Moxifloxacin-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Moxifloxacin-Teva (Moxifloxacin-Teva)

Composition:

Active substance: moxifloxacin;

1 vial (250 ml of solution) contains moxifloxacin 400 mg as anhydrous moxifloxacin hydrochloride;

Excipients: propylene glycol, water for injections.

Pharmaceutical form. Infusion solution.

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

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Antibacterial agents of the quinolone group. ATC code J01M A14.

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 concentration-dependent. 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 due to mutations in DNA gyrase and topoisomerase IV. Other mechanisms include overexpression of efflux pumps, impermeability, and protein-mediated protection of DNA gyrase. Cross-resistance is possible between moxifloxacin and other fluoroquinolones.

Resistance mechanisms characteristic of antibacterial agents from 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)

*Non-species-related breakpoints were primarily determined based on the relationship between pharmacokinetic and pharmacodynamic data and do not depend on the MIC values for individual species. These data are used for species that do not have individually defined breakpoints and are not applicable to species for which interpretive criteria require determination.

Microbiological susceptibility

The prevalence of acquired resistance among 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 considered when local resistance prevalence has reached a level at which the benefit of using the medicinal product is questionable, at least for certain types of infections.

*Efficacy has been sufficiently demonstrated in clinical studies.

+Methicillin-resistant S. aureus is very often simultaneously resistant to fluoroquinolones. In methicillin-resistant S. aureus, the resistance rate to moxifloxacin exceeds 50%.

#Strains producing extended-spectrum beta-lactamases (ESBL) are also resistant to fluoroquinolones.

Pharmacokinetics.

Absorption and Bioavailability

After a single 1-hour intravenous infusion of the drug at a dose of 400 mg, 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 (3.1 mg/L). The AUC value is approximately 39 mg·h/L after intravenous administration and only slightly exceeds the parameter after oral administration (35 mg·h/L); absolute bioavailability is approximately 91%. When moxifloxacin is administered intravenously, there is no need for dose adjustment based on patient age or gender.

Pharmacokinetics are linear within the range of 50–1200 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 that plasma protein binding is approximately 40–42%, independent of the active substance concentration. Moxifloxacin binds predominantly 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 dosing. 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 in interstitial fluid is similar to that in plasma, with maximum free concentration reaching 1.0 mg/L (geometric mean) approximately 1.8 hours after intravenous administration.

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 in humans and are microbiologically inactive.

During in vitro and phase I clinical studies, no metabolic pharmacokinetic interactions were observed with other drugs involved in phase I biotransformation, including cytochrome P450 enzyme systems. There is no evidence of oxidative metabolism.

Elimination

The plasma elimination half-life of moxifloxacin 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 drug was approximately 22%, and fecal excretion was 26%. Overall excretion (unchanged drug 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 the parent 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 (in patients with creatinine clearance < 30 mL/min/1.73 m²).

Hepatic Impairment

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

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 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 spreading to perivascular soft tissues were observed, indicating the necessity to avoid intra-arterial administration of moxifloxacin.

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

In vitro, at high concentrations, moxifloxacin 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, a relationship between the degree of QT interval prolongation and infusion rate was observed: the shorter the infusion time, the more pronounced the QT prolongation. No QT prolongation was observed when the 30 mg/kg dose was administered over 60 minutes.

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

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 prescribed only when the use of other antibacterial agents typically recommended for initial treatment of these infections is inappropriate.

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

Contraindications.

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

In preclinical and clinical studies, changes in cardiac electrophysiology characterized by QT interval prolongation have been observed following administration of moxifloxacin. Therefore, moxifloxacin is contraindicated in patients with the following conditions:

• 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 known to prolong the QT interval (see also section "Interaction with other medicinal products and other forms of interaction").

Due to insufficient clinical experience, the medicinal product 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 normal limit.

Special precautions.

Each vial is intended for single use only. Any unused solution must be discarded.

The following diluents have been shown to be compatible with moxifloxacin 400 mg infusion solution: Water for injections; 0.9% sodium chloride solution; 1-molar sodium chloride solution; 5%, 10%, 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.

The product must not be used if visible particulate matter is present or if the solution is cloudy.

Precipitation may occur upon storage at cool temperatures, but the precipitate dissolves at room temperature. Therefore, storage of the infusion solution at temperatures 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 that may cause QTc interval prolongation cannot be excluded. This interaction may increase the risk of ventricular arrhythmias, including torsade de pointes. Therefore, the concomitant use of moxifloxacin 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);
• Antipsychotics (e.g., phenothiazines, pimozide, sertindole, haloperidol, sulpiride);
• Tricyclic antidepressants;
• Certain antimicrobial agents (saquinavir, sparfloxacin, intravenous erythromycin, pentamidine, antimalarials including halofantrine);
• Certain antihistamines (terfenadine, astemizole, mizolastine);
• Other medicinal products (cisapride, intravenous vinpocetine, bepridil, difemanil).

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

Following multiple doses of moxifloxacin in healthy volunteers, an increase in digoxin Cmax of approximately 30% was observed, without affecting AUC or trough levels.

In studies involving volunteers and diabetic patients, concomitant oral administration of moxifloxacin and glyburide (glibenclamide) resulted in a reduction of glyburide's maximum concentration by approximately 21%. The combination of glyburide with moxifloxacin could theoretically lead to mild, transient hyperglycemia. However, the observed pharmacokinetic changes did not result in changes in pharmacodynamic parameters (blood glucose levels, insulin levels). Thus, no clinically relevant interaction between moxifloxacin and glyburide has been identified.

Changes in international normalized ratio (INR)

Numerous cases of increased effect 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 antimicrobial therapy. As a precaution, INR should be monitored more frequently. Dose adjustment of the oral anticoagulant should be performed as needed.

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

In vitro studies using human cytochrome P450 enzymes have confirmed these findings. Therefore, metabolic interactions mediated by cytochrome P450 enzymes are unlikely.

Interaction with food

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

Special precautions for use.

Avoid using moxifloxacin in patients with a history of serious adverse reactions after administration of quinolones or fluoroquinolones (see section "Adverse reactions"). Treatment with moxifloxacin should be initiated in such patients only if no alternative therapy is available and after careful benefit-risk assessment (see also section "Contraindications").

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

Prolonged, disabling, and potentially irreversible serious adverse reactions

In patients receiving quinolones and fluoroquinolones, regardless of age or presence of risk factors, very rare cases of prolonged (lasting months or years), disabling, and potentially irreversible serious adverse drug reactions affecting various, sometimes multiple, body systems (musculoskeletal, nervous system, psychiatric, sensory organs) have been observed. Moxifloxacin treatment must be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and patients should be advised to consult a physician.

QTc interval prolongation and clinical conditions associated with QTc prolongation

Moxifloxacin has been shown to prolong the QTc interval on 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, the recommended duration of infusion should be at least 60 minutes, and the intravenous dose should not exceed 400 mg once daily. For further details, see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction".

Treatment with moxifloxacin should be discontinued if symptoms suggestive of cardiac arrhythmia occur, regardless of whether they are confirmed by ECG.

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 [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 be more sensitive to the effects of drugs that prolong the QTc interval, such as moxifloxacin, and therefore require special attention.

Aneurysm and dissection (dissecting aneurysm) of the aorta, valvular regurgitation/insufficiency

Epidemiological studies indicate an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and valvular regurgitation/insufficiency have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").

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

• for both aortic aneurysm and dissection and valvular regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, hypertension, rheumatoid arthritis), or additionally,
• for aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, diagnosed atherosclerosis, or Sjögren’s syndrome), or additionally,
• for valvular regurgitation/insufficiency (e.g., infective endocarditis).

The risk of aortic aneurysm, dissection, and rupture may be increased in patients concurrently receiving systemic corticosteroids.

In case of sudden abdominal, chest, or back pain, patients should seek immediate medical attention in an emergency department.

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

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. In cases of clinical manifestations of severe hypersensitivity reactions, moxifloxacin should be discontinued 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 with moxifloxacin use (see section "Adverse reactions"). If symptoms of fulminant hepatitis such as rapidly developing fatigue accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy occur, patients are advised to consult a physician before continuing treatment.

Liver function tests should be performed if signs of hepatic dysfunction occur.

Severe skin adverse reactions

Cases of severe skin adverse reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN or Lyell’s syndrome), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported during moxifloxacin use (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin adverse reactions, and their condition should be closely monitored during treatment.

If signs or symptoms suggestive of severe skin reactions appear, moxifloxacin should be discontinued immediately, and alternative treatment options considered. Moxifloxacin treatment should never be resumed in patients who have experienced a serious reaction (SJS, TEN, AGEP, or DRESS) during previous use.

Patients predisposed to seizures

Quinolones are known to induce seizures. They should be prescribed 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. 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 potentially 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 advised when prescribing moxifloxacin to patients with current or past psychiatric disorders.

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. 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, antimicrobial treatment, including moxifloxacin, should be discontinued and appropriate therapeutic measures initiated immediately. Infection control measures should also be implemented to reduce transmission risk. Antiperistaltic agents are contraindicated in patients who develop severe diarrhea.

Patients with severe myasthenia

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

Tendinitis and tendon rupture

Tendinitis and tendon rupture (particularly of the Achilles tendon, but not limited to it), sometimes bilateral, may occur during treatment with quinolones and fluoroquinolones, even within 48 hours of starting therapy. Cases have also been reported several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients after solid organ transplantation, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant corticosteroid therapy should be avoided.

If initial symptoms of tendinitis (e.g., painful swelling, inflammation) appear, moxifloxacin treatment should be discontinued and alternative treatment considered. The affected limb(s) should receive appropriate treatment (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy appear.

Patients with renal impairment

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

Ocular disorders

In case of visual impairment 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" and "Adverse reactions").

Dysglycemia

As with all fluoroquinolones, cases of blood glucose deviations, both hypoglycemia and hyperglycemia, have been reported during moxifloxacin treatment (see section "Adverse reactions"). Dysglycemia occurred predominantly in elderly patients and diabetic patients receiving concomitant oral hypoglycemic agents (e.g., sulfonylureas) or insulin with moxifloxacin. Cases of hypoglycemic coma have been reported. Diabetic patients are advised to closely monitor blood glucose levels (see section "Adverse reactions").

Prevention of photosensitization reactions

Photosensitization reactions have been reported in patients receiving quinolones. Studies indicate a low risk of photosensitization reactions with moxifloxacin. However, 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 treatment. Therefore, moxifloxacin should be used with caution in these 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 associated with burns, fasciitis, and infected "diabetic foot" with osteomyelitis has not been established.

Effect on biological tests

Moxifloxacin may affect test results for Mycobacterium spp. by inhibiting mycobacterial growth, potentially leading to false-negative results in patients 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). If MRSA infection is suspected or confirmed, appropriate antibacterial therapy should be initiated (see section "Pharmacodynamics").

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 known. Due to the experimentally demonstrated 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").

Breastfeeding

There are no data on the use of moxifloxacin during breastfeeding in women. Preclinical studies show 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 intravenous infusion once daily.

Initial intravenous therapy may be continued with oral administration of 400 mg moxifloxacin tablets when clinically indicated.

In clinical trials, most patients switched to oral moxifloxacin within 4 days (community-acquired pneumonia) or 6 days (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 drug should be administered intravenously as a continuous infusion lasting at least 60 minutes (see also section "Special Instructions").

If indicated, the infusion solution may be administered through a Y-site catheter together with compatible infusion solutions (see section "Special Safety Precautions").

Renal or 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 data regarding moxifloxacin use in 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.

Specific interventions are not 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 a 400 mg dose of moxifloxacin, whether administered orally or intravenously, reduces systemic bioavailability by more than 80% or 20%, respectively. Administration of activated charcoal in the early stages of absorption may effectively prevent excessive systemic exposure to moxifloxacin in cases of oral overdose.

Side effects

The side effects listed below were observed in clinical trials and during the post-marketing period with the use of moxifloxacin at a dose of 400 mg once daily (intravenous therapy only, stepwise [intravenous/oral], and oral therapy).

All adverse reactions, except nausea and diarrhea, occurred at a frequency of less than 3%. Within each group, adverse reactions are listed in order of decreasing severity. Frequency is defined as follows: common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations. Common – superinfections associated with resistant bacteria or fungi, e.g., oral and vaginal candidiasis.

Blood and lymphatic system disorders. Uncommon – anemia, leukopenia, neutropenia, thrombocytopenia, thrombocytosis, eosinophilia, prolonged prothrombin time/increased INR; very rare – elevated prothrombin levels/decreased INR, agranulocytosis, pancytopenia.

Immune system disorders. Uncommon – allergic reactions; rare – anaphylaxis, including rare cases of shock (potentially life-threatening), angioedema/allergic edema, including laryngeal edema (potentially life-threatening) (see section "Special precautions for use").

Endocrine system disorders. Very rare – syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders. Uncommon – hyperlipidemia; rare – hyperglycemia, hyperuricemia; very rare – hypoglycemia, hypoglycemic coma.

Psychiatric disorders*. Uncommon – anxiety reactions, increased psychomotor activity/agitation; rare – mood lability, depression (in rare cases with possible self-harm, such as suicidal thoughts/ideation or suicide attempts), hallucinations, delirium; very rare – depersonalization, psychotic reactions (with possible self-harm, such as suicidal thoughts/ideation or suicide attempts) (see section "Special precautions for use").

Nervous system disorders*. Common – headache, dizziness; uncommon – paresthesia/dysesthesia, taste disturbances (including ageusia in rare cases), confusion and disorientation, sleep disorders (mainly insomnia), tremor, vertigo, somnolence; rare – hypoesthesia, smell disturbances (including loss of smell), pathological dreams, coordination disorders (including gait disturbance due to dizziness or vertigo), seizures (including "grand mal" seizures) (see section "Special precautions for use"), attention disorders, speech disorders, amnesia, peripheral neuropathy and polyneuropathy; very rare – hyperesthesia.

Eye disorders*. Uncommon – visual disturbances, including diplopia and blurred vision (especially during CNS-related reactions); rare – photophobia; very rare – transient loss of vision (especially during CNS-related reactions) (see sections "Special precautions for use" and "Ability to influence reaction rate when driving or operating machinery"), uveitis, and bilateral acute iris transillumination (see section "Special precautions for use").

Ear and labyrinth disorders*. Rare – tinnitus, hearing disturbances including deafness (usually reversible).

Cardiovascular system disorders**. Common – QT interval prolongation in patients with hypokalemia (see sections "Contraindications" and "Special precautions for use"); uncommon – QT interval prolongation, palpitations, tachycardia, atrial fibrillation, angina pectoris, vasodilation; rare – ventricular tachyarrhythmias, syncope (i.e., acute and transient loss of consciousness), arterial hypertension, arterial hypotension; very rare – non-specific arrhythmias, torsades de pointes (see section "Special precautions for use"), cardiac arrest, vasculitis.

Respiratory, thoracic and mediastinal disorders. Uncommon – dyspnea (including asthmatic state).

Gastrointestinal disorders. Common – nausea, vomiting, abdominal pain and discomfort, diarrhea; uncommon – decreased appetite and reduced food intake, constipation, dyspepsia, flatulence, gastritis, increased amylase levels; rare – dysphagia, stomatitis, antibiotic-associated colitis (including pseudomembranous colitis, in rare cases associated with life-threatening complications) (see section "Special precautions for use").

Hepatobiliary disorders. Common – elevated transaminase levels; uncommon – liver function abnormalities (including elevated LDH [lactate dehydrogenase]), increased bilirubin levels, elevated GGT (gamma-glutamyltransferase), elevated alkaline phosphatase in blood; rare – jaundice, hepatitis (predominantly cholestatic); very rare – fulminant hepatitis, potentially leading to life-threatening hepatic failure (including fatal outcomes).

Skin and subcutaneous tissue disorders. Uncommon – pruritus, rash, urticaria, dry skin; very rare – bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis (potentially life-threatening); frequency not known – acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), fixed drug eruption, photosensitivity reactions (see section "Special precautions for use").

Musculoskeletal and connective tissue disorders*. Uncommon – arthralgia, myalgia; rare – tendinitis (see section "Special precautions for use"), muscle twitching, muscle cramps, muscle weakness; very rare – tendon rupture, arthritis, muscle rigidity, exacerbation of symptoms of Myasthenia gravis (see section "Special precautions for use"); frequency not known – rhabdomyolysis.

Renal and urinary disorders. Uncommon – dehydration; rare – renal function impairment (including increased blood urea nitrogen and plasma creatinine), renal failure (see section "Special precautions for use").

General disorders and administration site conditions*. Common – infusion site reactions; uncommon – general weakness (mainly asthenia or fatigue), (thrombo-)phlebitis at infusion site, pain (including back, chest, pelvic, and limb pain), hyperhidrosis; rare – edema.

*With the use of quinolones and fluoroquinolones, very rare cases of prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions have been reported, sometimes affecting multiple body systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paresthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disturbances, anxiety, panic attacks, depression, and suicidal thoughts), memory and concentration difficulties, hearing, vision, taste, and smell disturbances), occurring in some cases regardless of age or presence of risk factors (see section "Special precautions for use").

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

The incidence of the following effects is higher with intravenous administration of the drug followed by oral therapy or without such transition.

Common: elevated gamma-glutamyltransferase levels.

Uncommon: ventricular tachyarrhythmia, 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 function impairment (including increased blood urea nitrogen and creatinine levels), renal failure (see section "Special precautions for use").

In very rare cases following treatment with other fluoroquinolones, the following adverse reactions have been reported, which may possibly also occur with moxifloxacin: increased intracranial pressure (including idiopathic intracranial hypertension – pseudotumor cerebri), hypernatremia, hypercalcemia, hemolytic anemia, photosensitivity reactions (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions.

Shelf life. 5 years.

Storage conditions. The medicinal product does not require special storage conditions. Keep out of reach and sight of children.

Incompatibilities.

The moxifloxacin infusion solution must not be administered simultaneously with incompatible solutions, which include: 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, 5, or 12 vials per carton.

Prescription category. Prescription only.

Manufacturer. PHARMATHEN S.A.

Manufacturer's address and place of business.

Derivenakion 6, Pallini, Attica, 15351, Greece.