Moxifloxacin - vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MOKSIFLOXACIN-VISTA MOXIFLOXACIN-VISTA

Composition:

Active substance: moxifloxacin;

1 vial contains 436.8 mg of moxifloxacin hydrochloride equivalent to 400 mg of moxifloxacin;

Excipients: sodium chloride, hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear yellow solution without visible particles.

Pharmacotherapeutic group.

Antimicrobial agents 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 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 groups 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 defined 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 require determination.

Microbiological susceptibility.

The prevalence of acquired resistance in isolated species may vary depending on geographical location and time; therefore, local information on resistance patterns is necessary, especially when treating severe infections. Consultation with specialists should be sought when local resistance prevalence reaches a level at which the benefit of using the medicinal product, at least for certain types of infections, is questionable.

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 intravenous 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 that observed after oral administration of moxifloxacin (3.1 mg/l). The AUC is approximately 39 mg•h/l after intravenous administration, slightly exceeding that after oral administration (35 mg•h/l); absolute bioavailability is approximately 91 %. With intravenous administration of moxifloxacin, dose adjustments according to patient age or gender are not required. Pharmacokinetics are linear within the range of 50–200 mg for single oral doses, up to 600 mg for single intravenous doses, and up to 600 mg administered 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 of approximately 40–42 %, independent of concentration. Moxifloxacin binds primarily 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. The corresponding maximum concentration in alveolar macrophages was 56.7 mg/kg. In skin blister fluid, a concentration of 1.75 mg/l was observed 10 hours after intravenous administration. The free concentration-time profile in interstitial fluid is similar to that in plasma, achieving a maximum free concentration of 1.0 mg/l (geometric mean) 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 as unchanged drug and as sulfate conjugate (M1) and glucuronide (M2) metabolites. M1 and M2 are metabolites relevant only in humans; both are microbiologically inactive. In vitro and phase I clinical studies showed no evidence of metabolic pharmacokinetic interactions with other medicinal products involved in phase I biotransformation, including cytochrome P450 enzymes. There is no indication of oxidative metabolism.

Elimination

The elimination half-life of moxifloxacin in plasma is approximately 12 hours. 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 %, and fecal excretion was 26 %. Cumulative excretion (unchanged moxifloxacin and metabolites) totaled approximately 98 % after intravenous administration. Renal clearance is approximately 24–53 ml/min, indicating partial tubular reabsorption of the drug from the kidneys. Concomitant administration of ranitidine and probenecid does not alter the renal clearance of moxifloxacin.

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, plasma concentration of metabolite M2 (glucuronide) increases by almost 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) are insufficient to definitively determine differences in pharmacokinetic parameters between patients with hepatic impairment and healthy volunteers. Hepatic impairment was associated with increased plasma exposure to metabolite M1, while exposure to the parent drug was similar to that in healthy volunteers. There is insufficient clinical experience with moxifloxacin to recommend its use in patients with hepatic impairment.

Preclinical safety data

In traditional repeated-dose toxicity studies in animals, moxifloxacin showed hematological toxicity and hepatotoxicity. Toxic effects on the central nervous system (CNS) were observed. 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 when moxifloxacin was given as bolus injections (45 mg/kg) and was not observed when administered as slow infusions (40 mg/kg) over 50 minutes. After intra-arterial administration, inflammatory changes extending into periarterial soft tissues were observed, indicating that intra-arterial administration of moxifloxacin should be avoided.

Moxifloxacin was genotoxic in in vitro tests using bacteria or mammalian cells. In vivo genotoxicity was not observed, even with very high doses of moxifloxacin. Moxifloxacin showed no carcinogenic potential in animal carcinogenicity studies.

In vitro, moxifloxacin at high concentrations affected cardiac electrophysiological parameters, potentially leading to 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 prolongation was dependent on infusion rate: shorter infusion times resulted in greater QT prolongation. QT prolongation was not observed when the 30 mg/kg dose was administered over 60 minutes.

Studies on the effects of moxifloxacin on animal reproductive function demonstrated that moxifloxacin crosses the placenta. Animal studies did not reveal teratogenic effects or impairment of fertility after moxifloxacin administration. Slight increases in the incidence of spinal and rib malformations were observed in animals, but only at a dose (20 mg/kg intravenously) associated with severe maternal toxicity. Increased rates of pregnancy loss were observed in animals at plasma concentrations corresponding to therapeutic levels expected in humans.

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

Clinical characteristics.

Indications.

Community-acquired pneumonia.

Complicated skin and soft tissue infections.

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

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

Contraindications.

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

During preclinical and clinical studies, administration of moxifloxacin was associated with changes in cardiac electrophysiological parameters manifested by QT interval prolongation. 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 concomitantly 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). The 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 if stored at cool temperatures, 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 between 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 torsade 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 antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (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, antimalarials such as halofantrine);
• Certain antihistamines (terfenadine, astemizole, mizolastine);
• Other medicinal products (cisapride, intravenous vincamine, bepridil, difemanil).

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 trough levels.

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

Changes 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 infection and inflammatory processes, age, and general patient condition. Therefore, it is difficult to determine whether changes in INR are due to the infection itself or to treatment. As a precaution, INR should be monitored more frequently. Dose adjustment of the oral anticoagulant should be performed as necessary.

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 serious adverse reactions following treatment with drugs containing quinolones or fluoroquinolones (see section "Adverse reactions"). Treatment of such patients with moxifloxacin should be initiated only if no alternative therapy is available and after careful assessment of benefit/risk ratio (see also section "Contraindications").

The benefits of moxifloxacin therapy, 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 have an increased risk of ventricular arrhythmias (including polymorphic ventricular tachycardia of the torsade de pointes type) and cardiac arrest (see also sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Caution is required when administering moxifloxacin to 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 be more sensitive to the effects of drugs that cause QTc interval prolongation, such as moxifloxacin, and therefore require special attention.

Hypersensitivity/allergic reactions.

Cases of hypersensitivity and allergic reactions have been reported after the first administration of fluoroquinolones, including moxifloxacin. Anaphylactic reactions may manifest as life-threatening shock even after the first dose. 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 liver failure, including fatal outcomes, have been reported during moxifloxacin treatment (see section "Adverse reactions"). If symptoms suggestive of fulminant hepatitis develop, such as rapidly progressing 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 occur.

Severe skin 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 reaction with eosinophilia and systemic symptoms (DRESS), have been reported during moxifloxacin treatment and may be life-threatening or fatal (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin reactions and closely monitored during treatment. If signs or symptoms indicative of these reactions occur, moxifloxacin should be discontinued immediately and alternative therapy considered. If a serious reaction such as SJS, TEN, AGEP, or DRESS develops during moxifloxacin treatment, re-administration of this drug to the patient is absolutely contraindicated.

Patients predisposed to seizures.

Quinolones are known to induce seizures. They should be used with caution in 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.

Prolonged, disabling, and potentially irreversible serious adverse reactions.

Rare cases of prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various, sometimes multiple organ systems (musculoskeletal, nervous, psychiatric, and sensory organs) have been reported in patients treated with quinolones and fluoroquinolones, regardless of patient age or existing risk factors. Moxifloxacin should be discontinued immediately upon the first symptoms of any serious adverse reaction, and patients should be advised to consult a physician.

Peripheral neuropathy.

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hyposthesia, dysesthesia, or weakness have been reported in patients receiving quinolones, including moxifloxacin. Patients receiving 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 may progress 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 is required when prescribing moxifloxacin to patients with a history of psychiatric disorders or current psychiatric conditions.

Diarrhea associated with antibiotic use, including colitis.

Diarrhea associated with antibiotic use (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been reported with broad-spectrum antibiotics, including moxifloxacin. The severity of these events may range from mild diarrhea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop severe diarrhea during or after moxifloxacin treatment. If suspected or confirmed AAD or AAC occurs, antimicrobial therapy, including moxifloxacin, should be discontinued immediately and appropriate therapeutic measures initiated. Additionally, infection control measures should be implemented to reduce transmission risk. Antiperistaltic agents 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, 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 as early as 48 hours after initiation of treatment and persisting for several months after discontinuation (see sections "Contraindications" and "Adverse reactions"). The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, solid organ transplant recipients, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of this medicinal product with corticosteroids should be avoided.

If early 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 in cases of tendonopathy.

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.

Disorders of the visual organs.

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 abnormalities, including both hypoglycemia and hyperglycemia, have been reported during moxifloxacin therapy. Dysglycemia occurred predominantly in elderly patients and diabetic patients receiving concomitant oral hypoglycemic agents (e.g., sulfonylureas) or insulin. Diabetic patients are advised to closely monitor blood glucose levels (see section "Adverse reactions").

Prevention of photosensitization reactions.

Quinolones have been shown to cause photosensitization reactions in patients. However, clinical studies 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 predisposed to hemolytic reactions during quinolone therapy. Therefore, moxifloxacin should be used with caution in such patients.

Periarterial tissue inflammation.

Moxifloxacin infusion solution 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 the treatment of severe infections related to burns, fasciitis, and infected diabetic foot with associated 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 aortic and mitral valve regurgitation 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 benefit/risk assessment and consideration of alternative therapeutic options in patients with a positive family history of aneurysm or congenital heart valve defect, or in patients with an 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 in case of sudden abdominal, chest, or back pain.

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

Impact on biological tests

Moxifloxacin may affect the results of tests for Mycobacterium spp. by inhibiting 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. If MRSA infection is suspected or confirmed, appropriate antibacterial therapy should be initiated (see section "Pharmacodynamics").

Important information about excipients.

The medicinal product contains 787 mg (approximately 34 µmol) of sodium per dose. Patients on a sodium-controlled 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 for humans has not been determined. Given the experimentally established risk of 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").

Period of breastfeeding.

There are no data on the use of the medicinal product during breastfeeding. Preclinical studies 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 speed when driving or operating machinery by causing central nervous system reactions (e.g., dizziness, acute transient loss of vision) 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 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 and patients undergoing chronic dialysis, such as those receiving hemodialysis or long-term ambulatory peritoneal dialysis, do not require dose adjustment (for further details, see section "Pharmacological Properties").

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 on cartilage in young animals (see section "Pharmacological Properties"), moxifloxacin is contraindicated in children (under 18 years of age) (see section "Contraindications").

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

Overdose

No specific interventions are recommended following accidental overdose. In case of overdose, symptomatic treatment should be administered. Since QT interval prolongation may occur, ECG monitoring is required. Concomitant administration of activated charcoal with an oral or intravenous 400 mg dose of moxifloxacin reduces systemic bioavailability by more than 80% or 20%, respectively. Administration of activated charcoal at the early stage of absorption may effectively prevent excessive systemic exposure to moxifloxacin in cases of overdose following oral intake of the drug.

Adverse reactions.

The adverse reactions listed below were observed during clinical trials and in the post-marketing period when moxifloxacin was administered at a dose of 400 mg once daily (intravenous therapy only, sequential [intravenous/oral], and oral) and 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); rare (≥1/10,000, <1/1000); very 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		anemia, leukopenia, neutropenia, thrombocytopenia, thrombocytosis, eosinophilia, prolonged prothrombin time/increased INR		elevated prothrombin level/decreased INR, agranulocy- tosis, pancytopenia
Immune system disorders		allergic reactions (see section "Special precautions")	anaphylaxis, including life-threatening shock in rare cases (see section "Special precautions"), angioedema/angioneurotic edema (including potentially life-threatening laryngeal edema) (see section "Special precautions")
Endocrine disorders				syndrome of inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders		hyperlipidemia	hyperglycemia, hyperuricemia	hypoglycemia, hypoglycemic coma
Psychiatric disorders*		anxiety reactions, increased psychomotor activity/agitation	mood lability, depression (in rare cases with possible self-harm manifested as suicidal ideation/thoughts or suicide attempts) (see section "Special precautions"), hallucinations, delirium	depersonalization, psychotic reactions (with possible self-harm manifested as suicidal ideation/thoughts or suicide attempts) (see section "Special precautions")
Nervous system disorders*	headache, dizziness	paraesthesia/dysesthesia, taste disturbances (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 disturbances (including gait disturbance due to dizziness or vertigo), seizures (including grand mal seizures) (see section "Special precautions"), 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 precautions")	photophobia	transient vision loss (especially during CNS reactions) (see sections "Special precautions", "Effect on ability to drive and use machines")
Ear and labyrinth disorders*			tinnitus, hearing disturbances, including deafness (usually reversible)
Cardiac disorders**	QT interval prolongation in patients with hypokalemia (see sections "Contraindications" and "Special precautions")	QT interval prolongation (see section "Special precautions"), palpitations, tachycardia, atrial fibrillation, angina pectoris	ventricular tachyarrhythmias, syncope (e.g. acute and short-term loss of consciousness)	non-specific arrhythmias, torsade de pointes (see section "Special precautions"), cardiac arrest (see section "Special precautions"), aortic aneurysm and dissection
Vascular disorders**		vasodilation	arterial hypertension, hypotension	vasculitis, aortic aneurysm and dissection
Respiratory system disorders		dyspnea (including asthmatic attack)
Gastrointestinal disorders	nausea, vomiting, abdominal pain and discomfort, diarrhea	decreased appetite and reduced food intake, constipation, dyspepsia, flatulence, gastritis, elevated amylase levels	dysphagia, stomatitis, antibiotic-associated colitis (including pseudomembranous colitis, which in rare cases may be associated with life-threatening complications) (see section "Special precautions")
Hepatobiliary disorders	elevated transaminase levels	liver function abnormalities (including elevated LDH (lactate dehydrogenase) levels), elevated bilirubin, GGT (gamma-glutamyl transferase), alkaline phosphatase	jaundice, hepatitis (mainly cholestatic)	fulminant hepatitis, which may lead to life-threatening liver failure (see section "Special precautions")
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 precautions")	acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special precautions"), fixed drug eruption, photosensitivity reactions (see section "Special precautions")
Musculoskeletal and connective tissue disorders*		arthralgia, myalgia	tendinitis (see section "Special precautions"), increased muscle tone, muscle cramps, muscle weakness	tendon rupture (see section "Special precautions"), arthritis, increased muscle rigidity as a symptom of myasthenia gravis (see section "Special precautions")	rhabdomyolysis
Renal and urinary disorders		dehydration	renal function impairment (including increased blood urea nitrogen and creatinine levels), renal failure (see section "Special precautions")
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	edema

* 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 peripheral 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").

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

The incidence of the following adverse effects is higher with intravenous administration of moxifloxacin, with or 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 idiopathic intracranial hypertension), hypernatremia, hypercalcemia, hemolytic anemia.

Anxiety, suicidal thoughts, panic attacks, neuralgia, and disturbances in attention concentration are potential aspects of prolonged and disabling adverse reactions induced by fluoroquinolones, which may lead to loss of work capacity.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after the authorization of a medicinal product is important. It allows continued 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.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.

Incompatibilities.

The moxifloxacin 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 of solution in a vial, 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

VEM ILAC San. ve Tik. A.S., Turkey.

Manufacturer's address and location of activity.

Cerkezkoy Organize Sanayi Bolgesi, Karaagac Mahallesi, Fatih Bulvari No: 38, Kapakli/Tekirdag/Turkey.