent. The presence of a bulky dicyclic amino group at position C-7 prevents active efflux mediated by the norA or pmrA genes identified in some Gram-positive bacteria.

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

Effect on intestinal flora in humans

In two studies involving healthy volunteers, the following changes in intestinal flora were observed after oral administration of moxifloxacin. Decreased numbers of E. coli, Bacillus spp., Enterococcus, and Klebsiella spp., as well as anaerobes 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

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 types of type II topoisomerases—DNA gyrase and topoisomerase IV. Moxifloxacin is a weak substrate for active efflux systems in Gram-positive microorganisms.

Cross-resistance with other fluoroquinolones occurs. However, because moxifloxacin inhibits both topoisomerase II enzymes (DNA gyrase and topoisomerase IV) with similar potency in some 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)

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

Microbiological susceptibility

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

Expert advice on antimicrobial resistance should be sought when local resistance prevalence is so high that the efficacy of a particular medicinal product against at least some infectious agents 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 ESBLs 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. 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 attributed to interaction with bacterial gyrase and, at higher concentrations, with mammalian topoisomerase II, a threshold concentration for genotoxicity may be assumed. No evidence of genotoxicity was found in in vivo tests, despite administration of high doses of moxifloxacin. Thus, the drug demonstrated an adequate safety margin when used at therapeutic human doses. Moxifloxacin did not show carcinogenic effects in studies conducted in rats.

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

At high concentrations, moxifloxacin acts as an inhibitor of the rapid component of the cardiac delayed rectifier potassium current, and thus may lead to QT interval prolongation. Toxicological studies in dogs, in which the drug was administered orally at doses ≥ 90 mg/kg, resulting in plasma concentrations ≥ 16 mg/L, revealed QT interval prolongation without arrhythmias. Reversible, non-lethal ventricular arrhythmias were observed only after intravenous administration of a high cumulative dose more than 50 times the human dose (> 300 mg/kg), resulting in plasma concentrations ≥ 200 mg/L (more than 40 times the therapeutic level).

It is known that quinolones cause cartilage damage in the large diarthrodial joints of 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), with plasma concentrations 2–3 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 the visual organs. In dog studies, only high oral doses (≥ 60 mg/kg) resulting in plasma concentrations ≥ 20 mg/L caused changes in electroretinograms and, in some cases, retinal atrophy.

Studies on the effects of moxifloxacin on animal reproductive function have shown that moxifloxacin crosses the placenta. Studies in rats (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 abortion rates were observed in monkeys and rabbits at therapeutic doses of moxifloxacin. In rats, reduced fetal weight, increased abortion rates, slight prolongation of gestation, 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%.

Pharmacokinetics are linear over a single-dose range of 50–800 mg and with 600 mg daily for 10 days. Steady state is achieved within three days. After a single 400 mg oral dose, peak plasma concentration (Cmax) is reached within 0.5–4 hours and amounts to 3.1 mg/L. Maximum and minimum plasma concentrations at steady state (400 mg once daily) are 3.2 and 0.6 mg/L, respectively. At steady state, exposure over the dosing interval is almost 30% higher than after the first dose.

Distribution

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

Table 2

Peak concentration (geometric mean) after single oral dose 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 feces/bile, both in unchanged form and as inactive sulfate (M1) and glucuronide (M2) metabolites. M1 and M2 are the only metabolites relevant in humans; both are microbiologically inactive. In vitro and Phase I clinical studies showed no metabolic pharmacokinetic interactions with other drugs metabolized by cytochrome P450 phase I 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 in the kidneys. After a 400 mg dose, excretion in urine (approximately 19% – unchanged drug, approximately 2.5% – M1, and approximately 14% – M2) and feces (approximately 25% – unchanged drug, approximately 36% – M1, and no excretion as M2) totaled approximately 96%. Concomitant administration of ranitidine and probenecid does not alter the renal clearance of the drug.

Pharmacokinetics in specific patient populations

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 renal dysfunction (including patients with creatinine clearance > 20 ml/min/1.73 m²). As renal function declines, the concentration of metabolite M2 (glucuronide) increases by a factor of 2.5 (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 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 for the treatment of patients with hepatic impairment.

Clinical characteristics.

Indications.

Treatment of the bacterial infections listed below, caused by microorganisms sensitive to the drug (see sections «Pharmacological properties», «Special instructions», «Adverse reactions»), in patients aged 18 years and older. Moxifloxacin should be prescribed only when the use of antibacterial agents usually 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).
• Exacerbation of chronic obstructive pulmonary disease, including bronchitis.
• Community-acquired pneumonia, except severe community-acquired pneumonia.
• Pelvic inflammatory disease of moderate to severe degree (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 Moximak is not recommended for use as monotherapy in moderate to severe pelvic inflammatory disease, 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 «Pharmacological properties», «Special instructions»).

The tablet form of moxifloxacin may be used to complete a course of treatment where initial therapy with parenteral moxifloxacin has been effective and was indicated for the following conditions:

− community-acquired pneumonia;

− complicated skin and skin structure infections.

The tablet form of Moximak is not recommended for initial treatment of any skin and skin structure 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 a history of tendon disorders related to quinolone therapy.

In preclinical and clinical studies, changes in cardiac electrophysiology, such as QT interval prolongation, have been observed after administration of moxifloxacin. Therefore, for safety reasons, the drug is contraindicated in patients with:

− congenital or diagnosed acquired QT prolongation;

− electrolyte imbalances, particularly uncorrected hypokalemia;

− clinically significant bradycardia;

− clinically significant heart failure with reduced left ventricular ejection fraction;

− history of symptomatic arrhythmias.

The 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, 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 above the upper limit of normal).

Interaction with other medicinal products and other types of interactions.

An additive effect of moxifloxacin and other medicinal products that may cause QT interval prolongation cannot be excluded. This interaction may lead to an increased risk of ventricular arrhythmias, including torsade de pointes. For this reason, the use of moxifloxacin in combination with any of the following medicinal products is contraindicated (see also section «Contraindications»):

• Class IA antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Antipsychotic agents (e.g., phenothiazines, pimozide, sertindole, haloperidol, sulpiride);
• Tricyclic antidepressants;
• Some antimicrobial agents (e.g., saquinavir, sparfloxacin, intravenous erythromycin, pentamidine, antimalarial agents, including halofantrine);
• Some antihistamines (e.g., terfenadine, astemizole, mizolastine);
• Others (e.g., cisapride, vinca alkaloids IV, bepridil, difemanyl).

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 of approximately 30% at steady state was observed, without affecting AUC or trough levels. Therefore, no precautionary measures are needed when digoxin is co-administered.

In studies involving diabetic volunteers, concomitant oral administration of moxifloxacin and glyburide resulted in a decrease of approximately 21% in peak glyburide concentration. 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 has been identified.

Change in international normalized ratio (INR)

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

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

Absorption of moxifloxacin is not affected by food intake (including dairy products). Therefore, moxifloxacin can be administered independently of food.

Special precautions for use.

Patients with a history of serious adverse reactions to quinolone or fluoroquinolone drugs (see section "Adverse reactions") should avoid using moxifloxacin. Treatment of such patients with moxifloxacin should only be considered after careful assessment of benefit versus risk and in the absence of alternative treatment options (see section "Contraindications").

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

Prolonged, disabling, and potentially irreversible serious adverse drug reactions

Rare cases of prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions have been observed in patients receiving quinolones and fluoroquinolones, regardless of age or presence of risk factors. These reactions may affect various, sometimes multiple, organ systems (musculoskeletal, nervous system, psyche, sensory organs). Moxifloxacin therapy should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and patients should be advised to seek medical advice.

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 development of regurgitation of the aortic and mitral valves following fluoroquinolone use. Rare cases of aortic aneurysm and aortic dissection, sometimes complicated by rupture (including fatal cases), 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, or in patients diagnosed with aortic aneurysm and/or aortic dissection, or with heart valve disease, as well as in the presence of other risk factors or conditions predisposing to aortic aneurysm and aortic 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 also aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren’s syndrome), or also valvular regurgitation/insufficiency (e.g., infective endocarditis).

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

In case of sudden abdominal pain, chest pain, or back pain, patients should immediately seek emergency medical help.

Patients should be advised to seek immediate medical attention if they experience acute shortness of breath, rapid heartbeat, or development of abdominal swelling or swelling of the lower limbs.

QTc interval prolongation and clinical conditions associated with QTc prolongation

With the use of moxifloxacin, QT interval prolongation on electrocardiogram (ECG) may occur in some patients. Analysis of ECG results from clinical trial programs showed that QTc prolongation with moxifloxacin was 6 ms ± 26 ms – 1.4% compared to baseline.

Since women have a longer QT interval than men, they may be more sensitive to drugs that prolong the QT interval. Elderly patients may also be more susceptible to drug-related effects on the QT interval.

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

Moxifloxacin should be used with caution in 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.

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 after the first administration of fluoroquinolones, including moxifloxacin. Anaphylactic reactions may present as life-threatening shock even after the first dose. In cases of clinically significant hypersensitivity reactions, moxifloxacin should be discontinued and appropriate therapy (e.g., anti-shock treatment) initiated.

Severe liver disease

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

In case of symptoms of liver dysfunction, liver function tests/liver assessment should be performed.

Severe skin reactions

During moxifloxacin use (see section "Adverse reactions"), cases of severe skin reactions have been reported, 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 syndrome), which may be life-threatening or fatal. When prescribing the medicinal product, 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 immediately discontinued and alternative treatment considered. If a patient develops severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or DRESS syndrome during moxifloxacin therapy, re-administration of moxifloxacin in this patient is absolutely contraindicated.

Patients with predisposition to seizures

Quinolones are known to provoke seizures. Moxifloxacin 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.

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. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop, patients receiving moxifloxacin should inform their physician before continuing treatment to prevent development of irreversible conditions (see section "Adverse reactions").

Psychiatric reactions

Psychiatric reactions may develop even after the first dose of quinolones, including moxifloxacin. In rare cases, depression or psychotic reactions have led to suicidal thoughts and self-harm, 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 psychosis or a history of psychiatric disorders.

Antibiotic-associated diarrhea, including colitis

Antibiotic-associated diarrhea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been reported with broad-spectrum antibiotics, including moxifloxacin, with severity ranging 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 and appropriate therapeutic measures initiated immediately. Appropriate hygiene and infection control measures should also be implemented to reduce transmission risk. Antiperistaltic agents are contraindicated in patients with severe diarrhea.

Patients with myasthenia gravis

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

Tendon inflammation and rupture

Tendon inflammation and rupture (especially of the Achilles tendon), sometimes bilateral, may occur during treatment with quinolones, including moxifloxacin, and fluoroquinolones, even within the first 48 hours of treatment initiation. Cases have also been reported months after discontinuation of therapy. There is an increased risk of tendon inflammation and rupture during quinolone therapy, including moxifloxacin, particularly in elderly patients, patients with renal impairment, organ transplant recipients, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

At the first symptoms of tendinitis (pain, swelling, or inflammation), patients should discontinue moxifloxacin, rest the affected limb(s), and immediately consult a physician for appropriate management (e.g., splinting) of the affected tendon (see sections "Contraindications", "Adverse reactions"). Concomitant use of corticosteroids is not recommended when symptoms of tendinopathy occur.

Patients with renal impairment

Moxifloxacin should be used with caution in elderly patients with renal impairment who cannot ensure adequate fluid intake, as dehydration may increase the risk of renal failure.

Visual disturbances

If visual disturbances or other effects on the eyes occur, patients should immediately consult an ophthalmologist (see sections "Ability to influence reaction speed when driving or operating machinery", "Adverse reactions").

Prevention of photosensitivity reactions

Photosensitivity reactions have been reported in patients receiving quinolones. However, studies have shown that moxifloxacin carries a lower risk of photosensitivity. Nevertheless, patients should be advised to avoid both ultraviolet radiation and prolonged and/or intense sunlight exposure during moxifloxacin therapy (see section "Adverse reactions").

Dysglycemia

As with other fluoroquinolones, glucose level disturbances, including hypoglycemia and hyperglycemia, have been observed with the medicinal product Moximak. Dysglycemia with Moximak predominantly occurred in elderly patients with diabetes receiving concomitant therapy with oral hypoglycemic agents (e.g., sulfonylureas) or insulin. Cases of hypoglycemic coma have been reported. Close monitoring of blood glucose levels is recommended in diabetic patients (see section "Adverse reactions").

Patients with glucose-6-phosphate dehydrogenase deficiency

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

Patients with pelvic inflammatory disease

For patients with complicated pelvic inflammatory disease (e.g., associated with tubo-ovarian abscess or pelvic abscess), for whom intravenous therapy is considered necessary, oral administration of the medicinal product Moximak 400 mg tablets is not recommended.

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 the presence of moxifloxacin-resistant Neisseria gonorrhoeae 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 such as burn-related infections, fasciitis, and diabetic foot associated with osteomyelitis has not been established.

Effect on biological tests

Moxifloxacin therapy may interfere with culture-based detection of Mycobacterium spp. due to inhibition 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 case of suspected or confirmed MRSA infection, appropriate antibacterial therapy should be initiated (see section "Pharmacological properties").

Children

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

Information on excipients

This medicinal product should not be taken by patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

This medicinal product contains less than 1 mmol sodium (23 mg) per 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 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 described in children treated with certain fluoroquinolones, moxifloxacin must not be administered to pregnant women (see section "Contraindications").

Breastfeeding

Moxifloxacin, like other quinolones, causes cartilage damage in young animals. Preclinical studies indicate that a small amount of moxifloxacin may pass into breast milk. There are no data on the use of the drug in breastfeeding women. Therefore, moxifloxacin is contraindicated during breastfeeding (see section "Contraindications").

Fertility

Animal studies have not shown any effect on fertility (see section "Pharmacological properties").

Ability to influence reaction speed when driving or operating machinery.

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

Adults

The recommended dose is 1 tablet (400 mg) of moxifloxacin once daily.

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

Duration of Therapy

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

• Exacerbation of chronic obstructive pulmonary disease, including bronchitis – 5–10 days;

• Community-acquired pneumonia – 10 days;

• Acute bacterial sinusitis – 7 days;

• Moderate to severe inflammatory diseases of the pelvic organs – 14 days.

According to clinical studies, the treatment duration with the tablet form of Moximak 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 treatment with Moximak tablets and infusion solution is 7–14 days for community-acquired pneumonia and 7–21 days for complicated skin and soft tissue infections.

It is not recommended to exceed the specified dose (400 mg once daily) or the duration of treatment for each indication.

Elderly patients / patients with low body weight

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

Hepatic impairment

There is no reliable data available for patients with hepatic impairment (see section "Contraindications").

Renal impairment

Dose adjustment is not required for patients with mild to moderate renal impairment, as well as for 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 antidotes are recommended. Management should be based on clinical symptoms 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 by more than 80%. In cases of oral overdose, administration of activated charcoal at the early stage of absorption may be effective in preventing increased systemic exposure to moxifloxacin.

Adverse reactions

The adverse reactions listed below were collected from all clinical trials involving moxifloxacin 400 mg once daily (intravenous therapy only, sequential [intravenous/oral], and oral) and from the post-marketing period. Adverse reactions are classified according to their frequency. The reactions listed under the "frequent" column were observed at a frequency of less than 3%, except for nausea and diarrhea.

Within each category, adverse reactions are listed in order of decreasing severity. Frequency is defined as follows: frequent (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), occasional (≥ 1/10,000, < 1/1000), rare (< 1/10,000), frequency not known (cannot be estimated based on available data).

Table 3

*Very rare cases of prolonged (for months or years), disabling and potentially irreversible serious adverse drug reactions have been reported with the use of quinolones and fluoroquinolones, sometimes affecting multiple body systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disorders, and disturbances of hearing, vision, taste, and smell), sometimes occurring regardless of the presence of risk factors (see section "Special precautions for use").

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

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

Description of selected adverse reactions: anxiety, suicidal thoughts, panic attacks, neuralgia, and disturbances in attention concentration as potential components of prolonged and disabling adverse reactions induced by fluoroquinolones, which may lead to loss of working capacity.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after registration of the medicinal product is of great importance. 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 Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

4 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

5 tablets in a blister. 1 blister per cardboard pack.

10 tablets in a blister. 1 or 10 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and site of operations.

Village Thedda, P.O. Lodhiamajra, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.