Moflaxia, 400 mg 7 pcs

Pharmacology

Pharmacodynamics

Mechanism of action

Inhibits topoisomerase II (DNA-gyrase) and topoisomerase IV – enzymes necessary for replication, transcription, repair and recombination of bacterial DNA. It disrupts DNA synthesis of the microbial cell and has a bactericidal effect.

The mechanism of action of fluoroquinolones including moxifloxacin is different from that of macrolides, beta-lactams, aminoglycosides or tetracyclines, so microorganisms resistant to these classes of drugs may be sensitive to moxifloxacin. Resistance to fluoroquinolones is primarily due to mutation of topoisomerase II (DNA-gyrase) or topoisomerase IV genes, reduced outer membrane permeability or efflux. Resistance to moxifloxacin in vitro develops slowly and is associated with multistep mutations. Resistance to moxifloxacin in vitro in Gram-positive bacteria occurs with a frequency of 1.8-10-9 to 1-10-11 or less.

Cross-resistance

Cross-resistance between moxifloxacin and other fluoroquinolones has been observed in Gram-negative bacteria. Gram-positive bacteria resistant to other fluoroquinolones may be sensitive to moxifloxacin. Cross-resistance between moxifloxacin and other classes of antimicrobial agents is unknown.

Moxifloxacin is active (both in vitro and by the results of clinical studies on the treatment of several infections) against most strains of the following microorganisms: Aerobic Gram-positive microorganisms – Enterococcus faecalis, Staphylococcus aureus, Streptococcus anginosus, Streptococcus constellatus, Streptococcus pneumoniae (including multi-resistant strains [MDRSP]*), Streptococcus pyogenes; aerobic gram-negative microorganisms – Enterobacter cloacae, Esherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Proteus mirabilis, Yersinia pestis; anaerobic microorganisms – Bacteroides fragilis, Bacteroides thetaiotaomicron, Clostridium perfringens, Peptostreptococcus spp., as well as other microorganisms – Chlamydia pneumoniae, Mycoplasma pneumoniae.

* Strains with multiple resistance to antibiotics (Multi-drug resistant Streptococcus pneumoniae, MDRSP), including strains formerly known as PRSP (Penicillin-resistant S. pneumoniae) and strains resistant to two or more of the following antibiotics: penicillin (at MPC ≥2 µg/mL), second-generation cephalosporins (e.g. cefuroxime), macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

According to in vitro studies, moxifloxacin is active (MPC ≤2 µg/mL) against most (over 90%) strains of the following microorganisms: aerobic gram-positive microorganisms – Staphylococcus epidermidis, Streptococcus agalactiae, Streptococcus viridans; aerobic gram-negative microorganisms – Citrobacter freundii, Klebsiella oxytoca, Legionella pneumophyla; anaerobic microorganisms – Fusobacterium spp., Prevotella spp. Clinical significance of the obtained in vitro data is not defined, safety and efficacy of moxifloxacin in the treatment of infections caused by these pathogens in adequate and well-controlled trials has not been established.

Photosensitivity. Study of skin reaction to ultraviolet light (UVA and UVB) and visible radiation, conducted with 32 healthy volunteers (8 per group) showed that moxifloxacin shows no phototoxicity compared to placebo. Minimum erythematous dose (MED) was determined before and after administration of moxifloxacin (200 or 400 mg once daily) or placebo. The MED measured for both doses of moxifloxacin was not significantly different from placebo.

Pharmacokinetics

Absorption. When administered orally, it is well absorbed from the gastrointestinal tract. Absolute bioavailability is almost 90%. Consumption of food with high content of fat (500 calories) has no effect on absorption of moxifloxacin. Simultaneous consumption of 1 cup of yogurt has no significant effect on the degree and rate of systemic absorption (AUC). In studies with healthy volunteers it was shown that Cmax after a single oral intake of 400 mg of moxifloxacin is (3.1±1) mg/l (n=372). Plasma concentration increases in proportion to dose in the dose range up to 1200 mg (maximum single test dose when taken orally). The plasma T1/2 is (12±1.3) h and equilibrium is reached after at least three days of administration (400 mg daily).

Distribution. Binding to serum proteins is approximately 30-50% and is independent of the substance concentration. Vd is 1.7-2.7 l/kg. Well distributed in the tissues and body fluids, with concentrations in the tissues often exceeding the plasma concentration of the substance. After oral administration or IV administration of 400 mg of moxifloxacin is detected in saliva, the mucous membrane of the nose, bronchi and sinuses, subcutaneous tissues, skeletal muscle and abdominal tissues. High concentrations exceeding the level of moxifloxacin in blood are created in the bronchial mucosa (tissue/plasma concentration ratio (1.7±0.3), alveolar macrophages (21.2±10.0), fluid covering the respiratory epithelium (8.7±6.1) mucosa of the maxillary sinus (2.0±0.3), ethmoidal sinus (2.2±0.6), nasal polyps (2.6±0.6), abdominal tissues (2.7±08), abdominal exudate (1.6±0.7), in the contents of blisters in skin inflammation (0.9±0.2), subcutaneous tissue (0.4±0.6), skeletal muscles (0.4±0.1).

The concentrations were measured 3 h after a single dose of 400 mg (except for measurements in abdominal tissue and exudate, which were taken 2 h after moxifloxacin administration, and in the sinuses, which were taken 2 h after moxifloxacin administration after 5 days of use). The elimination rate of moxifloxacin from tissues usually parallels the elimination rate from plasma.

Metabolism. Approximately 52% of the moxifloxacin dose (oral or IV) is metabolized by conjugation to form two inactive metabolites, sulfate (M1) and glucuronide (M2). M1 is approximately 38% of the dose and is excreted primarily with feces, M2 is 14% of the dose and is excreted only with the urine. Peak plasma concentrations of M2 are approximately 40% of the parent substance concentration, while plasma concentrations of M1 are typically less than 10% of the concentration of moxifloxacin.

Moxifloxacin is metabolized without involvement of the cytochrome P450 system (cytochrome P450 system activity is not affected). In vitro studies with cytochrome P450 isoenzymes show that moxifloxacin does not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP1A2.

Excretion. Approximately 45% of moxifloxacin (oral or IV) is excreted unchanged (of which approximately 20% in the urine, about 25% in the feces). (96±4)% of the oral dose is excreted either unchanged or as known metabolites. Total apparent clearance is (12±2) l/h, renal clearance is (2.6±0.5) l/h.

Dependence of pharmacokinetic parameters on some factors

There were no clinically significant differences in pharmacokinetics of moxifloxacin according to age, gender and race of patients.

Elderly age. No age-related changes in pharmacokinetics were observed in 16 elderly (8 men, 8 women) and 17 young (8 men, 9 women) healthy volunteers after oral administration of moxifloxacin at a dose of 400 mg for 10 days. In 16 healthy male volunteers (8 young; 8 elderly) after a single oral dose of moxifloxacin 200 mg the degree of systemic effect (AUC and Cmax) was not different in young and elderly men, T1/2 was not changed. No dose adjustment based on age is required. In large phase III studies moxifloxacin blood concentrations at the end of infusion in elderly patients after an IV infusion of 400 mg were similar to those observed in younger patients.

Paul. After oral administration of 400 mg of moxifloxacin daily for 10 days, 23 healthy men (19-75 years) and 24 healthy women (19-70 years) had mean AUC and Cmax values 8 and 16% higher in women compared with men. The differences were due to differences in body weight rather than sex.

A study of a single dose of 400 mg was conducted with 18 young men and women. A comparison of the pharmacokinetics of moxifloxacin in this study (9 women and 9 men) showed no difference in AUC or Cmax by sex. No adjustment of the dose of moxifloxacin according to sex is required.

Children. Pharmacokinetics of moxifloxacin in children has not been studied.

Race. Pharmacokinetics of moxifloxacin in equilibrium condition after daily oral intake in 400 mg dose in Japanese men was similar to that in European men and was characterized with values of Cmax 4.1 mcg /ml, AUC24 47 mcg-h /ml and T1/2 14 hours.

Renal insufficiency. No significant changes in pharmacokinetic parameters have been found in mild, moderate and severe renal dysfunction (including terminal stage). No dose adjustment is required in patients with renal impairment, including those on continuous hemodialysis and long-term ambulatory peritoneal dialysis.

Hepatic impairment. Dose adjustment is not recommended in mild, moderate and severe hepatic impairment (Child Pugh grades A, B and C). However, due to metabolic disorders associated with hepatic failure, which may lead to prolongation of the QT interval, moxifloxacin should be used with caution in these patients.

Preclinical toxicology

Carcinogenicity. No long-term animal studies have been conducted to evaluate the carcinogenic effects of moxifloxacin.

Mutagenicity. Mutagenicity or genotoxicity was not observed in a number of in vitro tests, including Ames test (using 4 bacterial strains of TA 98, TA 100, TA 1535, TA 1537), test with hypoxanthine-guanine phosphoribosyltransferase of Chinese hamster ovary cells, as well as in vivo (including micronucleus test in mice). Mutagenic activity was revealed (as for other quinolones) in Ames test using bacterial strain TA 102, probably caused by blockade of DNA-gyrase. It showed clastogenic activity in V-79 test for chromosomal aberrations, but did not cause atypical DNA synthesis in rat hepatocyte culture.

The effect on fertility. No effect of moxifloxacin on fertility was detected in male and female rats when administered orally at doses greater than 500 mg/kg/day (approximately 12-fold greater than MRDH, in terms of body surface area) or intravenously at doses of 45 mg/kg/day (approximately identical to MRDH, in terms of body surface area, mg/m2). Small effects on sperm morphology (head and tail separation) in male rats and on the sexual cycle of female rats were observed when doses of 500 mg/kg/day were administered orally.

Toxicology and/or pharmacology in animals

The quinolones cause arthropathy in young growing animals. In studies in dogs, pups have been shown to develop arthropathy on oral administration of moxifloxacin at doses ≥30 mg/kg/day (approximately 1.5 times the MRDH) for 28 days. Oral administration to mature monkeys and rats at doses of 135 and 500 mg/kg/day, respectively, was not accompanied by manifestations of arthropathy.

Some quinolones have proconvulsant activity that is enhanced when combined with NSAIDs. In studies on mice no increase of acute toxicity or potential toxic effect on CNS (including seizures) were found when applying moxifloxacin orally at a dose of 300 mg/kg together with NSAIDs (diclofenac, ibuprofen, fenbufen).

In studies on dogs it was shown that at plasma concentrations of moxifloxacin, 5 times higher than therapeutic levels in humans, prolongation of QT interval was observed. The main mechanism of QT interval prolongation (data from electrophysiological studies) is the inhibition of rapid activating component of delayed (delayed) rectifying potassium current. Simultaneous infusion of sotalol against the background of moxifloxacin administration in dogs led to a more pronounced prolongation of the QT interval c than when taking moxifloxacin alone at the same dose (30 mg/kg).

There were no signs of local intolerance in dogs when administered moxifloxacin by IV injection. Inflammatory changes affecting the periarterial soft tissues have been observed following an IV/a injection of moxifloxacin, suggesting that IV administration should be avoided.

Clinical Studies

The efficacy of moxifloxacin for systemic use has been evaluated in a number of clinical studies.

Acute bacterial sinusitis

The efficacy of moxifloxacin (400 mg once daily orally for 10 days) in treating patients with acute bacterial sinusitis was evaluated in a double-blind, controlled clinical trial conducted in the United States. The clinical efficacy of moxifloxacin (cure plus improvement) was 90%; the primary efficacy analysis was performed on days 7-21 after therapy.

In addition, studies were conducted to obtain bacteriological data to assess microbiological eradication in adult patients when treated with moxifloxacin (400 mg orally, once daily for 7 days). All patients (n=336) underwent an abdominal puncture. The clinical efficacy rate (eradication) at day 21-37 after treatment was 97% (29/30) for Streptococcus pneumoniae, 83% (15/18) for Moraxella catarrhalis, and 80% (24/30) for Haemophilus influenzae.

The exacerbation of chronic bronchitis

. According to the results of a large-scale randomized double-blind controlled clinical trial conducted in the United States, the clinical efficacy of moxifloxacin in the treatment of exacerbations of chronic bronchitis (oral dose of 400 mg once daily for 5 days) was 89% (222/250 patients), with the initial assessment of results on days 7-17 after therapy. The degree of microbiological eradication was: for Streptococcus pneumoniae and Haemophilus parainfluenzae 100% (16/16), Haemophilus influenzae 89% (33/37), Moraxella catarrhalis 85% (29/34), Staphylococcus aureus 94% (15/16), Klebsiella pneumoniae 90% (18/20).

Efficacy of moxifloxacin (oral dosage of 400 mg once daily) in the treatment of patients with clinically and radiographically documented community-acquired pneumonia was evaluated in a randomized, double-blind, controlled clinical trial conducted in the United States. The clinical efficacy of moxifloxacin was 95% (184/194), with an initial efficacy assessment in most patients on days 14-35 at follow-up visits.

A randomized, double-blind, controlled clinical trial conducted in the United States and Canada evaluated the efficacy of moxifloxacin when administered sequentially, v/v, then orally, in a dose of 400 mg once daily for 7-17 days in patients with a confirmed diagnosis of community-acquired pneumonia. The clinical efficacy of moxifloxacin was 86% (157/182), with primary efficacy analysis in most patients on day 7-30 after the end of therapy.

In an open-label study outside the United States, the clinical efficacy of moxifloxacin was 93% (241/258) on day 5-7 and 84% (216/258) 21-28 days after completion of treatment.

. Combined data of 4 researches suggest that degree of clinical effectiveness of moxifloxacin was 85% against Staphylococcus aureus, 92% against Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, 93% against Chlamydia pneumoniae, 94% against Streptococcus pneumoniae, 96% against Mycoplasma pneumoniae.

Out-of-hospital pneumonia caused by strains of Streptococcus pneumoniae with multiple resistance to antibiotics (see “Indications”). The clinical and bacteriological efficacy of moxifloxacin was 95% (35/37).

Uncomplicated infections of the skin and its appendages.

According to the results of a randomized double-blind controlled clinical trial conducted in the USA, in the treatment of skin infections (uncomplicated abscesses – 30%, furuncles – 8%, cellulitis – 16%, impetigo – 20%, other skin infections – 26%) the effectiveness of moxifloxacin (oral administration in a dose of 400 mg once daily for 7 days) was 89% (108/122).

Complicated infections of the skin and its appendages

The efficacy of moxifloxacin was evaluated in two randomized controlled clinical trials with the active drug. In a double-blind trial conducted primarily in North America, the clinical efficacy of moxifloxacin (sequential IV followed by oral administration at a dose of 400 mg once daily for 7-14 days) was 77.2% (125/162). In a second open international study, the clinical efficacy of moxifloxacin in a dose of 400 mg once daily for 7-21 days was 80.6% (254/315). Treatment success rates varied according to the type of diagnosis, ranging from 61% in patients with infected ulcers to 90% in patients with complicated rust inflammation.

The clinical efficacy of moxifloxacin was 82.2% (106/129) against Staphylococcus aureus (methicillin-sensitive strains), 81.6% (31/38) against Esherichia coli, 91.7% (11/12) against Klebsiella pneumoniae, 81.8% (9/11) against Enterobacter cloacae.

Complicated intra-abdominal infections

The efficacy of moxifloxacin has been evaluated in two randomized controlled clinical trials with the active drug. A double-blind study conducted in North America in the treatment of patients with intraabdominal infections such as peritonitis, abscess, appendicitis with perforation, and intestinal perforation reported 79.8% (146/183) effectiveness of moxifloxacin (sequential IV followed by oral administration at a dose of 400 mg once daily for 5-14 days). In a second open-label international study, the efficacy of moxifloxacin (400 mg once daily for 5-14 days c) was 80.9% (199/246).

Plague

The efficacy studies of moxifloxacin could not be conducted in people with pneumonic plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an animal efficacy study and supportive pharmacokinetic data in adult humans and animals.

A randomized, blind, placebo-controlled study was conducted in an animal model of African green monkey pneumonic plague. Twenty monkeys (10 males and 10 females) were exposed to a mean inhalation dose (±standard deviation) of (100±50) LD50 (range 92 to 127 LD50) of Yersinia pestis aerosol (strain CO92). The MPC of moxifloxacin for the Y. pestis strain used in this study was 0.06 µg/mL.

The development of a persistent fever of at least 4 h was used as a trigger for initiating a 10-day administration of either moxifloxacin or placebo. All of the animals studied had fever and bacteremia with Y. pestis before the start of follow-up. Ten of 10 (100%) animals receiving placebo died of the disease between 83 and 139 h (115±19) after infection. Ten of 10 (100%) animals receiving moxifloxacin survived for 30 days after study completion. Compared with the placebo group, mortality was significantly lower in the moxifloxacin group (survival difference: 100% with two-sided 95% CI (66.3%, 100%), p< 0.0001 value).

The mean plasma concentrations of moxifloxacin associated with a statistically significant improvement in survival compared with placebo, in an African green monkey model of pneumonic plague, achieved or exceeded those in adult humans when administered at the recommended oral and intravenous regimens. The mean (±standard deviation) plasma Cmax and total plasma exposure (AUC) in adults treated with 400 mg v/v were (3.9±0.9) µg/ml and (39.3±8.6) µg-h/ml, respectively. The mean (±standard deviation) plasma Cmax and AUC0-24 in monkeys after a one-day simulated dosing regimen simulating the achievement of AUC0-24 in humans at the 400 mg dose were (4.4±1.5) mcg/mL and (22±8) mcg-h/mL, respectively.

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to moxifloxacin:

acute sinusitis;

exacerbation of chronic bronchitis;

uncomplicated infections of the skin and subcutaneous structures;

community-acquired pneumonia, including community-acquired pneumonia, the causative agents of which are strains of microorganisms with multiple antibiotic resistance*;

complicated infections of the skin and subcutaneous structures (including infected diabetic foot);

complicated intra-abdominal infections, including polymicrobial infections, incl. intraperitoneal abscesses;

uncomplicated inflammatory diseases of the pelvic organs (including salpingitis and endometritis).

*Streptococcus pneumoniae with multiple antibiotic resistance includes strains resistant to penicillin and strains resistant to two or more antibiotics from groups such as penicillins (with MIC ≥2 μg/ml), second-generation cephalosporins (cefuroxime), macrolides, tetracyclines and trimethoprim/sulfamethoxazole. Current official guidelines on the use of antibacterial agents must be taken into account.

Pharmacological effect

Pharmacology

Pharmacodynamics

Mechanism of action

Inhibits topoisomerase II (DNA gyrase) and topoisomerase IV, enzymes necessary for replication, transcription, repair and recombination of bacterial DNA. It disrupts microbial cell DNA synthesis and has a bactericidal effect.

Mechanism of resistance

The mechanism of action of fluoroquinolones, including moxifloxacin, differs from that of macrolides, beta-lactams, aminoglycosides or tetracyclines, therefore microorganisms resistant to these classes of drugs may be sensitive to moxifloxacin. Resistance to fluoroquinolones occurs primarily due to mutation of the topoisomerase II (DNA gyrase) or topoisomerase IV genes, decreased outer membrane permeability or efflux. Resistance to moxifloxacin in vitro develops slowly and is associated with multistep mutations. Resistance to moxifloxacin in vitro in gram-positive bacteria occurs with a frequency of 1.8·10−9 to 1·10−11 or less.

Cross resistance

Cross-resistance between moxifloxacin and other fluoroquinolones has been observed in Gram-negative bacteria. Gram-positive bacteria resistant to other fluoroquinolones may be sensitive to moxifloxacin. Cross-resistance between moxifloxacin and other classes of antimicrobial agents is unknown.

Moxifloxacin is active (both in vitro and according to the results of clinical studies in the treatment of a number of infections) against most strains of the following microorganisms: aerobic gram-positive microorganisms – Enterococcus faecalis, Staphylococcus aureus, Streptococcus anginosus, Streptococcus constellatus, Streptococcus pneumoniae (including multidrug-resistant strains [MDRSP]*), Streptococcus pyogenes; aerobic gram-negative microorganisms – Enterobacter cloacae, Esherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Proteus mirabilis, Yersinia pestis; anaerobic microorganisms – Bacteroides fragilis, Bacteroides thetaiotaomicron, Clostridium perfringens, Peptostreptococcus spp., as well as other microorganisms – Chlamydia pneumoniae, Mycoplasma pneumoniae.

*Multi-drug resistant Streptococcus pneumoniae (MDRSP), including strains formerly known as PRSP (Penicillin-resistant S. pneumoniae) and strains resistant to two or more of the following antibiotics: penicillin (with MIC ≥2 μg/ml), second generation cephalosporins (e.g. cefuroxime), macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

According to in vitro studies, moxifloxacin is active (MIC ≤2 μg/ml) against the majority (more than 90%) strains of the following microorganisms: aerobic gram-positive microorganisms – Staphylococcus epidermidis, Streptococcus agalactiae, Streptococcus viridans; aerobic gram-negative microorganisms – Citrobacter freundii, Klebsiella oxytoca, Legionella pneumophyla; anaerobic microorganisms – Fusobacterium spp., Prevotella spp. The clinical significance of the in vitro data has not been determined, and the safety and effectiveness of moxifloxacin in the treatment of infections caused by these pathogens has not been established in adequate and well-controlled trials.

Photosensitivity. A skin response study to ultraviolet (UVA and UVB) and visible radiation conducted in 32 healthy volunteers (8 per group) showed that moxifloxacin was not phototoxic compared to placebo. The minimum erythematous dose (MED) was determined before and after the use of moxifloxacin (200 or 400 mg once daily) or placebo. MED measured for both doses of moxifloxacin was not significantly different from placebo.

Pharmacokinetics

Absorption. When taken orally, it is well absorbed from the gastrointestinal tract. Absolute bioavailability is almost 90%. A high-fat meal (500 calories) does not affect the absorption of moxifloxacin. Concomitant consumption of 1 cup of yogurt does not significantly affect the extent or rate of systemic absorption (AUC). Studies in healthy volunteers showed that Cmax after a single oral dose of 400 mg of moxifloxacin was (3.1 ± 1) mg/l (n = 372). Plasma concentrations increase dose proportionally over a dose range up to 1200 mg (maximum single oral dose tested). T1/2 from plasma is (12±1.3) hours, the equilibrium state is achieved after at least three days of administration (400 mg daily).

Distribution. Serum protein binding is approximately 30–50% and is independent of the concentration of the substance. Vd – 1.7–2.7 l/kg. It is well distributed throughout the tissues and body fluids, with concentrations in tissues often exceeding the concentration of the substance in plasma. After oral or intravenous administration at a dose of 400 mg, moxifloxacin is detected in saliva, the mucous membrane of the nose, bronchi and sinuses, in subcutaneous tissues, skeletal muscles and tissues of the abdominal organs. High concentrations exceeding the level of moxifloxacin in the blood are created in the bronchial mucosa (tissue/plasma concentration ratio (1.7±0.3), alveolar macrophages (21.2±10.0), fluid covering the respiratory epithelium (8.7±6.1), mucous membrane of the maxillary sinus (2.0±0.3), ethmoid sinus (2.2±0.6), nasal polyps (2.6±0.6), abdominal tissues (2.7±0.8), abdominal exudate (1.6±0.7), in the contents of blisters during skin inflammation (0.9±0.2), subcutaneous tissue (0.4±0.6), skeletal muscles (0.4±0.1).

Concentrations were measured 3 hours after a single 400 mg dose (except for measurements in abdominal tissue and exudate, which were taken 2 hours after moxifloxacin, and in the sinuses, which were taken 2 hours after moxifloxacin after 5 days of use). The rate of elimination of moxifloxacin from tissues generally parallels the rate of elimination from plasma.

Metabolism. Approximately 52% of a dose of moxifloxacin (oral or IV) is metabolized by conjugation to form two inactive metabolites, sulfate (M1) and glucuronide (M2). M1 makes up approximately 38% of the dose and is excreted mainly in feces, M2 – 14% of the dose, excreted only in urine. Peak plasma concentrations of M2 are approximately 40% of the parent concentration, while plasma concentrations of M1 are typically less than 10% of moxifloxacin.

Moxifloxacin is metabolized without the participation of the cytochrome P450 system (it does not affect the activity of the cytochrome P450 system). In vitro studies with cytochrome P450 isoenzymes indicate that moxifloxacin does not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP1A2.

Excretion. Approximately 45% of moxifloxacin (oral or IV) is excreted unchanged (of which approximately 20% in urine, about 25% in feces). (96±4)% of the oral dose is excreted either unchanged or in the form of known metabolites. The total apparent clearance is (12±2) l/h, renal clearance is (2.6±0.5) l/h.

Dependence of pharmacokinetic parameters on certain factors

There were no clinically significant differences in the pharmacokinetics of moxifloxacin depending on the age, gender and race of patients.

Old age. After oral administration of moxifloxacin at a dose of 400 mg for 10 days in 16 elderly (8 men, 8 women) and 17 young (8 men, 9 women) healthy volunteers, no changes in pharmacokinetics were observed depending on age. In 16 healthy male volunteers (8 young; 8 elderly), after a single oral dose of moxifloxacin at a dose of 200 mg, the degree of systemic exposure (AUC and Cmax) did not differ between young and elderly men, T1/2 did not change. No dose adjustment is required depending on age. In large phase III studies, moxifloxacin blood concentrations at the end of infusion in elderly patients following a 400 mg IV infusion were similar to those observed in younger patients.

Floor. Following oral administration of 400 mg moxifloxacin daily for 10 days to 23 healthy men (19–75 years) and 24 healthy women (19–70 years), mean AUC and Cmax values ​​were 8% and 16% higher in women compared with men. The differences are due to differences in body weight rather than gender.

A single dose 400 mg study was conducted in 18 young men and women. Comparison of the pharmacokinetics of moxifloxacin in this study (9 women and 9 men) showed no differences in AUC or Cmax by gender. No dosage adjustment of moxifloxacin is required based on gender.

Children. The pharmacokinetics of moxifloxacin in children has not been studied.

Race. The pharmacokinetics of moxifloxacin at steady state after daily oral administration at a dose of 400 mg in Japanese men was similar to that in Caucasians and was characterized by Cmax values ​​of 4.1 mcg/ml, AUC24 of 47 mcg h/ml and T1/2 of 14 hours.

Kidney failure. No significant changes in pharmacokinetic parameters have been established in cases of mild, moderate and severe renal dysfunction (including the terminal stage). In patients with renal failure, including those on continuous hemodialysis and long-term ambulatory peritoneal dialysis, no dose adjustment is required.

Liver failure. Dose adjustment is not recommended for mild, moderate and severe liver dysfunction (Child Pugh Classes A, B and C). However, due to metabolic abnormalities associated with hepatic impairment, which may lead to QT prolongation, moxifloxacin should be used with caution in these patients.

Preclinical toxicology

Carcinogenicity. No long-term animal studies have been conducted to evaluate the carcinogenic effects of moxifloxacin.

Mutagenicity. Did not show mutagenicity or genotoxicity in a number of in vitro tests, incl. in the Ames test (using 4 bacterial strains TA 98, TA 100, TA 1535, TA 1537), in the test with hypoxanthine-guanine phosphoribosyltransferase of Chinese hamster ovary cells, as well as in vivo (including in the micronucleus test in mice). Mutagenic activity was detected (as for other quinolones) in the Ames test using the bacterial strain TA 102, possibly due to blockade of DNA gyrase. It showed clastogenic activity in the V-79 test for chromosomal aberrations, but did not cause atypical DNA synthesis in cultured rat hepatocytes.

Effect on fertility. There was no effect of moxifloxacin on fertility in male and female rats when administered orally at doses above 500 mg/kg/day (approximately 12 times the MRFC, based on body surface area) or intravenously administered at doses of 45 mg/kg/day (approximately identical to the MRDC, based on body surface, mg/m2). When administered orally at doses of 500 mg/kg/day, there was little effect on sperm morphology (head-tail separation) in male rats and on the sexual cycle of female rats.

Toxicology and/or pharmacology in animals

Quinolones cause arthropathy in young growing animals. In canine studies, puppies have been shown to develop arthropathy when given oral moxifloxacin at doses ≥30 mg/kg/day (approximately 1.5 times the MRDI) for 28 days. Oral administration of doses of 135 and 500 mg/kg/day to mature monkeys and rats, respectively, was not accompanied by manifestations of arthropathy.

Some quinolones have proconvulsant activity, which is enhanced when used together with NSAIDs. A study in mice did not detect an increase in acute toxicity or potential toxic effects on the central nervous system (including the occurrence of seizures) when moxifloxacin was administered orally at a dose of 300 mg/kg together with the administration of NSAIDs (diclofenac, ibuprofen, fenbufen).

Studies in dogs have shown that at plasma concentrations of moxifloxacin 5 times the therapeutic level in humans, prolongation of the QT interval is observed. The main mechanism for prolongation of the QT interval (data from electrophysiological studies) is inhibition of the fast activating component of the delayed (slow) rectifying potassium current. Concomitant infusion of sotalol while taking moxifloxacin in dogs resulted in a more pronounced prolongation of the QTc interval than when taking moxifloxacin alone at the same dose (30 mg/kg).

There were no signs of local intolerance in dogs with intravenous administration of moxifloxacin. Inflammatory changes involving periarterial soft tissue have been observed following intravenous moxifloxacin injection, suggesting that intravenous administration should be avoided.

Clinical studies

The effectiveness of moxifloxacin for systemic use has been evaluated in a number of clinical studies.

Acute bacterial sinusitis

The effectiveness of moxifloxacin (400 mg once daily orally for 10 days) in the treatment of patients with acute bacterial sinusitis was assessed in a double-blind, controlled clinical trial conducted in the United States. The clinical efficacy of moxifloxacin (cure plus improvement) was 90%, the primary analysis of efficacy was carried out on days 7–21 after therapy.

In addition, studies were conducted to obtain bacteriological data to evaluate microbiological eradication in adult patients treated with moxifloxacin (400 mg orally, once daily for 7 days). All patients (n=336) underwent abdominal puncture. The rate of clinical efficacy (eradication) on days 21–37 after treatment was 97% (29/30) for Streptococcus pneumoniae, 83% (15/18) for Moraxella catarrhalis, 80% (24/30) for Haemophilus influenzae.

Exacerbation of chronic bronchitis

According to the results of a large-scale randomized, double-blind, controlled clinical trial conducted in the United States, the clinical efficacy of moxifloxacin in the treatment of exacerbations of chronic bronchitis (orally at a dose of 400 mg once daily for 5 days) was 89% (222/250 patients), with the primary outcome assessment carried out on days 7–17 after therapy. The degree of microbiological eradication was: for Streptococcus pneumoniae and Haemophilus parainfluenzae 100% (16/16), Haemophilus influenzae 89% (33/37), Moraxella catarrhalis 85% (29/34), Staphylococcus aureus 94% (15/16), Klebsiella pneumoniae 90% (18/20).

Community-acquired pneumonia

The effectiveness of moxifloxacin (400 mg orally once daily) in the treatment of patients with clinically and radiologically documented community-acquired pneumonia was assessed in a randomized, double-blind, controlled clinical trial conducted in the United States. Clinical efficacy of moxifloxacin was 95% (184/194), with initial efficacy assessments in most patients occurring at follow-up visits on days 14–35.

A randomized, double-blind, controlled clinical trial conducted in the United States and Canada assessed the effectiveness of moxifloxacin when administered sequentially – intravenously, then orally, at a dose of 400 mg once a day for 7-17 days in patients with a confirmed diagnosis of community-acquired pneumonia. The clinical efficacy of moxifloxacin was 86% (157/182), and the primary efficacy analysis in most patients was carried out on days 7–30 after the end of therapy.

In an open-label study outside the United States, the clinical efficacy of moxifloxacin was 93% (241/258) at days 5–7 and 84% (216/258) at 21–28 days after treatment.

Pooled data from 4 studies indicate that the clinical effectiveness of moxifloxacin is 85% against Staphylococcus aureus, 92% against Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, 93% against Chlamydia pneumoniae, 94% against Streptococcus pneumoniae, 96% against Mycoplasma pneumoniae.

Community-acquired pneumonia caused by strains of Streptococcus pneumoniae with multiple resistance to antibiotics (see “Indications”). The clinical and bacteriological effectiveness of moxifloxacin was 95% (35/37).

Uncomplicated infectious diseases of the skin and its appendages.

According to the results of a randomized, double-blind, controlled clinical trial conducted in the USA, in the treatment of skin infections (uncomplicated abscesses – 30%, boils – 8%, cellulitis – 16%, impetigo – 20%, other skin infections – 26%), the effectiveness of moxifloxacin (taken orally at a dose of 400 mg 1 time per day for 7 days) was 89% (108/122).

Complicated infectious diseases of the skin and its appendages

The effectiveness of moxifloxacin was assessed in two randomized controlled clinical trials with the active drug. In a double-blind trial conducted primarily in North America, the clinical efficacy of moxifloxacin (sequential IV followed by oral 400 mg once daily for 7 to 14 days) was 77.2% (125/162). In a second open-label international study, using moxifloxacin at a dose of 400 mg once daily for 7–21 days, clinical efficacy was 80.6% (254/315). Treatment success rates varied depending on the type of diagnosis, from 61% in patients with infected ulcers to 90% in patients with complicated erysipelas.

The clinical efficacy of moxifloxacin was 82.2% (106/129) against Staphylococcus aureus (methicillin-sensitive strains), 81.6% (31/38) against Esherichia coli, 91.7% (11/12) against Klebsiella pneumoniae, 81.8% (9/11) against Enterobacter cloacae.

Complicated intra-abdominal infections

The effectiveness of moxifloxacin was assessed in two randomized controlled clinical trials with the active drug. In a double-blind study conducted in North America, in the treatment of patients with intra-abdominal infections such as peritonitis, abscess, appendicitis with perforation, intestinal perforation, the effectiveness of moxifloxacin (sequential IV followed by oral administration at a dose of 400 mg once daily for 5-14 days) was 79.8% (146/183). In a second open-label international study, the efficacy of moxifloxacin (400 mg once daily for 5–14 days) was 80.9% (199/246).

Plague

Studies of the effectiveness of moxifloxacin could not be conducted in people with pneumonic plague for ethical and feasibility reasons. Therefore, the approval of this indication was based on an efficacy study performed in animals and supporting pharmacokinetic data in adult humans and animals.

A randomized, blinded, placebo-controlled study was conducted in the African green monkey animal model of pneumonic plague. Twenty monkeys (10 males and 10 females) were exposed to a mean inhalation dose (±standard deviation) of 100±50 LD50 (range 92 to 127 LD50) of Yersinia pestis (strain CO92) aerosol. The MIC of moxifloxacin for the Y. pestis strain used in this study was 0.06 μg/ml.

The development of persistent fever lasting at least 4 hours was used as a trigger to initiate 10 days of either moxifloxacin or placebo. All study animals had fever and Y. pestis bacteremia before the start of observation. Ten of 10 (100%) placebo-treated animals died of disease between 83 and 139 h (115 ± 19) h postchallenge. Ten of 10 (100%) animals treated with moxifloxacin survived the 30-day period after completion of the study. Compared with the placebo group, mortality in the moxifloxacin group was significantly lower (difference in survival: 100% with two-sided 95% CI (66.3%, 100%), p value < 0.0001).

The mean plasma concentrations of moxifloxacin associated with a statistically significant improvement in survival compared with placebo in the African green monkey model of pneumonic plague were equal to or greater than those in adults when administered in recommended oral and intravenous dosing regimens. The mean (±standard deviation) plasma Cmax and total plasma exposure (AUC) in adults receiving 400 mg IV were (3.9±0.9) mcg/mL and (39.3±8.6) mcg·h/mL, respectively. The mean (±standard deviation) plasma Cmax and AUC0-24 in monkeys after a one-day simulation of a dosing regimen simulating the achievement of AUC0-24 in humans at a dose of 400 mg were (4.4 ± 1.5) μg/ml and (22 ± 8) μg·h/ml, respectively.

Special instructions

In some cases, after the first use of the drug, hypersensitivity and allergic reactions may develop, which should be reported to your doctor immediately. Very rarely, even after the first use of the drug, anaphylactic reactions can progress to life-threatening anaphylactic shock. In these cases, treatment with Moflaxia should be stopped and the necessary therapeutic measures (including anti-shock) should be started immediately.

When using the drug Moflaxia, some patients may experience prolongation of the QT interval. Moflaxia should be used with caution in women and elderly patients. Because women have a longer QT interval than men, they may be more sensitive to drugs that prolong the QT interval. Elderly patients are also more susceptible to drugs that affect the QT interval.

Prolongation of the QT interval is associated with an increased risk of ventricular arrhythmias, including polymorphic ventricular tachycardia.

The degree of QT interval prolongation may increase with increasing plasma concentrations of moxifloxacin, so the recommended dose should not be exceeded. However, in patients with pneumonia, no correlation was observed between moxifloxacin plasma concentrations and QT interval prolongation. None of the 9,000 patients treated with moxifloxacin experienced cardiovascular complications or deaths associated with QT prolongation. When using the drug Moflaxia, the risk of developing ventricular arrhythmias may increase in patients with conditions predisposing to arrhythmias.

In this regard, the drug Moflaxia is contraindicated in case of changes in electrophysiological parameters of the heart, expressed in prolongation of the QT interval (congenital or acquired documented prolongation of the QT interval); electrolyte disturbances, especially with uncorrected hypokalemia; clinically significant bradycardia; clinically significant heart failure with reduced left ventricular ejection fraction; a history of rhythm disturbances accompanied by clinical symptoms; in combination with other drugs that prolong the QT interval (see “Interactions”).

Moflaxia should be used with caution:

– in patients with potentially proarrhythmic conditions such as acute myocardial ischemia and cardiac arrest;

– in patients with liver cirrhosis (since in this category of patients the risk of developing a prolongation of the QT interval cannot be excluded).

Cases of fulminant hepatitis, potentially leading to liver failure (including fatal cases), have been reported while taking moxifloxacin (see “Side effects”). The patient should be informed that if symptoms of liver failure occur, it is necessary to consult a doctor before continuing treatment with Moflaxia.

Bullous skin lesions such as Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported while taking moxifloxacin (see Side Effects). The patient should be informed that if symptoms of skin or mucous membrane lesions occur, it is necessary to consult a doctor before continuing treatment with Moflaxia.

The use of quinolone drugs is associated with a possible risk of developing seizures. Moflaxia should be used with caution in patients with diseases of the central nervous system and with disorders of the central nervous system that predispose to seizures or reduce the threshold for seizure activity.

The use of broad-spectrum antibacterial drugs, including Moflaxia, is associated with a risk of developing pseudomembranous colitis. This diagnosis should be considered in patients who develop severe diarrhea during treatment with Moflaxia. In this case, appropriate therapy should be prescribed immediately. Drugs that inhibit intestinal motility are contraindicated in the development of severe diarrhea.

Moflaxia should be used with caution in patients with myasthenia gravis due to a possible exacerbation of the disease.

During therapy with quinolones, incl. moxifloxacin, tendonitis and tendon rupture may develop, especially in elderly patients and patients receiving corticosteroids. Cases have been described that occurred within several months after completion of treatment. At the first symptoms (pain or inflammation at the site of injury), use of the drug Moflaxia should be stopped and the affected limb should be unloaded.

When using quinolones, photosensitivity reactions are observed. However, during preclinical and clinical studies, as well as when using moxifloxacin in clinical practice, no photosensitivity reactions were observed. However, patients receiving Moflaxia should avoid exposure to direct sunlight and UV radiation.

The use of Moflaxia in the form of oral tablets is not recommended in patients with complicated inflammatory diseases of the pelvic organs (for example, associated with tubo-ovarian or pelvic abscesses).

The use of moxifloxacin is not recommended for the treatment of infections caused by strains of Staphylococcus aureus resistant to methicillin. In cases of suspected or confirmed infections caused by MRSA, appropriate antibacterial drugs should be used for treatment (see “Pharmacodynamics”). The ability of moxifloxacin to inhibit the growth of mycobacteria may cause in vitro interaction between moxifloxacin and the test for Mycobacterium spp., resulting in false negative results when analyzing samples from patients who are being treated with Moflaxia during this period.

In patients treated with quinolones, including moxifloxacin, cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia or weakness have been described. Patients being treated with Moflaxia should be advised to seek immediate medical attention before continuing treatment if symptoms of neuropathy, including pain, burning, tingling, numbness or weakness, occur (see Side Effects). Psychiatric reactions may occur even after the first use of fluoroquinolones, including moxifloxacin. In very rare cases, depression or psychotic reactions progress to the occurrence of suicidal thoughts and behavior with a tendency to self-harm, including suicide attempts (see “Side effects”). If patients develop such reactions, Moflaxia should be discontinued and the necessary measures taken. Caution must be exercised when using the drug Moflaxia in patients with a history of psychosis and mental illness.

Due to the widespread and increasing incidence of infections caused by fluoroquinolone-resistant Neisseria gonorrhoeae, patients with pelvic inflammatory disease should not be treated with moxifloxacin monotherapy unless the presence of fluoroquinolone-resistant N. gonorrhoeae is excluded. If the presence of fluoroquinolone-resistant N. gonorrhoeae cannot be excluded, consideration should be given to supplementing empiric moxifloxacin therapy with an appropriate antibiotic that is active against N. gonorrhoeae (eg, a cephalosporin).

Dysglycemia

As with other fluoroquinolones, changes in blood glucose concentrations, including hypo- and hyperglycemia, were observed when using Moflaxia. During therapy with moxifloxacin, dysglycemia occurred predominantly in elderly patients with diabetes mellitus receiving concomitant therapy with oral hypoglycemic drugs (for example, sulfonylureas) or insulin. When conducting treatment in patients with diabetes mellitus, careful monitoring of blood glucose concentrations is recommended (see “Side Effects”).

Impact on the ability to perform potentially hazardous activities that require special attention and speed of reactions (for example, driving, working with moving mechanisms). Fluoroquinolones, including moxifloxacin, may impair the ability of patients to drive a car and engage in other potentially hazardous activities that require increased attention and speed of psychomotor reactions due to their effects on the central nervous system and visual impairment.

Active ingredient

Moxifloxacin

Composition

1 film-coated tablet contains:

Core:

active ingredient:

moxifloxacin hydrochloride 454.75 mg, equivalent to moxifloxacin 400.00 mg;

excipients:

microcrystalline cellulose 186.05 mg,

croscarmellose sodium 32.00 mg,

magnesium stearate 6.00 mg;

Film casing:

hypromellose 12.60 mg, macrogol-4000 4.20 mg, titanium dioxide (E171) 3.78 mg, iron dye red oxide (E172) 0.42 mg.

Pregnancy

The safety of moxifloxacin during pregnancy has not been established and its use is therefore contraindicated. Cases of reversible joint damage have been described in children receiving some quinolones, but this effect has not been reported in the fetus (when used by the mother during pregnancy).

Reproductive toxicity has been demonstrated in animal studies. The potential risk to humans is unknown.

Like other quinolones, moxifloxacin causes cartilage damage in large joints in premature animals.

Preclinical studies have shown that small amounts of moxifloxacin are excreted into breast milk. There are no data on its use in women during lactation. Therefore, the use of moxifloxacin during breastfeeding is contraindicated.

Contraindications

– hypersensitivity to moxifloxacin, other quinolones or any other component of the drug;

– a history of tendon pathology that developed as a result of treatment with quinolone antibiotics;

– patients of the following categories: congenital or acquired documented prolongation of the QT interval, electrolyte disturbances, especially uncorrected hypokalemia, clinically significant bradycardia, clinically significant chronic heart failure with reduced left ventricular ejection fraction, a history of rhythm disturbances accompanied by clinical symptoms (in preclinical and clinical studies, after the administration of moxifloxacin, changes in electrophysiological parameters of the heart were observed, expressed in prolongation of the QT interval);

– use with other drugs that prolong the QT interval;

– patients with impaired liver function (class C according to the Child-Pugh classification) and patients with increased transaminase activity more than 5 times higher than ULN (due to limited clinical data);

– pregnancy;

– breastfeeding period;

– age up to 18 years.

With caution: diseases of the central nervous system (including suspected central nervous system involvement), predisposing to the occurrence of seizures and lowering the threshold of seizure activity, patients with a history of psychosis and/or other mental illnesses, patients with potentially proarrhythmic conditions (especially in women and elderly patients), such as acute myocardial ischemia and cardiac arrest, patients with cirrhosis of the liver; myasthenia gravis; simultaneous use with drugs that reduce potassium levels; patients with a genetic predisposition or actual presence of glucose-6-phosphate dehydrogenase deficiency.

Side Effects

Data on adverse reactions reported with moxifloxacin 400 mg (oral, step-down therapy (IV moxifloxacin followed by oral administration), and IV alone) are derived from clinical studies and post-marketing reports (shown in italics). Adverse reactions listed in the “common” group occurred with an incidence of less than 3%, with the exception of nausea and diarrhea.

The frequency was classified as follows: often (from ?1/100 to <1/10); uncommon (from?1/1000 to <1/100); rare (from?1/10000 to <1/1000); very rare (<1/10000).

In each group, undesirable effects are listed in descending order of importance.

Table 3

System organ classes and conditions (MedDRA)
Incidence of adverse reactions
Often
Uncommon
Rarely
Very rarely
Infectious and parasitic diseases
Fungal superinfections
From the blood and lymphatic system
Anemia, leukopenia, neutropenia, thrombocytopenia, thrombocythemia, prolonged PT/increased INR
Changes in thromboplastin concentration in blood plasma
Increased prothrombin concentration/decrease INR
From the immune system
Allergic reactions, skin itching, skin rash, urticaria, eosinophilia
Anaphylactic/anaphylactoid reactions, angioedema (including potentially life-threatening laryngeal edema)
Anaphylactic/anaphylactoid shock (including potentially life-threatening)
Metabolism and nutrition
Hyperlipidemia
Hyperglycemia, hyperuricemia
Hypoglycemia
Mental disorders
Anxiety, psychomotor hyperactivity/agitation
Emotional lability, depression (in very rare cases, self-harming behavior such as suicidal thoughts or suicide attempts may occur), hallucinations
Depersonalization, psychotic reactions (potentially manifesting in behavior with a tendency to self-harm, such as suicidal ideation or suicide attempts)
From the nervous system
Headache, dizziness
Paresthesia/dysesthesia, taste disturbances (including in very rare cases ageusia), confusion and disorientation, sleep disturbances, tremor, vertigo, drowsiness
Hypoesthesia, disturbances of the sense of smell (including anosmia), atypical dreams, incoordination (including gait disturbance due to dizziness or vertigo, in very rare cases leading to injury due to a fall, especially in elderly patients), seizures with various clinical manifestations (including grand mal seizures), attention disorders, speech disorders, amnesia, peripheral neuropathy and polyneuropathy
Hyperesthesia
From the side of the organ of vision
Visual impairment (especially with reactions from the central nervous system)
Transient loss of vision (especially against the background of reactions from the central nervous system)
Hearing and labyrinth disorders
Tinnitus, hearing loss, including deafness (usually reversible)
From the heart and blood vessels
Prolongation of the QT interval in patients with concomitant hypokalemia
QT prolongation, palpitations, tachycardia, vasodilation
Ventricular tachyarrhythmias, syncope, increased/decreased blood pressure
Nonspecific arrhythmias, polymorphic ventricular tachycardia, cardiac arrest (mainly in persons with conditions predisposing to arrhythmias, such as clinically significant bradycardia, acute myocardial ischemia)
From the respiratory system, chest organs and mediastinum
Dyspnea (including asthmatic conditions)
From the gastrointestinal tract
Nausea, vomiting, abdominal pain, diarrhea
Decreased appetite and reduced food consumption, constipation, dyspepsia, flatulence, gastroenteritis (except erosive gastroenteritis), increased amylase activity in blood plasma
Dysphagia, stomatitis, pseudomembranous colitis (in very rare cases associated with life-threatening complications)
From the liver and biliary tract
Increased activity of liver transaminases
Liver dysfunction (including increased LDH activity), increased bilirubin concentration, increased GGT activity, increased plasma alkaline phosphatase activity
Jaundice, hepatitis (mainly cholestatic)
Fulminant hepatitis, potentially leading to life-threatening liver failure (including fatal cases)
From the skin and subcutaneous tissues
Bullous skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis (potentially life-threatening)
From the musculoskeletal and connective tissue side
Arthralgia, myalgia
Tendinitis, increased muscle tone and cramps, muscle weakness
Tendon ruptures, arthritis, gait disturbances due to damage to the musculoskeletal system, increased symptoms of myasthenia gravis
From the kidneys and urinary tract
Dehydration (caused by diarrhea or decreased fluid intake)
Impaired renal function, renal failure (due to dehydration, which can lead to kidney damage, especially in older patients with pre-existing renal impairment)
General and administration site disorders
Injection/infusion site reactions
General malaise, nonspecific pain, increased sweating, phlebitis/thrombophlebitis at the infusion site
Edema

The incidence of the following adverse reactions was higher in the group receiving stepwise therapy: often – increased GGT activity; uncommon – ventricular tachyarrhythmias, decreased blood pressure, edema, pseudomembranous colitis (in very rare cases associated with life-threatening complications), convulsions with various clinical manifestations (including grand mal seizures), hallucinations, renal dysfunction, renal failure (as a result of dehydration, which can lead to kidney damage, especially in elderly patients with pre-existing renal impairment).

Interaction

When used simultaneously with atenolol, ranitidine, calcium-containing supplements, theophylline, cyclosporine, oral contraceptives, glibenclamide, itraconazole, digoxin, morphine, probenecid (no clinically significant interaction with moxifloxacin has been confirmed), no dose adjustment is required.

Drugs that prolong the QT interval. The possible additive QT interval prolonging effect of moxifloxacin and other drugs that affect QT prolongation should be considered. Due to the simultaneous use of moxifloxacin and drugs that affect the prolongation of the QT interval, the risk of developing ventricular arrhythmia, including polymorphic ventricular tachycardia, increases.

The simultaneous use of moxifloxacin with the following drugs that affect the prolongation of the QT interval is contraindicated:

– class IA antiarrhythmic drugs (including quinidine, hydroquinidine, disopyramide);

– class III antiarrhythmic drugs (including amiodarone, sotalol, dofetilide, ibutilide);

– neuroleptics (including phenothiazine, pimozide, sertindole, haloperidol, sultopride);

– tricyclic antidepressants;

– antimicrobial drugs (sparfloxacin, erythromycin (iv), pentamidine, antimalarials, especially halofantrine);

– antihistamines (terfenadine, astemizole, mizolastine);

– others (cisapride, vincamine (iv), bepridil, difemanil).

Antacids, multivitamins and minerals. Taking moxifloxacin simultaneously with antacids, multivitamins and minerals may lead to impaired absorption of moxifloxacin due to the formation of chelate complexes with multivalent cations contained in these drugs. As a result, the plasma concentration of moxifloxacin may be significantly lower than desired. In this regard, antacids, antiretroviral drugs (eg didanosine) and other drugs containing magnesium or aluminum, sucralfate and other drugs containing iron or zinc should be taken at least 4 hours before or 4 hours after oral administration of moxifloxacin.

Warfarin. When used simultaneously with warfarin, PT and other blood coagulation parameters do not change.

Change in INR value. In patients receiving anticoagulants simultaneously with antibiotics, incl. with moxifloxacin, there have been cases of increased anticoagulant activity of anticoagulant drugs. Risk factors are the presence of an infectious disease (and concomitant inflammatory process), age and general condition of the patient. Although no interaction has been identified between moxifloxacin and warfarin, in patients receiving these drugs simultaneously, it is necessary to monitor the INR and, if necessary, adjust the dose of indirect anticoagulants.

Digoxin. Moxifloxacin and digoxin do not have a significant effect on each other’s pharmacokinetic parameters. When repeated doses of moxifloxacin were used, Cmax of digoxin in blood plasma increased by approximately 30%, while the AUC and Cmin of digoxin did not change.

Activated carbon. With the simultaneous use of activated carbon and moxifloxacin at a dose of 400 mg orally, the systemic bioavailability of moxifloxacin is reduced by more than 80% as a result of reduced absorption. In case of overdose, the use of activated carbon at an early stage of absorption prevents a further increase in systemic exposure.

Overdose

There are limited data on overdose with moxifloxacin. No side effects were observed when using moxifloxacin at a dose of up to 1200 mg once and 600 mg for 10 days or more.

Treatment: in case of overdose, one should focus on the clinical picture and carry out symptomatic maintenance therapy with ECG monitoring. Applying activated charcoal immediately after oral administration may help prevent excessive systemic exposure to moxifloxacin in the event of overdose.

Storage conditions

At a temperature not exceeding 25 °C, in the original packaging.

Keep out of the reach of children.

Shelf life

2 years.
Do not use the drug after the expiration date.

Manufacturer

KRKA dd Novo Mesto, Slovenia