Moxiflox-infusion®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MOKSIFLOX-INFUZIA® (MOXIFLOX-INFUZIA®)

Composition:

Active substance: moxifloxacin;

250 ml of solution contain: moxifloxacin hydrochloride (calculated as 100 % anhydrous moxifloxacin) 400 mg;

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

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear yellow-green liquid, theoretical osmolarity — 278 mosmol/L, pH 4.1–4.6.

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 test breakpoints for moxifloxacin according to EUCAST (European Committee on Antimicrobial Susceptibility Testing) (01.01.2012):

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. When necessary, consultation with specialists should be sought if local resistance prevalence has reached a level at which the benefit of using the agent is at least questionable for certain types of infections.

Pharmacokinetics.

Absorption and bioavailability. After a single 400 mg infusion administered over 1 hour, the maximum concentration of the drug is reached at the end of the infusion and is approximately 4.1 mg/l, corresponding to an increase of about 26 % compared to the value observed after oral administration (3.1 mg/l). The AUC value is approximately 39 mg*h/l after intravenous administration and only slightly exceeds this parameter after oral administration (35 mg*h/l), consistent with an absolute bioavailability of approximately 91 %. Intravenous administration of moxifloxacin does not require dose adjustments according to 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 protein binding of approximately 40–42 %, independent of drug 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. 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 of plasma, with a maximum free concentration of 1.0 mg/l (geometric mean) reached 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 sulfate conjugates (M1) and glucuronides (M2). M1 and M2 are metabolites relevant only in humans; both are microbiologically inactive. In vitro studies and Phase I clinical trials showed no evidence of metabolic pharmacokinetic interactions with other drugs involved in phase I biotransformation, including cytochrome P450 enzymes. There is no indication 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, unchanged drug excretion in urine is approximately 22 % and in feces approximately 26 %. Cumulative excretion (unchanged drug and metabolites) totals approximately 98 % after intravenous administration. Renal clearance is approximately 24–53 ml/min, indicating partial tubular reabsorption of the drug in the kidneys. Concomitant administration of ranitidine and probenecid does not alter the renal clearance of the drug.

Renal impairment. No significant changes in moxifloxacin pharmacokinetics have been observed in patients with renal impairment (including patients with creatinine clearance > 20 ml/min/1.73 m²). With decreasing renal function, the concentration of the glucuronide metabolite (M2) 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) do not allow definitive conclusions regarding differences in parameters between patients with hepatic impairment and healthy volunteers. Hepatic impairment 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 to draw definitive conclusions.

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. Systemic toxicity after intravenous administration was most pronounced when moxifloxacin was given as bolus injections (45 mg/kg) and was not observed when 40 mg/kg was administered via slow infusions over 50 minutes. After intra-arterial administration, inflammatory changes extending to perivascular soft tissues were observed, indicating that intra-arterial administration of moxifloxacin should be avoided. Moxifloxacin showed genotoxicity in vitro in bacterial and mammalian cell assays. 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 leading to QT interval prolongation. After intravenous administration of moxifloxacin to animals at 30 mg/kg via 15-, 30-, or 60-minute infusions, the degree of QT prolongation was infusion-rate-dependent: shorter infusion times resulted in more pronounced 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 impaired 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 marked maternal systemic 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 damage to cartilage of 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, 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 to any of the excipients;
• 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, changes in cardiac electrophysiological parameters, 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 arrhythmias.

Moxifloxacin must not be administered concomitantly with drugs known to 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.

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, sulpiride);
• Tricyclic antidepressants;
• Certain antimicrobial agents (saquinavir, sparfloxacin, intravenous erythromycin, pentamidine, antimalarials including halofantrine);
• Certain antihistamines (terfenadine, astemizole, mizolastine);
• Other medicinal products (cisapride, intravenous vincamine, bepridil, difeminal).

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 (in high doses), corticosteroids, amphotericin B) or medicinal products associated with clinically significant bradycardia.

After multiple dosing of moxifloxacin in healthy volunteers, an increase in digoxin Cmax by approximately 30% was observed, without affecting AUC or the shape of the concentration-time curve.

In studies involving diabetic volunteers, concomitant oral administration of moxifloxacin and glyburide resulted in a reduction of the maximum plasma concentration of glyburide by 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 levels, insulin levels). 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. Contributing 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 the treatment. As a precautionary measure, INR can be monitored more frequently. If necessary, appropriate dose adjustment of the oral anticoagulant should be performed.

In clinical studies, the following substances have been shown not to have a clinically significant interaction with moxifloxacin: 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 safety precautions.

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

The following solutions 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; however, the precipitate dissolves at room temperature. Therefore, storage of the infusion solution below 15°C is not recommended.

Special precautions for use.

The benefits of moxifloxacin treatment, especially in the case of mild infections, should be carefully weighed against the information presented in this section.

The use of moxifloxacin should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones. Treatment with moxifloxacin in such patients should only be initiated if no alternative treatment options are available and after a thorough benefit-risk assessment.

QTc interval prolongation and clinical conditions associated with QTc prolongation. Moxifloxacin has been shown to prolong the QTc interval on the electrocardiogram in some patients. The degree of QT 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 immediately if symptoms suggestive of cardiac arrhythmia occur during treatment, regardless of whether these 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 torsades de pointes) and cardiac arrest (see also sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Caution is also advised when using moxifloxacin 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 in 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 that cause QTc interval prolongation, such as moxifloxacin, and therefore require special attention.

Prolonged, disabling, and potentially irreversible serious adverse reactions. Very rarely, in patients receiving quinolones and fluoroquinolones, regardless of age or existing risk factors, prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions have been observed, affecting various systems of the body, sometimes simultaneously (including musculoskeletal, nervous, psychiatric, and sensory systems). The use of the drug should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

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 such cases, 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 cases), have been reported during moxifloxacin treatment (see section "Adverse reactions"). If symptoms of fulminant hepatitis occur, such as rapidly developing asthenia accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy, patients should 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, including toxic epidermal necrolysis (also known as Lyell's syndrome), Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms (DRESS), 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. Moxifloxacin should be discontinued immediately if signs or symptoms suggestive of these reactions occur, and alternative treatment should be considered. If a serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or DRESS occurs during moxifloxacin treatment, re-administration of moxifloxacin must never be attempted in that patient.

Patients predisposed to seizures. Quinolones are known to induce seizures. They should be used with caution in patients with CNS disorders or other risk factors that may provoke seizures or lower the seizure threshold. If seizures occur, moxifloxacin should be discontinued and appropriate measures taken.

Peripheral neuropathy. Cases of sensory or sensorimotor polyneuropathy, leading to paresthesia, hypaesthesia, dysesthesia, or weakness, have been reported in patients receiving quinolones and fluoroquinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, patients receiving moxifloxacin should inform their physician immediately to prevent potentially irreversible damage.

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 or current diagnosis of psychiatric disorders.

Antibiotic-associated diarrhea, including colitis. Cases of antibiotic-associated diarrhea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been reported with broad-spectrum antibiotics, including moxifloxacin. The severity of these conditions 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 AAD or AAC is suspected or confirmed, antimicrobial treatment including moxifloxacin should be discontinued immediately and appropriate therapeutic measures initiated. 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 gravis. Moxifloxacin should be used with caution in patients with severe myasthenia gravis, as symptoms may be exacerbated.

Tendinitis and tendon rupture. Tendinitis and tendon rupture (especially of the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting quinolone or fluoroquinolone therapy and have been reported even several months after discontinuation. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, organ transplant recipients, and those receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

At the first signs of tendinitis (e.g., painful swelling, inflammation), treatment should be discontinued, and alternative therapy considered. The affected limb should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

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.

Eye disorders. In case of visual deterioration or any effect on the eyes, immediate consultation with an ophthalmologist is required (see sections "Ability to affect reaction speed when driving or operating machinery" and "Adverse reactions").

Dysglycemia. As with other fluoroquinolones, 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. 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, studies have shown that moxifloxacin has a low risk of photosensitization. Nevertheless, patients should be advised to avoid exposure to ultraviolet radiation and prolonged or intense sunlight during moxifloxacin treatment (see section "Adverse reactions").

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

Periarterial tissue inflammation. Moxifloxacin 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 the treatment of severe infections associated with burns, fasciitis, and infected "diabetic foot" complicated by osteomyelitis has not been established.

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

Effect on biological tests. Moxifloxacin may affect the results of Mycobacterium spp. detection tests 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). In case of suspected or confirmed MRSA infection, appropriate antibacterial therapy should be initiated (see section "Pharmacodynamics").

Aortic aneurysm or dissection, valvular regurgitation/insufficiency. Epidemiological studies suggest an increased risk of aortic aneurysm and dissection, particularly in the elderly, and aortic or 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 only be used after a careful benefit-risk assessment and consideration of alternative treatments in patients with a family history of aortic aneurysm or congenital heart valve defects, or in patients with a confirmed diagnosis of aortic aneurysm, aortic dissection, valvular heart disease, or other risk factors, namely:

• Risk factors for aortic aneurysm, aortic dissection, or valvular regurgitation/insufficiency: connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, hypertension, rheumatoid arthritis;
• Risk factors for aortic aneurysm and dissection: vascular disorders such as Takayasu arteritis, giant cell arteritis, atherosclerosis, Sjögren’s syndrome;
• Risk factors for valvular regurgitation/insufficiency: infective endocarditis.

The risk of aortic aneurysm or dissection and rupture is increased in patients receiving systemic corticosteroids concomitantly.

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

Patients should be advised to seek immediate medical help if acute shortness of breath, sudden palpitations, or abdominal or lower limb edema develop.

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. Given the experimentally established risk of harmful effects of fluoroquinolones on weight-bearing cartilage in immature animals and considering the occurrence 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 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 have not shown any effect on fertility (see section "Pharmacological properties").

Ability to affect reaction speed when driving or operating machinery. No studies have been conducted on the effect of moxifloxacin on the ability to drive or operate machinery. However, fluoroquinolones, including moxifloxacin, may affect reaction speed by causing central nervous system reactions (e.g., dizziness, acute transient visual loss) or acute, brief 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 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 medicinal product should be administered intravenously as a continuous infusion lasting at least 60 minutes (see also section "Special Warnings").

When 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 undergoing chronic dialysis, such as 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 reduced 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.

Special 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 administered either orally or intravenously reduces systemic bioavailability by more than 80% or 20%, respectively. Administration of activated charcoal in the early phase of absorption may effectively prevent excessive systemic exposure to moxifloxacin in cases of oral overdose.

Adverse Reactions

Listed below are adverse reactions observed during clinical trials with moxifloxacin at a dose of 400 mg once daily (intravenous therapy only, sequential [intravenous/oral] and oral therapy), along with their frequencies.

All adverse reactions, except nausea and diarrhea, occurred at a frequency of less than 3%. Within each group, adverse events are listed in descending 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 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 international normalized ratio (INR).
Rare: elevated prothrombin levels, decreased INR, agranulocytosis, pancytopenia.

Immune system disorders.
Uncommon: allergic reactions (see section "Special warnings and precautions for use").
Rare: anaphylaxis, including life-threatening shock in rare cases (see section "Special warnings and precautions for use"), angioedema, allergic edema, angioneurotic edema (including potentially life-threatening laryngeal edema) (see section "Special warnings and precautions for use").

Endocrine disorders.
Rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Mental and behavioural disorders.
Uncommon: anxiety reactions, increased psychomotor activity, agitation.
Rare: mood lability, depression (in rare cases with possible self-harm, manifesting as suicidal ideation, thoughts or attempts) (see section "Special warnings and precautions for use"), hallucinations, delirium.
Very rare: depersonalization, psychotic reactions (with possible self-harm, manifesting as suicidal ideation, thoughts or attempts) (see section "Special warnings and precautions for use").

Nervous system disorders.
Common: headache, dizziness.
Uncommon: paraesthesia, dysaesthesia, taste disturbances (including ageusia in rare cases), confusion and disorientation, sleep disorders (mainly insomnia), tremor, vertigo, somnolence.
Rare: hypoaesthesia, smell 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 disorders, amnesia, peripheral neuropathy and polyneuropathy.
Very rare: hyperaesthesia.

Eye disorders.
Uncommon: visual disturbances, including diplopia and blurred vision (especially during CNS-related reactions) (see section "Special warnings and precautions for use").
Rare: photophobia.
Very rare: transient loss of vision (especially during CNS-related reactions) (see sections "Special warnings and precautions for use", "Effect on ability to drive and use machines"), uveitis and bilateral acute iris transillumination (see section "Special warnings and precautions for use").

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

Cardiac disorders.
Common: QT interval prolongation in patients with hypokalemia (see sections "Contraindications", "Special warnings and precautions for use").
Uncommon: QT interval prolongation (see section "Special warnings and precautions for use"), palpitations, tachycardia, atrial fibrillation, angina pectoris.
Rare: ventricular tachyarrhythmias, syncope (e.g., acute and short-term loss of consciousness).
Very rare: non-specific arrhythmias, torsade de pointes (see section "Special warnings and precautions for use"), cardiac arrest (see section "Special warnings and precautions for use").

Vascular disorders.
Uncommon: vasodilation.
Rare: arterial hypertension, hypotension.
Very rare: vasculitis.

Respiratory, thoracic and mediastinal disorders.
Uncommon: dyspnea (including asthmatic symptoms).

Gastrointestinal disorders.
Common: nausea, vomiting, abdominal pain and discomfort, diarrhea.
Uncommon: decreased appetite and reduced food intake, constipation, dyspepsia, flatulence, gastritis, elevated amylase levels.
Rare: 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.
Common: elevated transaminase levels.
Uncommon: liver function abnormalities (including elevated LDH [lactate dehydrogenase]), elevated bilirubin, GGT [gamma-glutamyl transferase], alkaline phosphatase.
Rare: jaundice, hepatitis (predominantly cholestatic).
Very rare: fulminant hepatitis, which may lead to life-threatening hepatic failure (see section "Special warnings and precautions for use").

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

Musculoskeletal and connective tissue disorders.
Uncommon: arthralgia, myalgia.
Rare: tendonitis (see section "Special warnings and precautions for use"), increased muscle tone, muscle cramps, muscle weakness.
Very rare: 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").
Frequency not known: rhabdomyolysis.

Renal and urinary disorders.
Uncommon: dehydration.
Rare: renal function abnormalities (including increased blood urea nitrogen and creatinine levels), renal failure (see section "Special warnings and precautions for use").

General disorders and administration site conditions.
Common: injection and infusion site reactions.
Uncommon: malaise (mainly asthenia or fatigue), pain (including back, chest, pelvic and limb pain), increased sweating, (thrombo-)phlebitis at infusion site.
Rare: edema.

The incidence of the following effects is higher when intravenous administration is used, with or without subsequent oral therapy:

Common: elevated gamma-glutamyl transferase levels.
Uncommon: ventricular tachyarrhythmia, hypotension, edema, 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"), seizures (including grand mal seizures) (see section "Special warnings and precautions for use"), hallucinations, renal function abnormalities (including increased blood urea nitrogen and creatinine levels), renal failure (see section "Special warnings and precautions for use").

Rarely, following treatment with other fluoroquinolones, adverse effects have been reported that may also potentially occur during moxifloxacin therapy: increased intracranial pressure (including idiopathic intracranial hypertension), hypernatremia, hypercalcemia, hemolytic anemia.

In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of age or existing risk factors, have experienced prolonged (lasting months or years), disabling and potentially irreversible serious adverse reactions affecting various, and sometimes multiple simultaneously, organ systems and sensory organs (including tendonitis, tendon rupture, arthralgia, limb pain, gait disturbances, paraesthesia and neuropathy-related neuralgia, fatigue, psychiatric symptoms (including sleep disturbances, anxiety, panic attacks, depression and suicidal thoughts), memory and concentration disturbances, hearing, vision, taste and smell disturbances).

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

Reporting suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions. Store in the original packaging at temperatures not exceeding 25 °C, in a place inaccessible to children. Do not refrigerate! Do not freeze!

Incompatibilities. 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 handling and disposal".

Packaging. 250 ml in a bottle, 1 bottle per carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Infuziya".

Manufacturer's address and location of operations.
84A Nemyrivske Highway, Vinnytski Khutory Village, Vinnytsia District, Vinnytsia Oblast, 23219, Ukraine.

Marketing authorization holder. Private Joint-Stock Company "Infuziya".

Address of marketing authorization holder. 21-A, Moskovskyi Avenue, Kyiv, 04073, Ukraine.