GRACEVIT

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Contents: Sitafloxacin hydrate
How Gracevit Works?

Gracevit contains sitafloxacin hydrate as an active ingredient, and is clinically effective in severe cases of bacterial infection where resistant bacteria are the suspected cause. This medication belongs to a class of drugs known as quinolone antibiotics and works by inhibiting the growth of bacteria. It is usually used to treat a wide range of infections including skin, respiratory, urinary tract, gynaecologic, otologic and dental infections.

Prescribing information
Indications / Uses

For infections caused by the following bacteria: Sitafloxacin-susceptible Staphylococcus sp, Streptococcus sp, Streptococcus pneumoniaeEnterococcus sp, Moraxella (Branhamella) catarrhalisEscherichia coliCitrobacter sp, Klebsiella sp, Enterobacter sp, Serratia sp, Proteus sp, Morganella morganiiHaemophilus influenzaePseudomonas aeruginosaLegionella pneumophilaPeptostreptococcus sp, Prevotella sp, Porphyromonas sp, Fusobacterium sp, Chlamydia trachomatis, Chlamydophila (Chlamydia) pneumoniae and Mycoplasma pneumoniae.
Laryngopharyngitis, tonsillitis (including peritonsillitis and peritonsillar abscess), acute bronchitis, pneumonia, secondary infection of chronic respiratory diseases, cystitis, pyelonephritis, urethritis, cervicitis, otitis media, sinusitis, periodontitis, pericoronitis and osteitis of jaw.

Dosage / Direction for Use

Adult: Usual Dose: 50 mg administered orally twice daily (ie, 1 tab twice daily). (See Table 8.)

Precautions for Dosage and Administration: As a general rule, the susceptibility of the causative bacteria to Gracevit should be confirmed and the duration of administration of Gracevit should be limited to the minimum period required for the treatment of the patient’s condition, in order to prevent the development of drug-resistant bacteria.
Higher blood levels of sitafloxacin have been noted following administration in patients with renal impairment; therefore, the dosage and dosing interval of Gracevit should be adjusted when used in this population. (See Pharmacokinetics under Actions.)
Gracevit should be taken at least 2 hrs before taking antacids containing aluminum or magnesium and drugs containing calcium and iron since the effect of sitafloxacin may be reduced when co-administered with these drugs.

Overdosage

Phototoxicity was observed after exposure to ultraviolet (UV) irradiation in subjects orally administered with sitafloxacin 500 mg once or twice daily. The QT interval was prolonged in a dose-dependent manner with a mean fluctuation range of ≤10 millisec, following IV administration of sitafloxacin 400-800 mg twice daily.

Administration

May be taken with or without food.

Contraindications

Patients with a history of hypersensitivity to any ingredients of Gracevit or other quinolones.
Use in Pregnancy & Lactation: Gracevit must not be used in pregnant women or women suspected of being pregnant. The safety of Gracevit in these populations has not been established.
Nursing mothers must be guided to avoid breastfeeding during treatment with Gracevit. Preclinical studies showed that sitafloxacin is excreted into milk in rats.
Use in Children: The safety of Gracevit in low birth weight infants, newborns, infants, toddlers, children and adolescents has not been established (see Toxicology: Preclinical Safety Data under Actions).

Special Precautions

Special Populations: Patients with Renal Impairment: Persistent increased serum sitafloxacin concentration has been reported in patients with renal impairment. (See Pharmacokinetics under Action.)
Patients with convulsive disorders eg, epilepsy or with a history of convulsive diseases. Convulsion in association with the use of other quinolones has been reported.
Patients with Myasthenia Gravis: Exacerbation of myasthenia gravis in association with the use of other quinolones has been reported.
Clinically Significant Adverse Reactions: Anaphylactoid Symptoms (Incidence Unknown*): Since anaphylactoid symptoms may occur, patients should be carefully monitored. Appropriate treatment should be taken when any abnormality is observed eg, dyspnea, rash, angioedema, etc.
*The incidence of adverse reactions is unknown as the adverse reaction is that which has been reported spontaneously.
Hepatic Function Disorders (Incidence <0.1%): Hepatic function disorders, including increased aspartate aminotransferase (AST) [glutamic oxaloacetic transaminase (GOT)] and increased alanine aminotransferase (ALT) [glutamic pyruvic transaminase (GPT)], have been reported with the use of Gracevit. Patients should be carefully monitored during treatment. If any abnormal symptoms occur in a patient being treated with Gracevit, it should be discontinued and appropriate therapies should be initiated immediately.
Precautions Concerning Use: Precaution Regarding Dispensing: When Gracevit is dispensed, patients should be instructed to remove each tablet from the PTP blister package before taking the drug. It has been reported that accidental ingestion of the blister package can lead to esophageal mucosal injury and subsequent perforation caused by the pointed corner of the package, resulting in serious complications eg, mediastinitis.
Effects on the Ability to Drive or Operate Machinery: Some undesirable effects (eg, dizziness or vertigo), which may affect the ability to drive or operate machinery, have been reported uncommonly (<1%). Sitafloxacin may have some influence on the ability to drive and use machines.
Use in Elderly: Since elderly patients generally have reduced physiological function, Gracevit should be used with caution while closely monitoring the patient’s condition. (See Pharmacokinetics under Actions.)

Use In Pregnancy & Lactation

Gracevit must not be used in pregnant women or women suspected of being pregnant. The safety of Gracevit in these populations has not been established.
Nursing mothers must be guided to avoid breastfeeding during treatment with Gracevit. Preclinical studies showed that sitafloxacin is excreted into milk in rats.

Adverse Reactions

In clinical trials conducted in Japan, adverse drug reactions (including abnormal changes in laboratory tests) were reported 409 patients (33.5%) out of 1220 patients. The frequently reported adverse drug reactions were diarrhea 69 patients (5.7%), loose stools 86 patients (7%), headache 26 patients (2.1%), increased ALT (GPT) 72 patients (5.9%), increased AST (GOT) 59 patients (4.8%), increased eosinophil count 47 patients (3.9%) and others.
In the post-marketing study (conducted between December 2008 and November 2010 in Japan), adverse drug reactions (including abnormal changes in laboratory tests) reported in 148 patients (4.4%) out of 3331 patients. The frequently reported adverse drug reactions were diarrhea 41 patients (1.2%), loose stools 14 patients (0.4%), increased ALT (GPT) 22 patients (0.7%), increased AST (GOT) 16 patients (0.5%) and rash 12 patients (0.4%) and others.
The following adverse reactions have been reported in association with the use of Gracevit. If any abnormal event is noted, appropriate measures eg, discontinuing treatment, should be taken as needed. (See Table 9.)

Clinically Significant Adverse Reactions Reported in Association with the Use of Other Quinolones:The following clinically significant adverse reactions have been reported in association with the use of other quinolones. Therefore, careful monitoring of patients being treated with Gracevit is recommended. Gracevit should be discontinued if any abnormal symptoms related to the events occur, and appropriate therapies should be initiated immediately.
Shock; toxic epidermal necrolysis (TEN), mucocutaneous ocular syndrome (Stevens-Johnson syndrome); convulsions; QT prolongation, ventricular tachycardia (including Torsades de pointes); acute renal failure; jaundice; interstitial pneumonia; pseudomembranous colitis; rhabdomyolysis; hypoglycemia; tendon disorders; agranulocytosis; pancytopenia; thrombocytopenia; hemolytic anemia; psychiatric symptoms eg, confusion, delirium and hallucination. Exacerbation of myasthenia gravis.

Click to View ADR Monitoring Form

 

Interactions

Gracevit should be co-administered with care when administered with the following drugs (see Table 10).ives (eg, ketoprofen) may cause convulsion.

Incompatibilities: Not applicable.

Storage

Store below 30°C.
Shelf-Life: 24 months

Description

Each tablet contains sitafloxacin hydrate 53.3 mg equivalent to sitafloxacin 50 mg. It also contains the following excipients: D-mannitol, corn starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate, hypromellose, titanium oxide, talc, macrogol 6000, polydimethylsiloxane, silicon dioxide mixture and carnauba wax.
Sitafloxacin occurs as pale yellowish white to yellowish white crystals or crystalline powder. It is sparingly soluble in phosphoric acid test solution (consisting of phosphoric acid 50 g dissolved in water 950 mL), slightly soluble in 0.1 mol/L hydrochloric acid test solution, acetonitrile and methanol, very slightly soluble in ethanol (99.5) and practically insoluble in water. It appears as light yellowish to brownish white depending on lighting conditions.
Sitafloxacin hydrate is (-)-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. Molecular Formula: C19H18ClF2N3O3. Molecular Weight: 409.81. Melting Point: 217-223°C. Distribution Coefficient: 1-octanol/water at 25°C; 0.244.

Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: The mechanism of action of sitafloxacin involves inhibition of bacterial deoxyribonucleic acid (DNA) gyrase and topoisomerase IV. Bactericidal activity of sitafloxacin results from inhibition of these enzymes. The inhibitory activity of sitafloxacin against these enzymes was higher than that of the other quinolone antimicrobials used as comparators. Sitafloxacin also has a potent inhibitory activity against enzymes from quinolone-resistant bacteria.
Antibacterial Activity: Sitafloxacin has a broad spectrum of antibacterial activity against aerobic and anaerobic gram-positive and gram-negative bacteria, as well as atypical bacteria. Sitafloxacin showed potent antibacterial activities against microorganisms eg, Staphylococcus sp, Streptococcus sp, Streptococcus pneumoniaeEnterococcus sp, Moraxella (Branhamella) catarrhalisEscherichia coliCitrobacter sp, Klebsiella sp, Enterobacter sp, Serratia sp, Proteus sp, Morganella morganiiHaemophilus influenzaePseudomonas aeruginosa, Legionella pneumophilaPeptostreptococcus sp, Prevotella sp, Porphyromonas sp, Fusobacterium sp, Chlamydia trachomatisChlamydophila (Chlamydia) pneumoniae and Mycoplasma pneumoniae. In comparison to other quinolone antimicrobials, sitafloxacin shows more potent antibacterial activities in particular against Streptococcus pneumoniae (including penicillin-resistant and macrolide-resistant Streptococcus pneumoniae), Enterococcus sp, Pseudomonas aeruginosa and Escherichia coli (including quinolone-resistant Escherichia coli).
Therapeutic Effects of Sitafloxacin for Experimental Infection: Sitafloxacin showed a therapeutic effect against infection, reflecting its antimicrobial activity in vitro in mouse models of sepsis caused by gram-positive or gram-negative organisms. Sitafloxacin also showed a greater therapeutic effect than the other quinolone antimicrobial agents used as controls in a mouse model of pneumococcal respiratory tract infection.
Pharmacokinetic and Pharmacodynamic (PK/PD) Analysis in Patients with Respiratory Infections: The results of the PK/PD analysis in a clinical study conducted in patients with respiratory tract infections demonstrated that the eradication rate of causative pathogens increased along with increase of AUC0-24hr/MIC or Cmax/MIC value. The rate of disappearance of major causative organisms in patients with respiratory tract infections, involving 22 Streptococcus pneumoniae strains, was 96.3% (78/81) for cases with an AUC0-24hr/MIC of >100 or 96.3% (79/82) for cases with a Cmax/MIC of >5.
Pharmacokinetics: Serum Drug Concentrations: The following figures and tables show serum concentrations and pharmacokinetic parameters of sitafloxacin following a single and repeated oral dose administered to healthy adults in the fasting or postprandial state. (See Figures 1, 2 and 3; and Tables 1, 2 and 3.)

Serum Protein-Binding: The mean serum protein-binding rate of sitafloxacin was practically constant ranging from 46-55%, as determined by ultrafiltration, 1, 4 and 8 hrs after being administered orally to healthy adults in a single dose of 100 mg.
Distribution: When sitafloxacin was administered orally in a single dose of 50 or 100 mg, the drug concentrations in different tissue and body fluid were as follows, indicating favorable drug transfer to these tissue/fluid. (See Table 4.)

Metabolism: Sitafloxacin was scarcely metabolized and was excreted as an unchanged form in the urine. Some of the metabolites identified in the serum, urine and feces are as follows: Glucuronide, 7′-oxo metabolite, 7’S-hydroxylated metabolite, glucuronide of 7’S-hydroxylated metabolite and N-acetyl conjugate.
An in vitro study performed using human tissue specimens showed that sitafloxacin modestly inhibited the CYP1A1 and CYP1A2 enzymatic activities, but did not cause any inhibition of other CYP isoforms eg, CYP2C9, CYP2D6 and CYP3A4.
Excretion: When sitafloxacin 50 or 100 mg was administered to healthy adults in the fasting state, approximately 70% of these administered doses was excreted in unchanged form in urine within 48 hrs.
Data of the United Kingdom showed that after administration of 14C-labeled sitafloxacin at a dose of 100 mg, approximately 80% of the administered radioactivity was excreted in urine within 72 hrs and approximately 20% was excreted in feces within 72 hrs.
Pharmacokinetics in Patients with Renal Function Disorders: In patients grouped according to creatinine clearance (CrCl) value who were administered a single oral dose of sitafloxacin 50 mg in the fasted state, a prolonged biological half-life (t½) of serum concentration and a delay of the urinary excretion were observed progressively with decreasing renal function. (See Tables 5 and 6.)

Pharmacokinetics in Elderly Subjects: Five (5) elderly and 6 non-elderly subjects 67-80 years and 25-35 years, respectively, received a single oral dose of sitafloxacin 100 mg in the fasting state. In the elderly subjects, prolonged t½ decreased Cmax and increased AUC0-24hr were observed in comparison to the non-elderly subjects. These findings suggest that the pharmacokinetic profile of sitafloxacin is influenced by age-related decline of the absorption and excretion functions. (See Table 7.)

Toxicology: Preclinical Safety Data: Single-Dose Toxicity: Approximate oral lethal doses (LD) were over 1880 and 469 mg/kg in rats and monkeys, respectively. Intravenous LD50 was 188 mg/kg in mice.
Repeated-Dose Toxicity: In rats, toxic findings included urinary medicine-like crystals with no renal lesions and exacerbation of spontaneous femoral osteochondrotic lesions after 4- and 13-week oral dosing, with 46.9 and 20 mg/kg/day of No Observed Adverse Effect Level (NOAEL). In monkeys, decreased spermatogenic cells in testis and a mild increase in serum phospholipid level were seen after 4- and 52-week oral dosing, with 28.1 and 25 mg/kg/day of NOAEL.
Genotoxicity: Sitafloxacin was positive in in vitro reverse mutation (Escherichia coli WP2uvrA/pKM101), chromosomal aberration and mouse lymphoma TK tests, but negative in in vivo micronucleus, unscheduled DNA synthesis and dominant lethality tests.
Reproductive Toxicity: Sitafloxacin had no effects on fertility, pregnancy and lactation in parental rats, but induced abortion in rabbits as a common effect of antibiotics. Sitafloxacin was not teratogenic in rats and rabbits although minor effects were noted in foetuses and offsprings.
Arthrotoxicity in Dogs: Sitafloxacin induced blister formation in the articular cartilage of juvenile, but not adult, dogs.
Phototoxicity: NOAELs were 20 and 93.8 mg/kg/day in albino and pigmented mice.
Photogenotoxicity: Sitafloxacin was positive in in vitro photogenotoxicity test, but NOAEL was 20 mg/kg in in vivo mouse test.

MIMS Class
ATC Classification

J01MA21 – sitafloxacin ; Belongs to the class of fluoroquinolones. Used in the systemic treatment of infections.

Thai FDA Category

D

Presentation / Packing
Form Photo Packing/Price
Gracevit FC tab 50 mg
10’s
Distributor
Indications / Uses

For infections caused by the following bacteria: Sitafloxacin-susceptible Staphylococcus sp, Streptococcus sp, Streptococcus pneumoniaeEnterococcus sp, Moraxella (Branhamella) catarrhalisEscherichia coliCitrobacter sp, Klebsiella sp, Enterobacter sp, Serratia sp, Proteus sp, Morganella morganiiHaemophilus influenzaePseudomonas aeruginosaLegionella pneumophilaPeptostreptococcus sp, Prevotella sp, Porphyromonas sp, Fusobacterium sp, Chlamydia trachomatis, Chlamydophila (Chlamydia) pneumoniae and Mycoplasma pneumoniae.
Laryngopharyngitis, tonsillitis (including peritonsillitis and peritonsillar abscess), acute bronchitis, pneumonia, secondary infection of chronic respiratory diseases, cystitis, pyelonephritis, urethritis, cervicitis, otitis media, sinusitis, periodontitis, pericoronitis and osteitis of jaw.

Dosage / Direction for Use

Adult: Usual Dose: 50 mg administered orally twice daily (ie, 1 tab twice daily). (See Table 8.)

Precautions for Dosage and Administration: As a general rule, the susceptibility of the causative bacteria to Gracevit should be confirmed and the duration of administration of Gracevit should be limited to the minimum period required for the treatment of the patient’s condition, in order to prevent the development of drug-resistant bacteria.
Higher blood levels of sitafloxacin have been noted following administration in patients with renal impairment; therefore, the dosage and dosing interval of Gracevit should be adjusted when used in this population. (See Pharmacokinetics under Actions.)
Gracevit should be taken at least 2 hrs before taking antacids containing aluminum or magnesium and drugs containing calcium and iron since the effect of sitafloxacin may be reduced when co-administered with these drugs.

Overdosage

Phototoxicity was observed after exposure to ultraviolet (UV) irradiation in subjects orally administered with sitafloxacin 500 mg once or twice daily. The QT interval was prolonged in a dose-dependent manner with a mean fluctuation range of ≤10 millisec, following IV administration of sitafloxacin 400-800 mg twice daily.

Administration

May be taken with or without food.

Contraindications

Patients with a history of hypersensitivity to any ingredients of Gracevit or other quinolones.
Use in Pregnancy & Lactation: Gracevit must not be used in pregnant women or women suspected of being pregnant. The safety of Gracevit in these populations has not been established.
Nursing mothers must be guided to avoid breastfeeding during treatment with Gracevit. Preclinical studies showed that sitafloxacin is excreted into milk in rats.
Use in Children: The safety of Gracevit in low birth weight infants, newborns, infants, toddlers, children and adolescents has not been established (see Toxicology: Preclinical Safety Data under Actions).

Special Precautions

Special Populations: Patients with Renal Impairment: Persistent increased serum sitafloxacin concentration has been reported in patients with renal impairment. (See Pharmacokinetics under Action.)
Patients with convulsive disorders eg, epilepsy or with a history of convulsive diseases. Convulsion in association with the use of other quinolones has been reported.
Patients with Myasthenia Gravis: Exacerbation of myasthenia gravis in association with the use of other quinolones has been reported.
Clinically Significant Adverse Reactions: Anaphylactoid Symptoms (Incidence Unknown*): Since anaphylactoid symptoms may occur, patients should be carefully monitored. Appropriate treatment should be taken when any abnormality is observed eg, dyspnea, rash, angioedema, etc.
*The incidence of adverse reactions is unknown as the adverse reaction is that which has been reported spontaneously.
Hepatic Function Disorders (Incidence <0.1%): Hepatic function disorders, including increased aspartate aminotransferase (AST) [glutamic oxaloacetic transaminase (GOT)] and increased alanine aminotransferase (ALT) [glutamic pyruvic transaminase (GPT)], have been reported with the use of Gracevit. Patients should be carefully monitored during treatment. If any abnormal symptoms occur in a patient being treated with Gracevit, it should be discontinued and appropriate therapies should be initiated immediately.
Precautions Concerning Use: Precaution Regarding Dispensing: When Gracevit is dispensed, patients should be instructed to remove each tablet from the PTP blister package before taking the drug. It has been reported that accidental ingestion of the blister package can lead to esophageal mucosal injury and subsequent perforation caused by the pointed corner of the package, resulting in serious complications eg, mediastinitis.
Effects on the Ability to Drive or Operate Machinery: Some undesirable effects (eg, dizziness or vertigo), which may affect the ability to drive or operate machinery, have been reported uncommonly (<1%). Sitafloxacin may have some influence on the ability to drive and use machines.
Use in Elderly: Since elderly patients generally have reduced physiological function, Gracevit should be used with caution while closely monitoring the patient’s condition. (See Pharmacokinetics under Actions.)

Use In Pregnancy & Lactation

Gracevit must not be used in pregnant women or women suspected of being pregnant. The safety of Gracevit in these populations has not been established.
Nursing mothers must be guided to avoid breastfeeding during treatment with Gracevit. Preclinical studies showed that sitafloxacin is excreted into milk in rats.

Adverse Reactions

In clinical trials conducted in Japan, adverse drug reactions (including abnormal changes in laboratory tests) were reported 409 patients (33.5%) out of 1220 patients. The frequently reported adverse drug reactions were diarrhea 69 patients (5.7%), loose stools 86 patients (7%), headache 26 patients (2.1%), increased ALT (GPT) 72 patients (5.9%), increased AST (GOT) 59 patients (4.8%), increased eosinophil count 47 patients (3.9%) and others.
In the post-marketing study (conducted between December 2008 and November 2010 in Japan), adverse drug reactions (including abnormal changes in laboratory tests) reported in 148 patients (4.4%) out of 3331 patients. The frequently reported adverse drug reactions were diarrhea 41 patients (1.2%), loose stools 14 patients (0.4%), increased ALT (GPT) 22 patients (0.7%), increased AST (GOT) 16 patients (0.5%) and rash 12 patients (0.4%) and others.
The following adverse reactions have been reported in association with the use of Gracevit. If any abnormal event is noted, appropriate measures eg, discontinuing treatment, should be taken as needed. (See Table 9.)

Clinically Significant Adverse Reactions Reported in Association with the Use of Other Quinolones:The following clinically significant adverse reactions have been reported in association with the use of other quinolones. Therefore, careful monitoring of patients being treated with Gracevit is recommended. Gracevit should be discontinued if any abnormal symptoms related to the events occur, and appropriate therapies should be initiated immediately.
Shock; toxic epidermal necrolysis (TEN), mucocutaneous ocular syndrome (Stevens-Johnson syndrome); convulsions; QT prolongation, ventricular tachycardia (including Torsades de pointes); acute renal failure; jaundice; interstitial pneumonia; pseudomembranous colitis; rhabdomyolysis; hypoglycemia; tendon disorders; agranulocytosis; pancytopenia; thrombocytopenia; hemolytic anemia; psychiatric symptoms eg, confusion, delirium and hallucination. Exacerbation of myasthenia gravis.

Click to View ADR Monitoring Form

 

Interactions

Gracevit should be co-administered with care when administered with the following drugs (see Table 10).ives (eg, ketoprofen) may cause convulsion.

Incompatibilities: Not applicable.

Storage

Store below 30°C.
Shelf-Life: 24 months

Description

Each tablet contains sitafloxacin hydrate 53.3 mg equivalent to sitafloxacin 50 mg. It also contains the following excipients: D-mannitol, corn starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate, hypromellose, titanium oxide, talc, macrogol 6000, polydimethylsiloxane, silicon dioxide mixture and carnauba wax.
Sitafloxacin occurs as pale yellowish white to yellowish white crystals or crystalline powder. It is sparingly soluble in phosphoric acid test solution (consisting of phosphoric acid 50 g dissolved in water 950 mL), slightly soluble in 0.1 mol/L hydrochloric acid test solution, acetonitrile and methanol, very slightly soluble in ethanol (99.5) and practically insoluble in water. It appears as light yellowish to brownish white depending on lighting conditions.
Sitafloxacin hydrate is (-)-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. Molecular Formula: C19H18ClF2N3O3. Molecular Weight: 409.81. Melting Point: 217-223°C. Distribution Coefficient: 1-octanol/water at 25°C; 0.244.

Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: The mechanism of action of sitafloxacin involves inhibition of bacterial deoxyribonucleic acid (DNA) gyrase and topoisomerase IV. Bactericidal activity of sitafloxacin results from inhibition of these enzymes. The inhibitory activity of sitafloxacin against these enzymes was higher than that of the other quinolone antimicrobials used as comparators. Sitafloxacin also has a potent inhibitory activity against enzymes from quinolone-resistant bacteria.
Antibacterial Activity: Sitafloxacin has a broad spectrum of antibacterial activity against aerobic and anaerobic gram-positive and gram-negative bacteria, as well as atypical bacteria. Sitafloxacin showed potent antibacterial activities against microorganisms eg, Staphylococcus sp, Streptococcus sp, Streptococcus pneumoniaeEnterococcus sp, Moraxella (Branhamella) catarrhalisEscherichia coliCitrobacter sp, Klebsiella sp, Enterobacter sp, Serratia sp, Proteus sp, Morganella morganiiHaemophilus influenzaePseudomonas aeruginosa, Legionella pneumophilaPeptostreptococcus sp, Prevotella sp, Porphyromonas sp, Fusobacterium sp, Chlamydia trachomatisChlamydophila (Chlamydia) pneumoniae and Mycoplasma pneumoniae. In comparison to other quinolone antimicrobials, sitafloxacin shows more potent antibacterial activities in particular against Streptococcus pneumoniae (including penicillin-resistant and macrolide-resistant Streptococcus pneumoniae), Enterococcus sp, Pseudomonas aeruginosa and Escherichia coli (including quinolone-resistant Escherichia coli).
Therapeutic Effects of Sitafloxacin for Experimental Infection: Sitafloxacin showed a therapeutic effect against infection, reflecting its antimicrobial activity in vitro in mouse models of sepsis caused by gram-positive or gram-negative organisms. Sitafloxacin also showed a greater therapeutic effect than the other quinolone antimicrobial agents used as controls in a mouse model of pneumococcal respiratory tract infection.
Pharmacokinetic and Pharmacodynamic (PK/PD) Analysis in Patients with Respiratory Infections: The results of the PK/PD analysis in a clinical study conducted in patients with respiratory tract infections demonstrated that the eradication rate of causative pathogens increased along with increase of AUC0-24hr/MIC or Cmax/MIC value. The rate of disappearance of major causative organisms in patients with respiratory tract infections, involving 22 Streptococcus pneumoniae strains, was 96.3% (78/81) for cases with an AUC0-24hr/MIC of >100 or 96.3% (79/82) for cases with a Cmax/MIC of >5.
Pharmacokinetics: Serum Drug Concentrations: The following figures and tables show serum concentrations and pharmacokinetic parameters of sitafloxacin following a single and repeated oral dose administered to healthy adults in the fasting or postprandial state. (See Figures 1, 2 and 3; and Tables 1, 2 and 3.)

Serum Protein-Binding: The mean serum protein-binding rate of sitafloxacin was practically constant ranging from 46-55%, as determined by ultrafiltration, 1, 4 and 8 hrs after being administered orally to healthy adults in a single dose of 100 mg.
Distribution: When sitafloxacin was administered orally in a single dose of 50 or 100 mg, the drug concentrations in different tissue and body fluid were as follows, indicating favorable drug transfer to these tissue/fluid. (See Table 4.)

Metabolism: Sitafloxacin was scarcely metabolized and was excreted as an unchanged form in the urine. Some of the metabolites identified in the serum, urine and feces are as follows: Glucuronide, 7′-oxo metabolite, 7’S-hydroxylated metabolite, glucuronide of 7’S-hydroxylated metabolite and N-acetyl conjugate.
An in vitro study performed using human tissue specimens showed that sitafloxacin modestly inhibited the CYP1A1 and CYP1A2 enzymatic activities, but did not cause any inhibition of other CYP isoforms eg, CYP2C9, CYP2D6 and CYP3A4.
Excretion: When sitafloxacin 50 or 100 mg was administered to healthy adults in the fasting state, approximately 70% of these administered doses was excreted in unchanged form in urine within 48 hrs.
Data of the United Kingdom showed that after administration of 14C-labeled sitafloxacin at a dose of 100 mg, approximately 80% of the administered radioactivity was excreted in urine within 72 hrs and approximately 20% was excreted in feces within 72 hrs.
Pharmacokinetics in Patients with Renal Function Disorders: In patients grouped according to creatinine clearance (CrCl) value who were administered a single oral dose of sitafloxacin 50 mg in the fasted state, a prolonged biological half-life (t½) of serum concentration and a delay of the urinary excretion were observed progressively with decreasing renal function. (See Tables 5 and 6.)

Pharmacokinetics in Elderly Subjects: Five (5) elderly and 6 non-elderly subjects 67-80 years and 25-35 years, respectively, received a single oral dose of sitafloxacin 100 mg in the fasting state. In the elderly subjects, prolonged t½ decreased Cmax and increased AUC0-24hr were observed in comparison to the non-elderly subjects. These findings suggest that the pharmacokinetic profile of sitafloxacin is influenced by age-related decline of the absorption and excretion functions. (See Table 7.)

Toxicology: Preclinical Safety Data: Single-Dose Toxicity: Approximate oral lethal doses (LD) were over 1880 and 469 mg/kg in rats and monkeys, respectively. Intravenous LD50 was 188 mg/kg in mice.
Repeated-Dose Toxicity: In rats, toxic findings included urinary medicine-like crystals with no renal lesions and exacerbation of spontaneous femoral osteochondrotic lesions after 4- and 13-week oral dosing, with 46.9 and 20 mg/kg/day of No Observed Adverse Effect Level (NOAEL). In monkeys, decreased spermatogenic cells in testis and a mild increase in serum phospholipid level were seen after 4- and 52-week oral dosing, with 28.1 and 25 mg/kg/day of NOAEL.
Genotoxicity: Sitafloxacin was positive in in vitro reverse mutation (Escherichia coli WP2uvrA/pKM101), chromosomal aberration and mouse lymphoma TK tests, but negative in in vivo micronucleus, unscheduled DNA synthesis and dominant lethality tests.
Reproductive Toxicity: Sitafloxacin had no effects on fertility, pregnancy and lactation in parental rats, but induced abortion in rabbits as a common effect of antibiotics. Sitafloxacin was not teratogenic in rats and rabbits although minor effects were noted in foetuses and offsprings.
Arthrotoxicity in Dogs: Sitafloxacin induced blister formation in the articular cartilage of juvenile, but not adult, dogs.
Phototoxicity: NOAELs were 20 and 93.8 mg/kg/day in albino and pigmented mice.
Photogenotoxicity: Sitafloxacin was positive in in vitro photogenotoxicity test, but NOAEL was 20 mg/kg in in vivo mouse test.

MIMS Class
ATC Classification

J01MA21 – sitafloxacin ; Belongs to the class of fluoroquinolones. Used in the systemic treatment of infections.

Thai FDA Category

D

Presentation / Packing
Form Photo Packing/Price
Gracevit FC tab 50 mg
10’s
Distributor