Moxanacin

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

Composition:

Active substance: moxifloxacin;

One vial (250 ml of solution) contains 436.33 mg of moxifloxacin hydrochloride, equivalent to 400 mg of moxifloxacin;

Excipients: sodium chloride, sodium sulfate anhydrous, hydrochloric acid 1.0 N and/or sodium hydroxide 1.0 N, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear greenish-yellow solution free from visible particles.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Moxifloxacin inhibits bacterial type II topoisomerases (DNA gyrase and topoisomerase IV), which are essential for replication, transcription, and repair of bacterial DNA. Pharmacokinetics/pharmacodynamics.

The ability of fluoroquinolones to kill bacteria is directly dependent on their concentration. Pharmacodynamic studies of fluoroquinolones in animal models of infectious-inflammatory diseases and in humans indicate that the primary determinant of efficacy is the ratio between the area under the pharmacokinetic curve (AUC24) and the minimum inhibitory concentration (MIC).

Mechanism of resistance.

Resistance to fluoroquinolones may arise as a result of mutations in DNA gyrase and topoisomerase IV. Other mechanisms include overexpression of efflux pumps, impermeability, and protein-mediated protection of DNA gyrase.

Cross-resistance can be expected between moxifloxacin and other fluoroquinolones. Resistance mechanisms characteristic of antibacterial agents belonging to other classes do not affect the antibacterial efficacy of moxifloxacin.

Breakpoints

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

Microorganism	Susceptible	Resistant
Staphylococcus spp.	≤ 0.5 mg/L ≥ 24 mm	> 1 mg/L < 21 mm
Streptococcus pneumoniae	≤ 0.5 mg/L ≥ 22 mm	> 0.5 mg/L < 22 mm
Streptococcus group A, B, C, G	≤ 0.5 mg/L ≥ 18 mm	> 1 mg/L < 15 mm
Haemophilus influenzae	≤ 0.5 mg/L ≥ 25 mm	> 0.5 mg/L < 25 mm
Moraxella catarrhalis	≤ 0.5 mg/L ≥ 23 mm	> 0.5 mg/L < 23 mm
Enterobacteriaceae	≤ 0.5 mg/L ≥ 20 mm	> 1 mg/L < 17 mm
Non-species-related breakpoints*	≤ 0.5 mg/L	> 1 mg/L
*Non-species-related breakpoints were primarily determined based on pharmacokinetic and pharmacodynamic data relationships and do not depend on MICs for individual species. These data are used for species without individually defined breakpoints and are not applied to species for which interpretive criteria remain to be defined.

Microbiological susceptibility.

The prevalence of acquired resistance in isolated species may vary depending on the geographical region and time; therefore, local information on resistance is necessary, especially when treating severe infections. When the local prevalence of resistance has reached a level that makes the benefit of using the medicinal product doubtful, at least for certain types of infections, consultation with specialists should be sought.

Usually susceptible microorganisms

Aerobic Gram-positive microorganisms Staphylococcus aureus* 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* Legionella pneumophila Moraxella (Branhamella) catarrhalis*

Anaerobic microorganisms Prevotella spp.

Other microorganisms Chlamydophila (Chlamydia) pneumoniae* Coxiella burnetii Mycoplasma pneumoniae*

Microorganisms for which resistance may develop

Aerobic Gram-positive microorganisms Enterococcus faecalis* Enterococcus faecium*

Aerobic Gram-negative microorganisms Enterobacter cloacae* Escherichia coli*# Klebsiella pneumoniae*# Klebsiella oxytoca Proteus mirabilis*

Anaerobic microorganisms Bacteroides fragilis*

Resistant microorganisms

Aerobic Gram-negative microorganisms Pseudomonas aeruginosa

*Clinical efficacy has been sufficiently demonstrated in clinical studies. +Methicillin-resistant Staphylococcus aureus is very often simultaneously resistant to fluoroquinolones. In methicillin-resistant Staphylococcus aureus, resistance rates to moxifloxacin exceed 50%. #Strains producing extended-spectrum β-lactamases (ESBL) are also resistant to fluoroquinolones.

Pharmacokinetics.

Absorption and bioavailability

After a single 1-hour infusion of 400 mg moxifloxacin, maximum concentration (Cmax) is reached at the end of the infusion and is approximately 4.1 mg/l, which is about 26 % higher than this parameter after oral administration of moxifloxacin (3.1 mg/l). AUC is approximately 39 mg•h/l after intravenous administration, which slightly exceeds this parameter after oral administration of moxifloxacin (35 mg•h/l); absolute bioavailability is approximately 91 %. With intravenous administration of moxifloxacin, there is no need for dose adjustment according to patient age or gender. Pharmacokinetics is linear in the range of 50–200 mg for a single oral dose, up to 600 mg for a single intravenous dose, and up to 600 mg for administration once daily for 10 days.

Distribution.

Moxifloxacin rapidly distributes into the extravascular space. The volume of distribution at steady state (Vss) is approximately 2 l/kg. In vitro and ex vivo studies indicate protein binding in blood of approximately 40–42 %, independent of concentration. Moxifloxacin is primarily bound to serum albumin. Maximum concentrations of 5.4 mg/kg and 20.7 mg/l (geometric mean values) were observed in bronchial mucosa and epithelial lining fluid, respectively, 2.2 hours after oral administration of the dose. The corresponding maximum concentration in alveolar macrophages was 56.7 mg/kg. A concentration of 1.75 mg/l was observed in skin blister fluid 10 hours after intravenous administration. The "free concentration-time" profile for interstitial fluid is similar to that for plasma, reaching a maximum free concentration of 1.0 mg/l (geometric mean value) approximately 1.8 hours after intravenous administration of moxifloxacin.

Metabolism.

Moxifloxacin undergoes phase II biotransformation and is eliminated via the kidneys (approximately 40 %) and feces/bile (approximately 60 %), both unchanged and as sulfated (M1) and glucuronide (M2) metabolites. M1 and M2 are metabolites relevant only to humans; both are microbiologically inactive. In vitro studies and phase I clinical trials did not reveal metabolic pharmacokinetic interactions with other medicinal products involved in phase I biotransformation, including cytochrome P450 enzyme system. There are no signs of oxidative metabolism.

Elimination.

The elimination half-life of moxifloxacin from plasma is approximately 12 hours. The mean steady-state total clearance after administration of 400 mg ranges from 179 to 246 ml/min. After intravenous administration of 400 mg, renal excretion of unchanged moxifloxacin was approximately 22 %, fecal excretion was 26 %. Cumulative excretion of the dose (unchanged moxifloxacin and metabolites) totaled approximately 98 % after intravenous administration of the drug. Renal clearance is approximately 24–53 ml/min, indicating partial tubular reabsorption of the drug from the kidneys. Concomitant administration of ranitidine and probenecid with moxifloxacin does not alter the renal clearance of the drug.

Renal impairment.

No significant changes in moxifloxacin pharmacokinetics have been observed in patients with renal dysfunction (including patients with creatinine clearance > 20 ml/min/1.73 m²). With decreasing renal function, the concentration of metabolite M2 (glucuronide) increases nearly 2.5-fold (with creatinine clearance <30 ml/min/1.73 m²).

Hepatic impairment.

Pharmacokinetic data from studies in patients with hepatic insufficiency (Child-Pugh classes A and B) do not allow definitive conclusions regarding differences in parameters between patients with hepatic dysfunction and healthy volunteers. Hepatic dysfunction was associated with greater plasma exposure to M1, while exposure to the parent drug was similar to that in healthy volunteers. There is insufficient clinical experience with the use of moxifloxacin for the treatment of patients with hepatic dysfunction.

Preclinical safety data.

In traditional repeated-dose toxicity studies in animals, hematological toxicity and hepatotoxicity were observed with moxifloxacin. Toxic effects on the central nervous system (CNS) were noted. These effects occurred after administration of high doses of moxifloxacin or prolonged treatment.

High oral doses in animals (≥60 mg/kg), resulting in plasma concentrations ≥20 mg/l, caused changes in electroretinogram parameters and, in some cases, retinal atrophy.

After intravenous administration, systemic toxicity was most pronounced following bolus injections (45 mg/kg) and was not observed when moxifloxacin (40 mg/kg) was administered via slow infusions over 50 minutes. After intra-arterial administration, inflammatory changes extending to periarterial soft tissues were observed, indicating the need to avoid intra-arterial administration of moxifloxacin.

Moxifloxacin was genotoxic in in vitro tests using bacteria or mammalian cells. In vivo genotoxicity was not observed, despite administration of very high doses of moxifloxacin. Moxifloxacin did not show carcinogenic effects in animal carcinogenicity studies.

In vitro, moxifloxacin at high concentrations affected cardiac electrophysiological parameters, potentially causing QT interval prolongation. After intravenous administration of moxifloxacin to animals at a dose of 30 mg/kg via 15-, 30-, or 60-minute infusions, the degree of QT interval prolongation was infusion-rate dependent: the shorter the infusion time, the more pronounced the QT interval prolongation. QT interval prolongation was not observed when the 30 mg/kg dose was administered via a 60-minute infusion.

In studies of the effect of moxifloxacin on animal reproductive function, it has been demonstrated that moxifloxacin crosses the placenta. Animal studies did not reveal teratogenic effects of moxifloxacin or impairment of fertility after its administration. In animals, a slight increase in the frequency of spinal and rib developmental abnormalities was observed, but only when a dose (20 mg/kg intravenously) associated with severe maternal toxicity was administered. An increased incidence of pregnancy loss was observed in animals at plasma concentrations corresponding to the therapeutic range predicted in humans.

It is known that quinolones, including moxifloxacin, cause damage to cartilage in large diarthrodial joints in immature animals.

Clinical characteristics.

Indications.

Community-acquired pneumonia.

Complicated skin and soft tissue infections.

Moxifloxacin should be used only when the use of other antibacterial agents, which are typically recommended for initial treatment of these infections, is inappropriate.

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

Contraindications.

• Hypersensitivity to moxifloxacin, other quinolone antibiotics, or to any of the excipients of the medicinal product;
• Pregnancy or breastfeeding (see section "Use in pregnancy or breastfeeding");
• Pediatric age (under 18 years);
• History of tendon disorders related to the use of quinolones.

During preclinical and clinical studies, changes in electrophysiological parameters of cardiac activity, manifested as QT interval prolongation, were observed after administration of moxifloxacin. For this reason, moxifloxacin is contraindicated in patients with:

• Congenital or acquired QT prolongation;
• Electrolyte imbalance, particularly uncorrected hypokalemia;
• Clinically significant bradycardia;
• Clinically significant heart failure with reduced left ventricular ejection fraction;
• History of symptomatic arrhythmia.

Moxifloxacin must not be administered concurrently with medicinal products that prolong the QT interval (see also section "Interaction with other medicinal products and other forms of interaction").

Due to insufficient clinical experience, moxifloxacin is contraindicated in patients with hepatic impairment (Child-Pugh class C) and in those with transaminase levels elevated five times or more above the upper limit of normal.

Special precautions.

One vial of the medicinal product is intended for single use only. Any unused solution must be discarded.

The following diluents have been shown to be compatible with the 400 mg moxifloxacin infusion solution: water for injections; 0.9% sodium chloride solution; 1-molar sodium chloride solution; 5%, 10%, and 40% glucose solutions; 20% xylitol solution; Ringer's solution; compound sodium lactate solutions (Hartmann's solution, lactated Ringer's solution). Moxifloxacin infusion solution must not be administered simultaneously with other medicinal products.

Do not use the medicinal product if visible particulate matter or cloudiness is present in the solution.

Precipitation may occur during storage in a cool place, but the precipitate dissolves at room temperature. Therefore, storage of the infusion solution below 15°C is not recommended.

Interaction with other medicinal products and other forms of interaction.

Interaction with medicinal products.

An additive effect of moxifloxacin and other medicinal products capable of causing QTc interval prolongation cannot be excluded. This effect may lead to the development of ventricular arrhythmias, including polymorphic ventricular tachycardia of the torsades de pointes type. Therefore, 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, sultopride);
• Tricyclic antidepressants;
• Certain antimicrobial agents (saquinavir, sparfloxacin, intravenous erythromycin, pentamidine, antimalarial agents, particularly halofantrine);
• Certain antihistamines (terfenadine, astemizole, mizolastine);
• Other medicinal products (cisapride, intravenous vinca alkaloids, bepridil, difemethiazine).

Moxifloxacin should be used with caution in patients receiving medicinal products that may reduce potassium levels (e.g., loop and thiazide diuretics, laxatives and enemas (at high doses), corticosteroids, amphotericin B), or medicinal products associated with clinically significant bradycardia.

After repeated administration of moxifloxacin in healthy volunteers, an increase in digoxin Cmax of approximately 30% was observed, without affecting AUC or the area under the curve.

In studies involving volunteers and diabetic patients, concomitant oral administration of moxifloxacin and glyburide resulted in a decrease in plasma glyburide Cmax of approximately 21%. The combination of glyburide with moxifloxacin may theoretically provoke mild, short-term hyperglycemia. However, the observed changes in glyburide pharmacokinetics did not result in changes in pharmacodynamic parameters (blood glucose level, insulin level). Therefore, there is no clinically significant interaction between moxifloxacin and glyburide.

Change in international normalized ratio (INR).

Numerous cases of increased activity of oral anticoagulants have been reported in patients receiving antimicrobial agents, particularly fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and certain cephalosporins. Risk factors include infectious diseases and inflammatory processes, age, and the patient's general condition. Therefore, it is difficult to determine whether changes in INR are caused by the infection or by the treatment. As a precautionary measure, INR may be monitored more frequently. If necessary, appropriate dose adjustment of the oral anticoagulant should be performed.

In clinical studies, the absence of clinically significant interaction with moxifloxacin has been demonstrated for the following substances: ranitidine, probenecid, oral contraceptives, calcium supplements, morphine administered parenterally, theophylline, cyclosporine, or itraconazole.

In vitro studies using human cytochrome P450 enzymes have confirmed these results. Thus, metabolic interaction via cytochrome P450 enzymes is unlikely.

Interaction with food.

Moxifloxacin does not exhibit clinically significant interaction with food, including dairy products.

Special precautions for use.

The use of moxifloxacin should be avoided in patients with a history of severe adverse reactions following treatment with quinolone or fluoroquinolone-containing medicinal products (see section "Adverse reactions"). Treatment with moxifloxacin in such patients should be initiated only if no alternative therapy is available and after careful assessment of the benefit-risk ratio (see also section "Contraindications").

The benefits of moxifloxacin treatment, especially in mild infections, should be evaluated considering the information contained in this section.

QTc interval prolongation and clinical conditions associated with QTc interval prolongation
Moxifloxacin has been shown to prolong the QTc interval on the electrocardiogram (ECG) in some patients. The degree of QT interval prolongation may increase with higher plasma concentrations of the drug during rapid intravenous infusion. Therefore, it is essential to follow the recommended infusion duration of at least 60 minutes and not exceed the intravenous dose of 400 mg once daily. For further details, see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction".

Moxifloxacin therapy should be discontinued if symptoms suggestive of cardiac arrhythmia occur, regardless of whether they are confirmed by ECG findings. Moxifloxacin should be used with caution in patients with conditions predisposing to arrhythmia (e.g., acute myocardial ischemia), as such patients are at increased risk of ventricular arrhythmias (including polymorphic ventricular tachycardia such as torsade de pointes) and cardiac arrest (see also sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Moxifloxacin should be used cautiously in patients receiving medicinal products that may reduce potassium levels (see also sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Moxifloxacin should be prescribed with caution to patients receiving medicinal products associated with clinically significant bradycardia (see also section "Contraindications"). Women and elderly patients may exhibit increased sensitivity to the effects of drugs causing QTc interval prolongation, such as moxifloxacin; therefore, these patients require special attention.

Hypersensitivity/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 treatment initiated (e.g., shock therapy).

Severe hepatic impairment.
Cases of fulminant hepatitis, which may lead to hepatic failure including fatal outcomes, have been reported during moxifloxacin treatment (see section "Adverse reactions"). If symptoms suggestive of fulminant hepatitis occur, such as rapidly developing asthenia accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy, patients are advised to consult a physician before continuing treatment. Liver function tests should be performed if signs of hepatic dysfunction appear.

Severe skin adverse reactions.
Severe skin adverse reactions (SSARs), including toxic epidermal necrolysis (TEN, also known as Lyell's syndrome), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and drug-induced eosinophilia with systemic symptoms (DRESS), which may be life-threatening or result in death, have been reported during moxifloxacin treatment (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin reactions and monitored closely during treatment. If signs or symptoms suggestive of these reactions occur, moxifloxacin should be discontinued immediately and alternative therapy considered. If a patient develops a serious reaction such as SJS, TEN, AGEP, or DRESS associated with moxifloxacin, re-administration of moxifloxacin to this patient is absolutely contraindicated.

Patients predisposed to seizures.
Quinolones are known to induce seizures. They should be prescribed with caution to patients with central nervous system (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.

Long-lasting, disabling, and potentially irreversible serious adverse reactions.
Rare cases of long-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 onset of any symptoms of a serious adverse reaction, and patients should seek medical advice.

Peripheral neuropathy.
Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones, including moxifloxacin. Patients taking moxifloxacin should be advised to inform their physician about the development of neuropathic symptoms such as pain, burning, tingling, numbness, or weakness before continuing treatment to prevent irreversible conditions (see section "Adverse reactions").

Psychiatric reactions.
Psychiatric reactions may occur even after the first dose of fluoroquinolones, including moxifloxacin. In rare cases, depression or psychiatric reactions have progressed to suicidal ideation and self-harming behaviors such as suicide attempts (see section "Adverse reactions"). If such reactions occur, moxifloxacin treatment should be discontinued and appropriate measures taken. Caution should be exercised when prescribing moxifloxacin to patients with a history of psychiatric disorders or current psychiatric conditions.

Diarrhea associated with antibiotic use, including colitis.
Cases of antibiotic-associated diarrhea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been observed with 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 treatment. If suspected or confirmed AAD or AAC occurs, antimicrobial treatment, including moxifloxacin, should be discontinued immediately and appropriate therapeutic measures initiated. Additionally, appropriate measures should be taken to control infection and reduce transmission risk. Medicinal products that inhibit peristalsis are contraindicated in patients who develop severe diarrhea.

Patients with severe myasthenia gravis.
Moxifloxacin should be used with caution in patients with severe myasthenia gravis (myasthenia gravis), as symptoms may be exacerbated.

Tendon inflammation, tendon rupture.
Tendon inflammation and ruptures (particularly, but not limited to, Achilles tendon), sometimes bilateral, may occur during therapy with quinolones and fluoroquinolones, developing even within 48 hours of treatment initiation and persisting for several months after treatment 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 of this medicinal product with corticosteroids should be avoided.

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

Patients with renal impairment.
Moxifloxacin should be prescribed 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 disturbances.
In case of visual deterioration or any effect on the eyes, immediate consultation with an ophthalmologist is required (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 treatment. Dysglycemia occurred predominantly in elderly patients and diabetic patients receiving concomitant oral hypoglycemic agents (e.g., sulfonylureas) or insulin along with moxifloxacin. Diabetic patients are advised to closely monitor their blood glucose levels (see section "Adverse reactions").

Prevention of photosensitization reactions.
Photosensitization reactions have been reported in patients receiving quinolones. However, study data indicate a low risk of photosensitization reactions with moxifloxacin. Nevertheless, patients should avoid prolonged and/or intense exposure to sunlight or ultraviolet radiation during moxifloxacin treatment (see section "Adverse reactions").

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

Periarterial tissue inflammation.
Moxifloxacin, solution for infusion, is intended for intravenous use only. Intraarterial administration should be avoided, as periarterial tissue inflammation has been observed in preclinical studies with this route of administration.

Patients with specific complicated skin and soft tissue infections.
The clinical efficacy of moxifloxacin in treating severe infections associated with burns, fasciitis, and infected diabetic foot accompanied by osteomyelitis has not been established.

Aortic aneurysm and dissection, and cardiac valve regurgitation/insufficiency.
Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and regurgitation/insufficiency of aortic and mitral valves following fluoroquinolone use, especially in older individuals. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and cardiac valve regurgitation/insufficiency have been reported in patients receiving fluoroquinolones.

Therefore, fluoroquinolones should be used only after careful assessment of the benefit-risk ratio and consideration of alternative therapeutic options in patients with a positive family history of aneurysm or congenital heart valve defect, or in patients with existing diagnosis of aneurysm and/or aortic dissection, or heart valve disease, or in the presence of other risk factors or predisposing conditions:

• for both aortic aneurysm and dissection, and cardiac valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or vascular Ehlers-Danlos syndrome, Turner syndrome, Takayasu arteritis, giant cell arteritis, Behçet's disease, hypertension, rheumatoid arthritis, known atherosclerosis), or additionally:
• for aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren's syndrome), or additionally:
• for cardiac valve regurgitation/insufficiency (e.g., infective endocarditis). The risk of aortic aneurysm, dissection, and rupture may be increased in patients receiving systemic corticosteroids concomitantly.

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

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

Effect on biological tests.
Moxifloxacin may affect Mycobacterium spp. detection test results by suppressing mycobacterial growth, potentially leading to false-negative results in patients taking moxifloxacin.

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

Important information about excipients.

The medicinal product contains 787 mg (approximately 34 µmol) of sodium in one dose. Patients on a controlled-salt diet should take this into account.

Use during pregnancy or breastfeeding.

Pregnancy.
The safety of moxifloxacin use during pregnancy in humans has not been established. Animal studies indicate reproductive toxicity (see section "Pharmacological properties"). The potential risk in humans is not established. Given the experimentally demonstrated harmful effects of fluoroquinolones on weight-bearing cartilage in immature animals and considering the development of reversible joint lesions in children treated with certain fluoroquinolones, moxifloxacin should not be administered to pregnant women (see section "Contraindications").

Breastfeeding period.
There are no data on the use of the medicinal product during breastfeeding. Preclinical study results indicate that a small amount of moxifloxacin passes into breast milk. Due to the lack of data on effects in breastfed infants and considering the experimental risk of harmful effects of fluoroquinolones on weight-bearing cartilage in immature animals, breastfeeding is contraindicated during moxifloxacin treatment (see section "Contraindications").

Fertility.
Animal studies did not reveal 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 affect reaction rate when driving or operating machinery by causing central nervous system reactions (e.g., dizziness, acute transient visual loss) or acute and short-term loss of consciousness (syncope) (see section "Adverse reactions"). Patients are advised to assess their individual response to moxifloxacin before driving or operating machinery.

Method of Administration and Dosage

Dosage.

The recommended dosage regimen is 400 mg of moxifloxacin administered as an infusion once daily. Initial intravenous therapy may be continued with oral administration of 400 mg moxifloxacin tablets, provided there are clinical indications. In clinical trials, most patients switched to oral moxifloxacin within 4 days (for community-acquired pneumonia) or 6 days (for complicated skin and soft tissue infections). The recommended total duration of intravenous and oral treatment is 7–14 days for community-acquired pneumonia and 7–21 days for complicated skin and soft tissue infections.

Method of Administration. The medicinal product should be administered intravenously as a continuous infusion lasting at least 60 minutes (see also section "Special Warnings and Precautions for Use"). If indicated, the infusion solution may be administered via a Y-site catheter together with compatible infusion solutions (see section "Special Precautions for Safety"). Renal/hepatic impairment. Patients with mild to severe renal impairment, as well as patients on chronic dialysis (e.g., undergoing hemodialysis or long-term ambulatory peritoneal dialysis), do not require dose adjustment (see section "Pharmacological Properties" for further details).

There is insufficient information regarding patients with hepatic impairment (see section "Contraindications").

Other special patient groups. Elderly patients and patients with low body weight do not require dose adjustment.

Children.

Due to the negative effects observed on cartilage in young animals (see section "Pharmacological Properties"), the use of Moxanacin in children (under 18 years of age) is contraindicated (see section "Contraindications").

The efficacy and safety of moxifloxacin in children and adolescents have not been established (see section "Contraindications").

Overdose.

Specific interventions are not recommended following accidental overdose. In case of overdose, symptomatic treatment should be initiated. Since QT interval prolongation may occur, ECG monitoring is required. Concomitant administration of activated charcoal with a 400 mg dose of moxifloxacin, either orally or intravenously administered, reduces systemic bioavailability by more than 80% or 20%, respectively. Administration of activated charcoal during the early stages of absorption may effectively prevent excessive systemic exposure to moxifloxacin in cases of oral overdose.

Adverse reactions

The adverse reactions listed below were observed during clinical studies and the post-marketing period with the use of moxifloxacin at a dose of 400 mg once daily (intravenous therapy only, sequential [intravenous/oral], and oral administration), along with their frequencies. All adverse reactions, except nausea and diarrhea, occurred at a frequency of less than 3%. Within each category, adverse reactions are listed in decreasing order of severity. Frequency is defined as follows: common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), infrequent (≥1/10,000, <1/1000), rare (<1/10,000), frequency not known (cannot be estimated based on available data).

System organ classes	Common	Uncommon	Occasional	Rare	Frequency not known
Infections and infestations	superinfections associated with resistant bacteria or fungi, e.g. oral and vaginal candidiasis
Blood and lymphatic system disorders		anaemia, leucopenia, neutropenia, thrombocytopenia, thrombocytosis, eosinophilia, prolonged prothrombin time/increased INR		increased prothrombin level/decreased INR, agranulocytosis, pancytopenia
Immune system disorders		allergic reactions (see section "Special warnings and precautions for use")	anaphylaxis, including life-threatening shock in rare cases (see section "Special warnings and precautions for use"), allergic oedema/angioedema (including potentially life-threatening laryngeal oedema) (see section "Special warnings and precautions for use")
Endocrine disorders				Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
Metabolism and nutrition disorders		hyperlipidaemia	hyperglycaemia, hyperuricaemia	hypoglycaemia, hypoglycaemic coma
Psychiatric disorders*		anxiety reactions, increased psychomotor activity/agitation	mood lability, depression (in rare cases with possible self-harm manifested as suicidal thoughts/ideation or suicide attempts) (see section "Special warnings and precautions for use"), hallucinations, delirium	Depersonalisation, psychotic reactions (with possible self-harm manifested as suicidal thoughts/ideation or suicide attempts) (see section "Special warnings and precautions for use")
Nervous system disorders*	headache, dizziness	paraesthesia/dysesthesia, taste disturbance (including ageusia in rare cases), confusion and disorientation, sleep disorders (mainly insomnia), tremor, vertigo, somnolence	hypoesthesia, olfactory disturbances (including loss of smell), pathological dreams, coordination disorders (including gait disturbances due to dizziness or vertigo), seizures (including grand mal seizures) (see section "Special warnings and precautions for use"), attention disturbances, speech disorder, amnesia, peripheral neuropathy and polyneuropathy	hyperesthesia
Eye disorders*		visual disturbances, including diplopia and blurred vision (especially during CNS reactions) (see section "Special warnings and precautions for use")	photophobia	transient loss of vision (especially during CNS reactions) (see sections "Special warnings and precautions for use", "Effect on ability to drive and use machines"), uveitis and bilateral acute transient iris transillumination (see section "Special warnings and precautions for use")
Ear and labyrinth disorders*			tinnitus, hearing disturbances, including deafness (usually reversible)
Cardiac disorders**	prolongation of QT interval in patients with hypokalaemia (see sections "Contraindications" and "Special warnings and precautions for use")	prolongation of QT interval (see section "Special warnings and precautions for use"), palpitations, tachycardia, atrial fibrillation, angina pectoris	ventricular tachyarrhythmias, syncope (e.g. acute and brief loss of consciousness)	non-specific arrhythmias, torsade de pointes (see section "Special warnings and precautions for use"), cardiac arrest (see section "Special warnings and precautions for use"), aortic aneurysm and dissection
Vascular disorders**		vasodilation	arterial hypertension, hypotension	vasculitis
Respiratory system disorders		dyspnoea (including asthmatic attack)
Gastrointestinal disorders	nausea, vomiting, abdominal pain and discomfort, diarrhoea	decreased appetite and reduced food intake, constipation, dyspepsia, flatulence, gastritis, increased amylase levels	dysphagia, stomatitis, antibiotic-associated colitis (including pseudomembranous colitis, which in rare cases may be associated with life-threatening complications) (see section "Special warnings and precautions for use")
Hepatobiliary disorders	increased transaminase levels	liver function abnormalities (including increased LDH (lactate dehydrogenase) levels), increased bilirubin, GGT (gamma-glutamyl transferase), alkaline phosphatase levels	jaundice, hepatitis (mainly cholestatic)	fulminant hepatitis which may lead to life-threatening liver failure (including fatal outcome) (see section "Special warnings and precautions for use")
Skin and subcutaneous tissue disorders		pruritus, rash, urticaria, dry skin		bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis (potentially life-threatening) (see section "Special warnings and precautions for use)	acute generalised exanthematous pustulosis (AGEP) (see section "Special warnings and precautions for use"); drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special warnings and precautions for use"), fixed drug eruption, photosensitivity reactions (see section "Special warnings and precautions for use")
Musculoskeletal and connective tissue disorders*		arthralgia, myalgia	tendinitis (see section "Special warnings and precautions for use"), muscle twitching, increased muscle tone, muscle cramps, muscle weakness	tendon rupture (see section "Special warnings and precautions for use"), arthritis, increased muscle rigidity as a symptom of myasthenia gravis (see section "Special warnings and precautions for use")	rhabdomyolysis
Renal and urinary disorders		dehydration	renal function impairment (including increased blood urea nitrogen and creatinine levels), renal failure (see section "Special warnings and precautions for use")
General disorders and administration site conditions	injection and infusion site reactions	malaise (mainly asthenia or fatigue), pain (including back, chest, pelvic and limb pain), increased sweating, (thrombo-)phlebitis at infusion site	oedema

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

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

The frequency of the following effects is higher when intravenous administration of moxifloxacin is followed by oral therapy or administered without subsequent oral therapy.

Common: increased gamma-glutamyltransferase levels.

Uncommon: ventricular tachyarrhythmia, arterial hypotension, edema, antibiotic-associated colitis (including pseudomembranous colitis, in rare cases associated with life-threatening complications, see section "Special precautions for use"), seizures (including grand mal seizures) (see section "Special precautions for use"), hallucinations, renal dysfunction (including increased blood urea nitrogen and creatinine levels), renal failure (see section "Special precautions for use").

Description of selected adverse reactions

Rarely, after treatment with other fluoroquinolones, adverse effects have been reported that may also potentially occur during treatment with moxifloxacin: increased intracranial pressure (including pseudotumor cerebri), hypernatremia, hypercalcemia, hemolytic anemia, rhabdomyolysis.

Anxiety, suicidal thoughts, panic attacks, neuralgia, and difficulty concentrating, as potential components of prolonged and disabling fluoroquinolone-induced adverse reactions, which may lead to loss of working ability.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 5 years.

Storage conditions.

Store in the original packaging at a temperature not below 15 °C. Do not freeze. Keep out of reach and sight of children.

Incompatibilities.

The Moxanacin infusion solution must not be administered simultaneously with other incompatible solutions, including: 10% sodium chloride solution; 20% sodium chloride solution; 4.2% sodium bicarbonate solution; 8.4% sodium bicarbonate solution. This medicinal product should not be mixed with other medicinal products except those specified in the section "Special precautions for safety."

Packaging.

250 ml (400 mg) solution in a vial, 1 vial per carton.

Prescription status. Prescription only.

Manufacturer.

ANFARM HELLAS S.A./ANFARM HELLAS S.A.

Manufacturer's address and place of business.

61st km Nat. Rd. Athens-Lamia, Schimatari Viotias 32009, Greece / 61st km Nat. Rd. Athens-Lamia, Schimatari Viotias 32009, Greece.