Maxicin®

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

Composition:

Active substance: moxifloxacin;

1 ml of solution contains moxifloxacin hydrochloride (calculated as moxifloxacin) 20 mg;

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

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: transparent 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 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 MIC breakpoints 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 may vary geographically and over time for individual species; therefore, local information on microbial resistance should be sought, especially when treating severe infections. If necessary, expert advice should be consulted when local resistance prevalence has reached a level at which the utility of the medicinal product, at least for certain types of infections, is questionable.

Pharmacokinetics.

Absorption and Bioavailability

After a single 60-minute intravenous infusion of moxifloxacin at a dose of 400 mg, maximum drug concentration is reached at the end of the infusion and is approximately 4.1 mg/L, which is about 26% higher than the value 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 parameter after oral administration (35 mg×h/L). Absolute bioavailability is approximately 91%.

There is no need for dose adjustment according to age or gender of patients when moxifloxacin is administered intravenously.

Pharmacokinetics are linear within the range of 50 mg to 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 compartment. 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. In skin blister fluid, a concentration of 1.75 mg/L was observed 10 hours after intravenous administration. The "free concentration–time" profile in interstitial fluid is similar to that in plasma, achieving a maximum free concentration of 1.0 mg/L (geometric mean) approximately 1.8 hours after intravenous administration.

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; both 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. No evidence of oxidative metabolism was found.

Elimination

The elimination half-life of moxifloxacin in plasma is approximately 12 hours. Mean steady-state total clearance after administration of 400 mg ranges from 179 to 246 mL/min. After intravenous administration of 400 mg moxifloxacin, urinary excretion of unchanged drug was approximately 22% and fecal excretion 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 in the kidneys. Concomitant administration of ranitidine and probenecid with moxifloxacin 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 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 involving 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 level of unchanged drug remains similar to that in healthy volunteers. There is insufficient clinical experience with moxifloxacin to recommend its use in patients with hepatic impairment.

Preclinical Safety Data

In traditional repeated-dose toxicity studies in animals, 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 administered as a bolus injection (45 mg/kg), and was not observed when moxifloxacin (40 mg/kg) was administered by 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, genotoxicity was not observed in vivo, even with very high doses of moxifloxacin. Moxifloxacin did not show carcinogenic effects in animal carcinogenicity studies.

In vitro, moxifloxacin at high concentrations affected cardiac electrophysiological parameters, potentially causing QT interval prolongation.

After intravenous administration of moxifloxacin to animals at a dose of 30 mg/kg by infusions lasting 15, 30, or 60 minutes, the degree of QT interval prolongation was infusion-rate-dependent: the shorter the infusion duration, the more pronounced the QT prolongation. QT prolongation was not observed when the 30 mg/kg dose was administered by 60-minute infusion.

In studies of moxifloxacin's effects on animal reproductive function, it was demonstrated that moxifloxacin crosses the placenta. Animal studies did not reveal teratogenic effects or impaired fertility after moxifloxacin administration. Minor 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 in large joints of 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, typically recommended for initial treatment of these infections, is inappropriate.

Official guidelines on the 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 in pregnancy or lactation");
• Pediatric age (patients under 18 years of age);
• History of tendon disorders related to the use of quinolones.

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

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

Moxifloxacin must not be used 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 five times or more above the upper limit of normal.

Special precautions.

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

Do not use the medicinal product if visible particles are present or if the concentrate is cloudy.

Precipitation may occur during storage at cool temperatures, but the precipitate dissolves at room temperature. Therefore, storage of the concentrate for 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 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 vinpocetine, bepridil, difemanil).

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

After multiple doses 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 not altered. When moxifloxacin is used concomitantly with digoxin, no special precautions are required.

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 could theoretically lead to 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.

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, co-trimoxazole, and certain cephalosporins. Risk factors include infectious diseases and inflammatory processes, age, and the patient's general condition. Therefore, it is difficult to determine whether changes in INR are caused by the infection itself or by its treatment. As a precautionary measure, coagulation parameters may be monitored more frequently. Dose adjustment of the oral anticoagulant should be performed as needed.

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

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

Interaction with food

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

Special precautions for use.

Moxifloxacin should be avoided in patients with a history of serious adverse reactions associated with quinolone and fluoroquinolone-containing medicinal products (see section "Adverse reactions"). Treatment of such patients with moxifloxacin should only be initiated 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, particularly in mild infections, should be carefully evaluated considering the information provided in this section.

QTc interval prolongation and clinical conditions associated with potential QTc interval prolongation

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 developing cardiac arrhythmias (e.g., acute myocardial ischemia), as they have an increased risk of 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 with caution 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 administered 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 following 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 with moxifloxacin use, 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 liver dysfunction occur.

Severe skin reactions caused by drug intake

Severe skin adverse reactions caused by drug intake, 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"). Patients should be informed about the signs and symptoms of severe skin reactions when moxifloxacin therapy is prescribed, and their condition should be closely monitored. At the first signs or symptoms suggestive of these reactions, moxifloxacin intake should be immediately discontinued, 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 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.

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 mental 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 immediately discontinued and medical advice sought.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy have been observed 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, in order to prevent 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 progressed to suicidal thoughts 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 the possibility of this diagnosis in patients who develop severe diarrhea during or after moxifloxacin treatment. If AAD or AAC is suspected or confirmed, treatment with antibacterial agents, including moxifloxacin, should be discontinued and appropriate therapeutic measures initiated immediately. Additionally, appropriate infection control measures should be implemented to reduce the risk of transmission. Medicinal products that inhibit peristalsis 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 worsen.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (especially of the Achilles tendon), sometimes bilateral, may occur within 48 hours of initiating 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 concurrently receiving corticosteroids. Concomitant use of corticosteroids and fluoroquinolones should be avoided. At the first signs of tendinitis (e.g., painful swelling or joint inflammation), moxifloxacin treatment should be immediately discontinued, 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 valve 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 regurgitation/insufficiency of any cardiac valve 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 valve defect), diagnosed aortic aneurysm and/or aortic dissection, or valvular heart disease, or in the presence of other risk factors, namely:

• risk factors for both aortic aneurysm and aortic dissection, and valve 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 valve regurgitation/insufficiency: infective endocarditis.

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

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

Patients should be advised to seek immediate medical help if they experience dyspnea, palpitations, 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 speed 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 treatment (see section "Adverse reactions").

Dysglycemia predominantly occurred in elderly patients with diabetes who were concurrently receiving 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, study data indicate that the risk of inducing photosensitization reactions with moxifloxacin is low. Nevertheless, patients should avoid prolonged and/or intense exposure to sunlight or ultraviolet radiation during moxifloxacin treatment (see section "Adverse reactions").

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with reduced glucose-6-phosphate dehydrogenase activity, 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, concentrate for solution for infusion, is intended exclusively for intravenous administration. Intra-arterial injection 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 accompanied by osteomyelitis has not been established.

Impact on microbiological testing

Moxifloxacin may affect the results of tests for Mycobacterium spp. by suppressing mycobacterial growth, which may lead 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").

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 established. Given the experimentally demonstrated risk of harmful effects of fluoroquinolones on weight-bearing joint cartilage in immature animals, and considering the development of reversible joint damage in children treated with certain fluoroquinolones, moxifloxacin should not be administered to pregnant women (see section "Contraindications").

Period of breastfeeding

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

Fertility

Animal studies did not reveal any effect on fertility (see section "Pharmacological properties").

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect of moxifloxacin on the ability to drive or operate machinery have not been conducted. However, fluoroquinolones, including moxifloxacin, may affect reaction speed when driving or operating machinery, causing CNS 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 total recommended 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/hepatic impairment

Patients with mild to severe renal impairment, as well as patients undergoing dialysis (hemodialysis or continuous ambulatory peritoneal dialysis), do not require dose adjustment (see section "Pharmacological properties" for details).

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

Other special patient groups

Elderly patients and patients with low body weight do not require dose adjustment.

Method of Administration

The medicinal product should be administered intravenously as a continuous infusion lasting at least 60 minutes (see also section "Special instructions for use").

Preparation of the solution

Only diluted medicinal product should be used!

To prepare the infusion solution, the contents of the Maxicin® vial should be diluted in a compatible infusion solution (see below). The minimum volume of the final infusion solution should be at least 250 ml.

The following solutions have been shown to be compatible with Maxicin® concentrate for infusion solution:

• Water for injections;
• 0.9% sodium chloride solution.

Moxifloxacin concentrate for infusion solution must not be administered simultaneously with other medicinal products.

From a microbiological standpoint, the solution should be used immediately after preparation.

If indicated, the prepared infusion solution may be administered through a Y-type catheter together with compatible infusion solutions.

Children

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

Overdose

No specific measures are recommended following accidental overdose. In case of overdose, symptomatic treatment should be initiated. Since QT interval prolongation is possible, ECG monitoring is required. Concomitant administration of activated charcoal with a 400 mg dose of moxifloxacin given orally or intravenously reduces systemic bioavailability by over 80% or 20%, respectively. Administration of activated charcoal at the early stage of absorption may effectively prevent excessive plasma concentrations of moxifloxacin in cases of oral overdose.

Adverse Reactions

The adverse reactions listed below were observed during clinical trials and the post-marketing period of moxifloxacin use at a dose of 400 mg once daily (intravenous only, sequential [intravenous/oral], and oral administration). Adverse reactions are classified according to their frequency of occurrence.

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

Within each group, adverse effects are listed in order of decreasing severity. The frequency of adverse reactions is defined as follows: common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 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 (see section "Special warnings and precautions for use").

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

Endocrine 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, increased psychomotor activity / agitation.

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

Very rare: depersonalization, psychotic reactions (with possible self-harm, manifested as suicidal thoughts or suicide attempts) (see section "Special warnings and 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, olfactory disturbances (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 disturbances, speech disorder, amnesia, peripheral neuropathy and polyneuropathy.

Very rare: hyperesthesia.

Eye disorders*

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

Rare: photophobia.

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

Ear and labyrinth disorders*

Rare: tinnitus, hearing disturbances including hearing loss (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., sudden and brief loss of consciousness).

Very rare: non-specific arrhythmia, 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, arterial hypotension.

Very rare: vasculitis.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnea (including asthmatic conditions).

Gastrointestinal disorders

Common: nausea, vomiting, gastrointestinal pain and abdominal pain, diarrhea.

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: elevated transaminase levels.

Uncommon: liver function abnormalities (including increased lactate dehydrogenase (LDH) levels), increased bilirubin, gamma-glutamyl transferase (GGT), alkaline phosphatase.

Rare: jaundice, hepatitis (predominantly 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: pruritus, rash, urticaria, dry skin.

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

Frequency not known: generalized hypersensitivity 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: 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 dysfunction (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: reactions at the infusion site.

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

Rare: edema.

* Cases of very rare, prolonged (several months or years), disabling and potentially irreversible serious adverse reactions affecting multiple organ systems have been reported with quinolone and fluoroquinolone use, 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 paresthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disturbances, anxiety, panic attacks, depression, and suicidal thoughts), memory and concentration difficulties, hearing disturbances, visual disturbances, taste and smell disturbances.

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

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

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

Reporting of suspected adverse reactions

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

Incompatibility.

Maxicin®, concentrate for 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 "Dosage and administration".

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging. Do not freeze.

Keep out of reach and sight of children.

Packaging.

20 ml in a vial; 1 vial in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's location and address of its business activity.

108, Kobzarska Street, Cherkasy, Cherkasy region, 18030, Ukraine. Tel.: (044) 281-01-01.