Maxicin

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

Composition:

Active substance: moxifloxacin;

One tablet contains 454.27 mg of moxifloxacin hydrochloride monohydrate, equivalent to 400 mg of moxifloxacin;

Excipients: microcrystalline cellulose, mannitol (E 421), sodium croscarmellose, magnesium stearate, coating (film-coating mixture Opadry Y-1-7000: polyethylene glycol 400, titanium dioxide (E 171), hypromellose).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, oval-shaped, film-coated tablets with an embossed mark "S9" on one side and no markings on the other.

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

ATC code J01M A14.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Moxifloxacin is an 8-methoxy-fluoroquinolone agent with broad-spectrum bactericidal activity. In vitro, moxifloxacin is active against many Gram-positive and Gram-negative microorganisms.

Moxifloxacin has been shown to be effective against bacteria resistant to β-lactam and macrolide agents.

The bactericidal effect of moxifloxacin is due to inhibition of both types II topoisomerases (DNA gyrase and topoisomerase IV), which are essential for replication, transcription, and repair of bacterial DNA.

The C8-methoxy substituent is believed to enhance activity and reduce the selection of resistant mutants among Gram-positive bacteria compared to the C8-H substituent. The presence of a large dicycloamine substituent at the C7 position prevents active efflux associated with norA or pmrA genes found in some Gram-positive bacteria.

Moxifloxacin exhibits concentration-dependent bactericidal activity. Minimal bactericidal concentrations (MBC) are generally equivalent to minimal inhibitory concentrations (MIC).

Effect on intestinal flora in humans

In two studies involving healthy volunteers, the following changes in intestinal flora were observed after oral administration of moxifloxacin. The numbers of E. coli, Bacillus spp., Enterococcus, and Klebsiella spp., as well as anaerobes Bacteroides vulgatus, Bifidobacterium spp., Eubacterium, and Peptostreptococcus, decreased. An increase in the number of Bacteroides fragilis was observed. The counts of the above-mentioned microorganisms returned to normal ranges within two weeks.

Resistance

Resistance mechanisms that inactivate penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines do not affect the antibacterial efficacy of moxifloxacin. Other resistance mechanisms, such as permeability barriers (common in Pseudomonas aeruginosa) and efflux mechanisms, may influence susceptibility to moxifloxacin.

Development of resistance to moxifloxacin in vitro has been observed as a gradual process involving point mutations in both type II topoisomerases, DNA gyrase and topoisomerase IV. Moxifloxacin is a weak substrate for active efflux mechanisms in Gram-positive microorganisms.

Cross-resistance with other fluoroquinolones is observed. However, because moxifloxacin inhibits both topoisomerase II and IV with similar potency in certain Gram-positive bacteria, these bacteria may be resistant to other quinolones but remain susceptible to moxifloxacin.

Clinical breakpoints

Clinical MIC and disk diffusion breakpoints for moxifloxacin (01.01.2012) according to EUCAST (European Committee on Antimicrobial Susceptibility Testing)

Table 1

* Non-species-related breakpoints were established primarily based on pharmacokinetic/pharmacodynamic data and do not depend on the distribution of MICs of specific species. These data apply only to species for which specific species breakpoints have not been defined and are not used for species where interpretive criteria are subject to determination.

Microbiological susceptibility

The frequency of acquired resistance may vary geographically and over time for specific microorganisms. It is desirable to have access to local information on microbial resistance, especially when treating severe infections.

Expert advice on antibiotic resistance should be sought when local resistance prevalence is so high that the efficacy of a particular medicinal product against at least some infectious agents is in doubt.

Susceptible species

Aerobic Gram-positive microorganisms

Gardnerella vaginalis

Staphylococcus aureus * (methicillin-susceptible)

Streptococcus agalactiae (Group B)

Streptococcus milleri group* (Streptococcus anginosus, Streptococcus constellatus, and Staphylococcus intermedius)

Streptococcus pneumoniae *

Streptococcus pyogenes * (Group A)

Streptococcus viridans group (Streptococcus viridans, Streptococcus mutans, Streptococcus mitis, *Streptoc游戏副本

* Intravenous administration of a single 400 mg dose.

1 10 hours after administration.

2 Free concentration.

3 From 3 hours to 36 hours after dose administration.

4 At the end of infusion.

Metabolism

Moxifloxacin undergoes phase II biotransformation and is excreted via the kidneys as well as in feces/bile, both unchanged and as inactive sulfate (M1) and glucuronide (M2) metabolites. M1 and M2 are the only metabolites relevant in humans; both are microbiologically inactive. In vitro studies and Phase I clinical trials showed no evidence of metabolic pharmacokinetic interactions with other drugs metabolized by cytochrome P450 enzyme system in phase I. There are no signs of oxidative metabolism.

Elimination

The elimination half-life of the drug is approximately 12 hours. The mean total clearance after administration of 400 mg ranges from 179 to 246 ml/min. Renal clearance is approximately 24–53 ml/min, indicating partial tubular reabsorption of the drug by the kidneys. After a 400 mg dose, urinary excretion (approximately 19% unchanged drug, approximately 2.5% as M1, and approximately 14% as M2) and fecal excretion (approximately 25% unchanged drug, approximately 36% as M1, and no excretion as M2) together accounted for approximately 96% of the dose. Concomitant administration of ranitidine and probenecid does not alter the renal clearance of the drug.

Pharmacokinetics in specific patient populations.

Elderly patients and patients with low body weight

Higher plasma concentrations of the drug were observed in healthy volunteers with low body weight (particularly in women) and in healthy elderly volunteers.

Renal impairment

No significant changes in moxifloxacin pharmacokinetics have been observed in patients with impaired renal function (including patients with creatinine clearance > 20 ml/min/1.73 m²). As renal function declines, the concentration of metabolite M2 (glucuronide) increases up to 2.5-fold (in patients with creatinine clearance < 30 ml/min/1.73 m²).

Hepatic impairment

Based on pharmacokinetic data from studies involving patients with hepatic insufficiency (Child-Pugh classes A-C), it is not possible to determine whether there is a difference compared to healthy volunteers. Hepatic impairment was associated with higher plasma exposure of metabolite M1, while exposure to the parent drug was comparable to that in healthy volunteers. There is insufficient clinical experience with moxifloxacin to support its use in patients with hepatic impairment.

Clinical characteristics.

Indications.

Treatment of the bacterial infections listed below, caused by microorganisms sensitive to the drug (see sections «Special precautions», «Adverse reactions», «Pharmacological properties»), in patients aged 18 years and older. Moxifloxacin should be prescribed only when the use of antibacterial agents typically recommended for initial treatment of the infections listed below is inappropriate or when such treatment has been ineffective.

• Acute bacterial sinusitis (diagnosed with high probability).
• Acute exacerbation of chronic bronchitis (diagnosed with high probability).
• Community-acquired pneumonia, excluding community-acquired pneumonia with severe course.
• Moderate to severe pelvic inflammatory diseases (including infectious involvement of the upper genital tract in women, such as salpingitis and endometritis), not associated with tubo-ovarian abscess or pelvic abscesses. The tablet form of Maxicin is not recommended for use as monotherapy in moderate to severe pelvic inflammatory diseases, but may be used in combination with other appropriate antibacterial agents (e.g., cephalosporins) due to increasing resistance of moxifloxacin to Neisseria gonorrhoeae (except for moxifloxacin-resistant strains of Neisseria gonorrhoeae) (see sections «Special precautions», «Pharmacological properties»).

The tablet form of Maxicin is recommended for completing treatment courses in which initial parenteral therapy with Maxicin has been effective and was indicated for the following conditions:

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

The tablet form of Maxicin is not recommended for initial treatment of any skin and soft tissue infections or in cases of severe community-acquired pneumonia.

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

Contraindications.

• Known hypersensitivity to moxifloxacin or to other quinolones or to any excipient of the drug.
• Age under 18 years.
• Pregnancy or breastfeeding (see section «Use during pregnancy or breastfeeding»).
• Patients with a history of tendon disorders related to treatment with quinolones.

During preclinical and clinical studies, administration of moxifloxacin was associated with changes in cardiac electrophysiology, such as QT interval prolongation. Therefore, for safety reasons, the drug is contraindicated in patients with:

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

The drug should not be used concomitantly with other drugs that prolong the QT interval (see section «Interaction with other medicinal products and other types of interactions»).

Due to limited clinical data, the drug is also contraindicated in patients with hepatic impairment (Child-Pugh class C) and in patients with elevated transaminase levels (more than 5 times the upper limit of normal).

Interaction with other medicinal products and other types of interactions.

An additive effect of moxifloxacin and other medicinal products that may cause QT interval prolongation cannot be excluded. This interaction may increase the risk of ventricular arrhythmias, including torsade de pointes. For this reason, 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;
• Some antimicrobial agents (squalamine, sparfloxacin, intravenous erythromycin, pentamidine, antimalarial agents, including halofantrine);
• Some antihistamines (terfenadine, astemizole, mizolastine);
• Others (cisapride, vinca alkaloids IV, bepridil, difemanyl).

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

An interval of approximately 6 hours should be maintained between the administration of products containing divalent or trivalent cations (such as antacids containing magnesium or aluminum, didanosine tablets, sucralfate, and products containing iron or zinc) and moxifloxacin.

Concomitant oral administration of activated charcoal and moxifloxacin at a dose of 400 mg reduces systemic bioavailability of the drug by more than 80% due to inhibition of its absorption. Therefore, concomitant use of these two agents is not recommended (except in cases of overdose; see also section «Overdose»).

After repeated administration of moxifloxacin in healthy volunteers, an increase in digoxin Cmax by approximately 30% at steady state was observed, without affecting AUC (area under the concentration-time curve) or trough levels. Therefore, no precautionary measures are required when co-administering digoxin.

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

In patients receiving oral anticoagulants in combination with antibacterial agents, including fluoroquinolones, macrolides, tetracyclines, cotrimoxazole, and some cephalosporins, numerous cases of increased anticoagulant activity have been reported. Risk factors include infectious diseases (and associated inflammatory processes), age, and the patient's general condition. Due to these circumstances, it is difficult to determine whether infection or treatment causes deviations in INR. As a precautionary measure, more frequent INR monitoring may be advisable. If necessary, appropriate dose adjustment of the oral anticoagulant should be performed.

Substances for which absence of clinically significant interaction with moxifloxacin has been demonstrated: ranitidine, calcium supplements, theophylline, oral contraceptives, cyclosporine, itraconazole, morphine administered parenterally, probenecid. In vitro studies of human cytochrome P450 enzymes confirmed the above. Based on these results, metabolic interaction via cytochrome P450 enzymes is unlikely.

Moxifloxacin absorption is not affected by food intake (including dairy products). Therefore, moxifloxacin can be administered independently of food.

Special precautions for use.

Hypersensitivity and allergic reactions to fluoroquinolones, including moxifloxacin, have been reported after the first dose. Anaphylactic reactions may progress to life-threatening anaphylactic shock even after the first administration. In such cases, the drug should be discontinued immediately and appropriate therapy initiated (e.g., anti-shock treatment).

Prolongation of the QT interval on electrocardiogram (ECG) may occur in some patients receiving moxifloxacin. Analysis of ECG data from clinical trial programs showed that QTc prolongation with moxifloxacin was 6 ms ± 26 ms — 1.4% compared to baseline levels.

Since women have a longer QT interval than men, they may be more susceptible to drugs that prolong the QT interval. Elderly patients may also be more sensitive to QT interval-related effects of the drug.

Patients receiving moxifloxacin should use with caution medicinal products that may lead to decreased potassium levels (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction").

Moxifloxacin should be prescribed with caution to patients with ongoing proarrhythmic conditions (particularly women and elderly patients), such as acute myocardial ischemia or prolonged QT interval, as this may increase the risk of ventricular arrhythmias, including torsade de pointes, and cardiac arrest (see section "Contraindications"). The degree of QT interval prolongation may increase with higher drug concentrations. Therefore, the recommended dose should not be exceeded.

The benefit of treatment with moxifloxacin should be carefully considered, especially in cases of mild infections, according to the information provided in the section "Special precautions for use".

If symptoms of arrhythmia occur during treatment, therapy should be discontinued and an ECG should be performed.

Cases of fulminant hepatitis potentially leading to liver failure (including fatal outcomes) have been reported with moxifloxacin use (see section "Side effects"). Patients should be advised to consult a physician before continuing treatment if symptoms of fulminant hepatitis develop, such as jaundice-related asthenia, rapidly developing fatigue, dark urine, bleeding tendencies, or hepatic encephalopathy.

If symptoms of liver dysfunction occur, liver function tests/investigations should be performed.

Bullous skin reactions, such as Stevens–Johnson syndrome or toxic epidermal necrolysis, have been reported during moxifloxacin use (see section "Side effects"). If skin and/or mucous membrane reactions occur, patients should be advised to seek immediate medical advice before continuing treatment.

Quinolones are known to provoke seizures. Moxifloxacin 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.

Cases of sensory or sensorimotor polyneuropathy, leading to paresthesia, hyposthesia, dysesthesia, or weakness, have been reported in patients receiving quinolones, including moxifloxacin. If neuropathic symptoms such as pain, burning, tingling, numbness, or weakness develop, patients receiving moxifloxacin should inform their physician before continuing treatment (see section "Side effects").

Psychiatric reactions may occur even after the first dose of quinolones, including moxifloxacin. In rare cases, depression or psychotic reactions have led to suicidal thoughts and self-harming behaviors, including suicide attempts (see section "Side effects"). If such reactions occur, moxifloxacin should be discontinued and appropriate measures taken. Moxifloxacin should be prescribed with caution to patients with a history of psychosis or psychiatric disorders.

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

Moxifloxacin should be used with caution in patients with myasthenia gravis due to the possibility of symptom exacerbation.

Tendon inflammation and rupture (particularly of the Achilles tendon), sometimes bilateral, may occur during treatment with quinolones, including moxifloxacin, even within the first 48 hours of therapy. Cases have also been reported months after discontinuation of treatment. During therapy with quinolones, including moxifloxacin, there is an increased risk of tendon inflammation and rupture, particularly in elderly patients and those receiving concomitant corticosteroid therapy.

If symptoms of pain or inflammation occur, patients should discontinue moxifloxacin, rest the affected limb(s), and seek immediate medical advice for appropriate management (e.g., splinting) of the affected tendon (see sections "Contraindications", "Side effects").

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

If visual disturbances or other ocular effects occur, patients should seek immediate ophthalmological evaluation (see sections "Ability to influence reaction rate when driving or operating machinery", "Side effects").

Photosensitivity reactions have been reported with quinolone use. However, studies have shown that moxifloxacin carries a lower risk of photosensitivity. Nevertheless, patients should be advised to avoid both ultraviolet radiation and prolonged and/or intense sunlight exposure during moxifloxacin therapy.

Patients with a family or personal history of glucose-6-phosphate dehydrogenase (G6PD) deficiency may be prone to hemolytic reactions during quinolone therapy. Therefore, moxifloxacin should be used with caution in such patients.

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Oral treatment with Maxicin 400 mg tablets is not recommended for patients with complicated pelvic inflammatory disease (e.g., associated with tubo-ovarian abscess or pelvic abscess) who require intravenous therapy.

Pelvic inflammatory disease may be caused by Neisseria gonorrhoeae resistant to fluoroquinolones. Therefore, empirical use of moxifloxacin in such cases should be combined with another appropriate antibiotic (e.g., a cephalosporin) if Neisseria gonorrhoeae resistance to moxifloxacin cannot be fully excluded.

If there is no clinical improvement after 3 days of treatment, the therapy should be re-evaluated.

Moxifloxacin causes cartilage damage in young animals; therefore, its use in children (under 18 years of age) is contraindicated.

Moxifloxacin is not recommended for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In cases of suspected or confirmed MRSA infection, appropriate antibacterial therapy should be initiated (see section "Pharmacological properties").

The clinical efficacy of intravenous moxifloxacin in the treatment of severe infections associated with burns, fasciitis, and diabetic foot with osteomyelitis has not been established.

Moxifloxacin therapy may interfere with microbiological culture for detection of Mycobacterium spp. due to suppression of microbial growth, potentially leading to false-negative results in samples from patients currently receiving moxifloxacin.

Animal studies did not reveal impairment of fertility (see section "Pharmacological properties").

Hypoglycemia

As with other fluoroquinolones, disturbances in blood glucose levels, including hypoglycemia and hyperglycemia, have been observed with Maxicin. Dysglycemia with Maxicin occurred predominantly in elderly patients with diabetes receiving concomitant therapy with oral hypoglycemic agents (e.g., sulfonylureas) or insulin. Close monitoring of blood glucose levels is recommended in diabetic patients (see section "Side effects").

Use during pregnancy or breastfeeding.

Pregnancy

The safety of moxifloxacin use during pregnancy has not been established. Animal studies indicate reproductive toxicity (see section "Pharmacological properties"). The potential risk in humans is not known.

Due to the risk of fluoroquinolone-induced damage to weight-bearing joints in young animals (based on experimental data) and reversible joint damage described in children treated with certain fluoroquinolones, moxifloxacin should not be administered to pregnant women (see section "Contraindications").

Breastfeeding

Moxifloxacin, like other quinolones, has been shown to cause damage to the joint cartilage in young animals. Preclinical studies indicate that a small amount of moxifloxacin may pass into breast milk. There are no data on the use of the drug in breastfeeding women. Therefore, moxifloxacin is contraindicated during breastfeeding (see section "Contraindications").

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 impair the ability to drive or operate machinery due to central nervous system reactions (e.g., dizziness, acute transient loss of vision, see section "Side effects") or acute transient loss of consciousness (syncope, see section "Side effects"). Patients should be advised to monitor their response to moxifloxacin before driving or operating machinery.

Dosage and Administration

Adults

It is recommended to take 1 tablet (400 mg) of moxifloxacin once daily.

The tablets should be taken without chewing, with sufficient amount of water. The drug can be taken regardless of food intake.

Treatment Duration

The duration of treatment with Maxicin tablets depends on the type of infection and is as follows:

• Exacerbation of chronic bronchitis – 5–10 days;
• Community-acquired pneumonia – 10 days;
• Acute bacterial sinusitis – 7 days;
• Moderate to severe pelvic inflammatory disease – 14 days.

According to clinical studies, the treatment duration with Maxicin tablets was up to 14 days.

Sequential (intravenous followed by oral) therapy

During clinical studies of sequential therapy, most patients switched from intravenous to oral administration of moxifloxacin within 4 days (community-acquired pneumonia) or 6 days (complicated skin and soft tissue infections). The recommended total duration of treatment with Maxicin tablets and infusion solution is 7–14 days for community-acquired pneumonia and 7–21 days for complicated skin and soft tissue infections.

The specified dose (400 mg once daily) and treatment duration for each indication should not be exceeded.

Elderly patients / patients with low body weight

Dose adjustment in elderly patients or patients with low body weight is not required.

Hepatic impairment

Dose adjustment is not required in patients with hepatic impairment (see also section "Special Warnings and Precautions for Use").

Renal impairment

Dose adjustment is not required in patients with mild to moderate renal impairment (including creatinine clearance < 30 mL/min/1.73 m²), as well as in patients undergoing continuous hemodialysis or long-term ambulatory peritoneal dialysis (see section "Pharmacological Properties").

Children

Moxifloxacin is contraindicated in children (under 18 years of age). The efficacy and safety of moxifloxacin in children have not been established (see also section "Contraindications").

Overdose

In case of accidental overdose, no specific measures are recommended. In the event of overdose, treatment should be based on the clinical picture, including symptomatic and supportive therapy, and ECG monitoring due to the potential for QT interval prolongation.

Concomitant administration of activated charcoal with a 400 mg oral dose of moxifloxacin results in more than 80% reduction in systemic bioavailability of the drug. In case of oral overdose, early administration of activated charcoal may be effective in preventing increased systemic exposure to moxifloxacin.

Adverse reactions

Below are the adverse effects reported from all clinical trials involving moxifloxacin 400 mg (oral and sequential therapy) and their frequency. The adverse reactions listed under "frequent" occurred at a rate of less than 3%, except for nausea and diarrhea.

Within each group, adverse events are listed in decreasing order of severity. Frequency is defined as follows: frequent (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10,000, <1/1000), very rare (<1/10,000).

Table 3

In rare cases, the following adverse reactions have been reported after treatment with other fluoroquinolones, which might possibly also occur during moxifloxacin use: hypernatraemia, hypercalcaemia, haemolytic anaemia, rhabdomyolysis, photosensitization reactions (see section "Special precautions").

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

5, 7, or 10 tablets per blister; 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Sanshine Lake Pharma Co., Ltd./Sunshine Lake Pharma Co., Ltd.

Manufacturer's address.

Norsen Industry Road, Norsen Industry Park of Song Shan Lake No.1, Dongguan, Guangdong Province, 523808, China / Northern Industry Road, Northern Industry Park of Song Shan Lake No.1, Dongguan, Guangdong Province, 523808, China.

Marketing Authorisation Holder: LLC "Yuria-Pharm".

Address of the Marketing Authorisation Holder:

10 M. Amosova St., Kyiv, 03680, Ukraine. Tel.: (044) 246-83-83, (044) 275-01-08.