Maxicin®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MAXICIN® (MAXICIN)

Composition:

Active substance: moxifloxacin;

1 ml of solution contains moxifloxacin hydrochloride 1.744 mg, equivalent to 1.6 mg of moxifloxacin;

Excipients: sodium chloride, hydrochloric acid concentrated*, water for injections.

* For pH adjustment.

Pharmaceutical form. Infusion solution.

Main physicochemical characteristics: clear greenish-yellow solution.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Antibacterial agents of the quinolone group. Fluoroquinolones. Moxifloxacin.

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.

Pharmacokinetic/pharmacodynamic relationship

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 may 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 MIC and disk diffusion test breakpoints for moxifloxacin, as defined by 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
S. 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
H. influenzae	≤ 0.5 mg/l ≥ 25 mm	> 0.5 mg/l < 25 mm
M. 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
Species-independent breakpoint values*	≤ 0.5 mg/l	> 1 mg/l
* Species-independent breakpoint values were primarily determined based on pharmacokinetic/pharmacodynamic data relationships and are not dependent on MICs for individual species. These data are used for species without individually defined breakpoint values and do not apply to species for which interpretive criteria are to be determined.

Microbiological susceptibility

The prevalence of acquired resistance in individual species may vary depending on geographical location and over time; therefore, it is advisable to use local information on microbial resistance, especially when treating severe infections. If necessary, consultation with a specialist should be sought when local resistance prevalence has reached 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 group milleri* (S. anginosus, S. constellatus and S. intermedius) Streptococcus pneumoniae* Streptococcus pyogenes* (group A) Streptococcus group viridans (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 Chlamydia (Chlamydophila) pneumoniae* Coxiella burnetii Mycoplasma pneumoniae*

Microorganisms that may develop resistance

Aerobic gram-positive microorganisms Enterococcus faecalis* Enterococcus faecium*

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

Anaerobic microorganisms Bacteroides fragilis*

Naturally resistant microorganisms

Aerobic gram-negative microorganisms Pseudomonas aeruginosa

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

Pharmacokinetics.

Absorption and Bioavailability

After a single 60-minute intravenous infusion of 400 mg moxifloxacin, maximum drug concentration 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). Following intravenous administration, the area under the concentration–time curve (AUC) is approximately 39 mg×h/L, slightly exceeding the value observed after oral administration (35 mg×h/L). Absolute bioavailability is approximately 91%.

There is no need to adjust the dosage of moxifloxacin according to patient age or gender following intravenous administration.

Pharmacokinetics are linear within the dose range of 50 mg to 1200 mg for a single oral dose, up to 600 mg for a single intravenous dose, 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 protein binding is 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 in interstitial fluid is similar to that in plasma, with a maximum free concentration of 1.0 mg/L (geometric mean) reached approximately 1.8 hours after intravenous administration.

Biotransformation

Moxifloxacin undergoes phase II biotransformation and is eliminated via the kidneys (approximately 40%) and bile (approximately 60%) both unchanged and as sulfate conjugate (M1) and glucuronides (M2). M1 and M2 are metabolites relevant only in humans, and both are microbiologically inactive.

No metabolic pharmacokinetic interactions with other drugs metabolized via phase I biotransformation, including cytochrome P450 enzymes, were observed in in vitro and phase I clinical studies. No evidence of oxidative metabolism was detected.

Elimination

The elimination half-life of moxifloxacin in plasma is approximately 12 hours. Mean total clearance after administration of 400 mg ranges from 179 to 246 mL/min. After intravenous administration of 400 mg moxifloxacin, unchanged drug excreted in urine was approximately 22% and in feces approximately 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. Concomitant administration of ranitidine and probenecid with moxifloxacin does not alter renal clearance of the parent drug.

Renal Impairment

No significant changes in moxifloxacin pharmacokinetics were observed in patients with renal impairment (including patients with creatinine clearance > 20 mL/min/1.73 m²). With decreasing renal function, the concentration of metabolite M2 (acyl 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) do not allow definitive conclusions regarding differences in parameters between patients with impaired liver function and healthy volunteers. Hepatic impairment was associated with increased plasma levels of metabolite M1. The levels of unchanged drug remain similar to those 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, hematological toxicity, hepatotoxicity, and toxic effects on the central nervous system (CNS) were observed with moxifloxacin. These effects occurred after administration of high doses 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 administered as a bolus injection (45 mg/kg), whereas no toxicity was observed when 40 mg/kg was administered via slow infusion over 50 minutes.

After intra-arterial administration, inflammatory changes extending into perivascular soft tissues were observed, indicating that this route of administration should be avoided.

Moxifloxacin was genotoxic in in vitro tests using bacteria or mammalian cells. However, no genotoxicity was observed in vivo, even with very high doses of moxifloxacin. Moxifloxacin showed no 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 a dose of 30 mg/kg via 15-, 30-, or 60-minute infusions, the degree of QT interval prolongation was infusion-rate-dependent: the shorter the infusion time, the greater 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 demonstrated that moxifloxacin crosses the placenta. Animal studies did not reveal teratogenic effects or impaired fertility after moxifloxacin administration. Slight increases in 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 comparable to therapeutic levels expected in humans.

It is known that quinolones, including moxifloxacin, cause damage to weight-bearing joint cartilage in immature animals.

Clinical characteristics.

Indications.

Maxicin**®** is indicated for the treatment of the following infectious diseases:

• Community-acquired pneumonia;
• Complicated skin and soft tissue infections.

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

Official guidelines on appropriate use of antibacterial agents should be taken into account.

Contraindications.

• Hypersensitivity to moxifloxacin, to other quinolones, 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 electrophysiological parameters of cardiac activity, manifested as QT interval prolongation, were observed after administration of moxifloxacin. For this reason, moxifloxacin is contraindicated in patients with:

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

Moxifloxacin should not be administered concomitantly with drugs 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 fivefold or more.

Special precautions.

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

The following diluents have been shown to be compatible with the moxifloxacin 400 mg infusion solution: Water for Injections, 0.9% Sodium Chloride Solution, 5%, 10%, and 40% Glucose Solutions, Ringer's Solution, and compound Sodium Lactate solutions (Hartmann's solution, Lactated Ringer's solution).

Moxifloxacin infusion solution should not be administered simultaneously with other drugs.

Do not use the medicinal product if particulate matter is visible or if the solution is cloudy.

Precipitation may occur during storage in a cool place, 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 other 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 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);
• Antipsychotics (e.g., phenothiazines, pimozide, sertindole, haloperidol, sulpiride);
• Tricyclic antidepressants;
• Certain antimicrobials (e.g., saquinavir, sparfloxacin, intravenous erythromycin, pentamidine, antimalarials including halofantrine);
• Certain antihistamines (e.g., terfenadine, astemizole, mizolastine);
• Other medicinal products: cisapride, intravenous vinca alkaloids, bepridil, difemanil.

Moxifloxacin should be used with caution in patients receiving treatment with drugs that may reduce potassium levels (e.g., loop and thiazide diuretics, laxatives and enemas (frequent use), corticosteroids, amphotericin B), or drugs that may cause clinically significant bradycardia.

Following repeated administration of moxifloxacin, an increase in the maximum plasma concentration of digoxin by approximately 30% was observed. However, the AUC and minimum plasma concentration of digoxin were unchanged. No special precautions are required when moxifloxacin is used concomitantly with digoxin.

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

Changes in international normalized ratio (INR)

Numerous cases of increased activity of oral anticoagulants have been reported in patients receiving antibacterial agents, particularly fluoroquinolones, macrolides, tetracyclines, cotrimoxazole, and certain cephalosporins. Risk factors include infectious diseases and inflammatory conditions, advanced age, and poor general health. Therefore, it is difficult to determine whether changes in INR are caused by the infection itself or by its treatment. More frequent monitoring of coagulation parameters is recommended. If necessary, appropriate dose adjustment of the oral anticoagulant should be performed.

Clinical studies have demonstrated no interaction between moxifloxacin and the following drugs: ranitidine, probenecid, oral contraceptives, calcium supplements, parenteral morphine, theophylline, cyclosporine, or itraconazole.

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

Interaction with food

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

Special Warnings and Precautions.

Moxifloxacin should be avoided in patients with a history of serious adverse reactions associated with quinolone or fluoroquinolone-containing medicinal products (see section "Adverse Reactions"). Treatment with moxifloxacin in such patients should be initiated only if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (see also section "Contraindications").

The benefits of moxifloxacin therapy, especially in mild infections, should be carefully weighed against the information provided in this section.

QTc interval prolongation and clinical conditions in which QTc interval prolongation may occur

In some patients, moxifloxacin may cause QTc interval prolongation on the electrocardiogram (ECG). The degree of QT interval prolongation may increase with rising plasma drug concentrations due to too rapid intravenous infusion. Therefore, the recommended infusion duration, which should be at least 60 minutes, must be observed, 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".

If signs or symptoms of cardiac arrhythmia occur during treatment, therapy should be discontinued, regardless of whether this is confirmed by ECG findings.

Moxifloxacin should be used with caution in patients predisposed to cardiac arrhythmia (e.g., acute myocardial ischemia), as they have an increased risk of developing ventricular arrhythmias (including polymorphic ventricular tachycardia of the torsades de pointes type) 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 that may cause clinically significant bradycardia (see also section “Contraindications”).

Women and elderly patients may exhibit increased sensitivity to the effects of drugs that prolong the QTc interval, such as moxifloxacin; therefore, these patients require special attention.

Increased sensitivity / allergic reactions

Cases of hypersensitivity and allergic reactions have been reported after the first administration of fluoroquinolones, including moxifloxacin. Anaphylactic reactions may progress to life-threatening anaphylactic shock even after the first dose of the drug. In the event 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 have been reported during moxifloxacin therapy, which may lead to hepatic failure (including fatal cases) (see section “Adverse reactions”). If signs and symptoms of fulminant liver disease occur, such as rapidly developing asthenia accompanied by jaundice, darkening of urine, bleeding tendency, or hepatic encephalopathy, patients are advised to consult a physician before continuing treatment.

Appropriate investigations should be performed if signs of hepatic dysfunction occur.

Severe drug-induced skin reactions

Severe drug-induced skin adverse reactions, which may be fatal, 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 in patients receiving moxifloxacin (see section “Adverse reactions”). When prescribing moxifloxacin, patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. At the first signs or symptoms suggestive of such reactions, moxifloxacin should be discontinued immediately and alternative therapy considered. If a patient develops a serious skin reaction such as SJS, TEN, AGEP, or DRESS while receiving moxifloxacin, re-initiation of moxifloxacin therapy in this patient is absolutely contraindicated.

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.

Prolonged, disabling, and potentially irreversible serious adverse reactions

Very rare, prolonged (several months or years), disabling, and potentially irreversible serious adverse reactions affecting various body systems (musculoskeletal, nervous, and psychiatric systems, sensory organs) have been reported in patients receiving quinolones and fluoroquinolones, regardless of patient age or presence of risk factors. At the first signs or symptoms of any serious adverse reaction, moxifloxacin should be discontinued immediately and medical advice sought.

Peripheral neuropathy

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

Psychiatric reactions

Psychiatric reactions may occur even after the first dose of quinolones, 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 therapy should be discontinued and appropriate measures taken. Caution should be exercised when prescribing moxifloxacin to patients with psychiatric disorders or a history of psychiatric illness.

Antibiotic-associated diarrhea, including colitis

With the use of broad-spectrum antibiotics, including moxifloxacin, cases of antibiotic-associated diarrhea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been observed, ranging in severity from mild diarrhea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop severe diarrhea during or after moxifloxacin therapy. If AAD or AAC is suspected or confirmed, treatment with antibacterial agents, including moxifloxacin, should be discontinued immediately and appropriate therapeutic measures initiated. In addition, appropriate infection control measures should be implemented to reduce the risk of transmission. Antiperistaltic agents are contraindicated in patients who develop severe diarrhea.

Patients with myasthenia gravis

Moxifloxacin should be used with caution in patients with myasthenia gravis, as their 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 treatment with quinolones and fluoroquinolones, and occasionally several months after discontinuation of the drug (see sections “Contraindications” and “Adverse reactions”). 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 corticosteroids. Concomitant use of corticosteroids and fluoroquinolones should be avoided. At the first signs of tendinitis (e.g., painful swelling or joint inflammation), moxifloxacin therapy should be discontinued immediately and alternative therapy considered. The affected limb should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy appear.

Aortic aneurysm and aortic dissection, and valvular regurgitation/insufficiency

Epidemiological studies indicate an increased risk of aortic aneurysm and aortic dissection, particularly in elderly patients, as well as aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and aortic 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 therapies in patients with a significant family history (presence of aneurysm or congenital heart valve malformation), diagnosed aortic aneurysm and/or aortic dissection, heart valve disease, or other risk factors, namely:

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

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

If sudden abdominal, chest, or back pain occurs, patients should seek immediate medical attention at an emergency department.

Patients should be advised to seek immediate medical help if they experience dyspnea, rapid heartbeat, or swelling of the abdomen or lower limbs.

Patients with renal impairment

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

Visual disturbances

In case of visual deterioration or other disturbances of the visual organs, immediate consultation with an ophthalmologist is required (see sections “Ability to influence reaction rate when driving or operating machinery”, “Adverse reactions”).

Fluctuations in blood glucose levels

As with other fluoroquinolones, fluctuations in blood glucose levels, including cases of hyperglycemia and hypoglycemia, have been reported during moxifloxacin therapy (see section “Adverse reactions”).

Dysglycemia occurred predominantly in elderly patients with diabetes 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 their blood glucose levels.

Prevention of photosensitization reactions

Cases of photosensitization have been reported with quinolone use. However, studies indicate that the risk of photosensitization reactions with moxifloxacin is low. Nevertheless, patients should avoid prolonged and/or intense exposure to sunlight or ultraviolet radiation during moxifloxacin therapy (see section “Adverse reactions”).

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with glucose-6-phosphate dehydrogenase deficiency, as well as those with a family history of this condition, are prone to hemolytic reactions during quinolone therapy. Therefore, moxifloxacin should be used with caution in this patient group.

Periarterial tissue inflammation

Moxifloxacin infusion solution is intended for intravenous use only. Intra-arterial 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 burns, fasciitis, and infected diabetic foot with accompanying osteomyelitis has not been established.

Impact on microbiological testing

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 MRSA. If MRSA infection is suspected or confirmed, appropriate antibacterial therapy should be initiated (see section “Pharmacological properties”).

Information on excipients

One vial of the medicinal product (250 mL infusion solution) contains 787 mg (34 mmol) of sodium, which corresponds to 39.35% of the maximum daily sodium intake (2 g) recommended by WHO for adults.

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 to humans is not known. Given the experimentally demonstrated harmful effects of fluoroquinolones on weight-bearing joint 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 the medicinal product during lactation 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 risk of harmful effects of fluoroquinolones on weight-bearing joint cartilage, as demonstrated experimentally in immature animals, breastfeeding during moxifloxacin therapy is contraindicated (see section “Contraindications”).

Fertility

Animal studies did not reveal effects 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 during 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 monitor their individual response to moxifloxacin before driving or operating machinery.

Method of Administration and Dosage

Dosing

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.

Renal or hepatic impairment

Patients with mild to severe renal impairment and patients undergoing dialysis (hemodialysis or long-term ambulatory peritoneal dialysis) do not require dose adjustment (see section "Pharmacological Properties" for details).

There is insufficient data 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.

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").

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

Children

The efficacy and safety of Maxicin® in children have not been established; therefore, its use in children is contraindicated (see section "Contraindications").

Overdose.

There are no specific recommendations for management following accidental overdose. In case of overdose, symptomatic treatment should be initiated. Since QT interval prolongation may occur, ECG monitoring is required. Concomitant administration of activated charcoal with a 400 mg dose of moxifloxacin given orally or intravenously reduces systemic bioavailability by more than 80% or 20%, respectively. Administration of activated charcoal in the early stage of absorption may effectively prevent excessive plasma concentrations of moxifloxacin in case of oral overdose.

Adverse Reactions

The adverse reactions listed below were observed during clinical trials and in the post-marketing period of moxifloxacin use at a dose of 400 mg once daily [intravenous, sequential intravenous/oral, and oral administration only].

All adverse reactions, except nausea and diarrhea, occurred at a frequency of less than 3%.

Adverse effects within each category are listed in order of decreasing severity. The frequency of adverse reactions 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: Anaemia, leucopenia, neutropenia, thrombocytopenia, thrombocytosis, eosinophilia, prolonged prothrombin time / increased INR.

Very rare: Increased 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 oedema (including life-threatening laryngeal oedema) (see section "Special warnings and precautions for use").

Endocrine disorders

Very rare: Syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Metabolism and nutrition disorders

Uncommon: Hyperlipidaemia.

Rare: Hyperglycaemia, hyperuricaemia.

Very rare: Hypoglycaemia, hypoglycaemic coma.

Psychiatric disorders*

Uncommon: Anxiety, increased psychomotor activity / restlessness.

Rare: Emotional lability, depression (in rare cases with self-harm manifested as suicidal thoughts or suicide attempts) (see section "Special warnings and precautions for use"), hallucinations, delirium.

Very rare: Depersonalisation, psychotic reactions (possibly with self-harm manifested as suicidal thoughts or suicide attempts) (see section "Special warnings and precautions for use").

Neurological disorders*

Common: Headache, dizziness.

Uncommon: Paraesthesia / dysaesthesia, taste disturbance (including ageusia in rare cases), confusion and disorientation, sleep disorders (mainly insomnia), tremor, vertigo, somnolence.

Rare: Hypaesthesia, smell disturbance (including loss of smell), pathological dreams, coordination disorders (including gait disturbance due to dizziness or vertigo), seizures (including tonic-clonic seizures) (see section "Special warnings and precautions for use"), attention disorders, speech disorder, amnesia, peripheral neuropathy and polyneuropathy.

Very rare: Hyperaesthesia.

Eye disorders*

Uncommon: Visual disturbance, including diplopia, and blurred vision (especially during CNS reactions) (see section "Special warnings and precautions for use").

Rare: Photophobia.

Very rare: Transient loss of vision (especially during CNS reactions) (see sections "Special warnings and precautions for use", "Effects on ability to drive and use machines"), uveitis and bilateral acute transient mydriasis (see section "Special warnings and precautions for use").

Ear and labyrinth disorders*

Rare: Tinnitus, hearing impairment, including deafness (usually reversible).

Cardiac disorders**

Common: QT interval prolongation in patients with hypokalaemia (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. sudden and brief loss of consciousness).

Very rare: Non-specific arrhythmia, torsades 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, arterial hypotension.

Very rare: Vasculitis.

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea (including asthmatic attack).

Gastrointestinal disorders

Common: Nausea, vomiting, gastrointestinal pain and abdominal pain, diarrhoea.

Uncommon: Decreased appetite and reduced food intake, constipation, dyspepsia, bloating, gastritis, increased 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: Increased transaminase levels.

Uncommon: Liver function disorders [including increased lactate dehydrogenase (LDH) levels], increased bilirubin, gamma-glutamyl transferase (GGT), alkaline phosphatase.

Rare: Jaundice, hepatitis (mainly cholestatic).

Very rare: Fulminant hepatitis, which may lead to life-threatening liver failure (see section "Special warnings and precautions for use").

Skin and subcutaneous tissue disorders

Uncommon: Itching, rash, urticaria, dry skin.

Very rare: Bullous skin reactions such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) (life-threatening) (see section "Special warnings and precautions for use").

Frequency not known: Acute generalised exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special warnings and precautions for use"), fixed drug eruption, photosensitisation reactions (see section "Special warnings and precautions for use").

Musculoskeletal and connective tissue disorders*

Uncommon: Arthralgia, myalgia.

Rare: Tendinitis (see section "Special warnings and precautions for use"), muscle cramps, muscle twitching, muscle weakness.

Very rare: Tendon rupture (see section "Special warnings and precautions for use"), arthritis, increased muscle rigidity, exacerbation of symptoms of myasthenia gravis (see section "Special warnings and precautions for use").

Frequency not known: Rhabdomyolysis.

Renal and urinary disorders

Uncommon: Dehydration.

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

General disorders and administration site conditions*

Common: Administration site reactions.

Uncommon: General weakness (mainly asthenia or fatigue), pain (including back, chest, pelvic and limb pain), increased sweating, phlebitis.

Rare: Oedema.

* Very rare cases of long-term (months or years), disabling and potentially irreversible serious adverse reactions affecting various organ systems have been reported following use of quinolones and fluoroquinolones, regardless of the presence of risk factors (see section "Special warnings and precautions for use"). These include tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paraesthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disturbances, anxiety, panic attacks, depression and suicidal thoughts), memory and concentration impairment, hearing disturbances, visual disturbances, and disturbances of taste and smell.

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

The incidence of the adverse effects listed below was higher in patients who received parenteral treatment (regardless of subsequent oral therapy).

Often

increased GGT levels

Uncommon

ventricular tachyarrhythmia, hypotension, edema, antibiotic-associated colitis (including pseudomembranous colitis, in rare cases associated with life-threatening complications, see section "Special precautions"), seizures (including tonic-clonic seizures) (see section "Special precautions"), hallucinations, renal dysfunction (including increased blood urea nitrogen and creatinine levels), renal failure (see section "Special precautions")

Very rarely, when treating with other fluoroquinolones, adverse effects have been reported which may also occur during treatment with moxifloxacin: increased intracranial pressure (including benign intracranial hypertension), hypernatremia, hypercalcemia, hemolytic anemia.

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions.

Store in a light-protected place at a temperature not exceeding 25 °C, in the original packaging. Keep out of reach of children.

Incompatibilities.

Maxicin®, solution for infusion, should not be administered simultaneously with the following solutions:

• 10 %, 20 % sodium chloride solution;
• 4.2 %, 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 polymer bottles. One bottle per cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address and location of manufacturing activities.

108, Kobzarska Street, Cherkasy, Cherkasy region, Ukraine. Tel.: (044) 281-01-01.