Gracevit

White to pale yellowish white, film-coated round and biconvex tablet with
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printed on one side. (See Table 1.)

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One tablet contains Sitafloxacin hydrate 53.3 mg. equivalent to Sitafloxacin 50 mg.
Sitafloxacin occurs as pale yellowish white to yellowish white crystals or crystalline powder. It is sparingly soluble in phosphoric acid test solution (consisting of 50 g phosphoric acid dissolved in 950 mL water), 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 brownish white depending on lighting conditions.
Physicochemistry: Nonproprietary name: Sitafloxacin hydrate.
Chemical name: (-)-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 to 223°C.
Distribution coefficient: 1-octanol/water at 25°C; 0.244.
Excipients/Inactive Ingredients: D-mannitol (JP), corn starch (JP), low substituted hydroxypropylcellulose (JP), hydroxypropylcellulose (JP), magnesium stearate (JP), hypromellose (JP), titanium oxide (JP), talc (JP), macrogol 6000 (JP), polydimethylsiloxane and silicon dioxide mixture (JPE), carnauba wax (JP).
(JP): The Japanese Pharmacopoeia, (JPE): Japanese Pharmaceutical Excipients.

Pharmacology: Pharmacodynamics: Mechanism of Action: The mechanism of action of sitafloxacin involves inhibition of bacterial 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 such as Staphylococcus sp., Streptococcus sp., Streptococcus pneumoniae, Enterococcus sp., Moraxella (Branhamella) catarrhalis, Escherichia coli, Citrobacter sp., Klebsiella sp., Enterobacter sp., Serratia sp., Proteus sp., Morganella morganii, Haemophilus influenzae, Pseudomonas aeruginosa, Legionella pneumophila, Peptostreptococcus sp., Prevotella sp., Porphyromonas sp., Fusobacterium sp., Chlamydia trachomatis, Chlamydophila (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 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 AUC_0-24hr/MIC or C_max/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 AUC_0-24hr/MIC of more than 100 or 96.3% (79/82) for cases with a C_max/MIC of more than 5. The results of clinical studies conducted in patients with respiratory tract infections due to Streptococcus pneumoniae strains, demonstrated that the eradication rates of the pathogens were both 98.9% (89/90) in case with an ƒAUC_0-24hr/MIC greater than 30 and in case with an ƒC_peak/MIC greater than 2, as estimated for the serum concentration of unbinding form of sitafloxacin, respectively.
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 2, 3 and 4.)

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Serum Protein Binding: The mean serum protein-binding rate of sitafloxacin was practically constant ranging from 46% to 55%, as determined by ultrafiltration, 1, 4 and 8 hours 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 5.

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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 such as CYP2C9, CYP2D6 and CYP3A4.
Excretion: When 50 or 100 mg of sitafloxacin was administered to healthy adults in the fasting state, approximately 70% of these administered doses was excreted in an unchanged form in urine within 48 hours.
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 hours and approximately 20% was excreted in feces within 72 hours.
Pharmacokinetics in Patients with Renal Function Disorders: In patients grouped according to creatinine clearance value (CLcr) who were administered a single oral dose of 50 mg sitafloxacin in the fasted state, a prolonged biological half-life of serum concentration and a delay of the urinary excretion were observed progressively with decreasing renal function. (See Tables 6 and 7.)

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Pharmacokinetics in Elderly Subjects: Five elderly and 6 non-elderly subjects aged from 67 to 80 years and from 25 to 35 years, respectively, received a single oral dose of 100 mg of sitafloxacin in the fasting state. In the elderly subjects, prolonged t_½ decreased C_max and increased AUC_0-24hr 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 8.)

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Toxicology: Preclinical Safety Data: Single dose toxicity: Approximate oral lethal doses 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.

Gracevit Tab 50 can be used for infections caused by the following bacteria: Sitafloxacin-susceptible Staphylococcus sp., Streptococcus sp., Streptococcus pneumoniae, Enterococcus sp., Moraxella (Branhamella) catarrhalis, Escherichia coli, Citrobacter sp., Klebsiella sp., Enterobacter sp., Serratia sp., Proteus sp., Morganella morganii, Haemophilus influenzae, Pseudomonas aeruginosa, Legionella pneumophila, Peptostreptococcus 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, and secondary infection of chronic respiratory diseases; Cystitis, pyelonephritis, and urethritis; Cervicitis; Otitis media and sinusitis; Periodontitis, pericoronitis, and osteitis of jaw.
Precaution for indications: Gracevit Tab 50 should be used in consideration for benefit-risk balance since a high incidence of diarrhea and loose stools has been observed (see Adverse Reactions).

The usual dosage of Gracevit Tab 50 in adult patients is 50 mg administered orally twice daily (i.e. 1 tablet twice daily) or 100 mg administered orally once daily (i.e. 2 tablets once daily). (See Table 9.)

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Precautions Related to Dosage and Administration: As a general rule, the susceptibility of the causative bacteria to this drug should be confirmed and the duration of administration of this drug 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 the drug should be adjusted when used in this population (see Pharmacology: Pharmacokinetics under Actions). (See Table 10.)

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Gracevit Tab 50 should be taken at least 2 hours before taking antacids containing aluminum or magnesium, drugs containing calcium and drugs containing iron since the effect of sitafloxacin may be reduced when in concomitant use with these drugs.

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

Gracevit Tab 50 is contraindicated in the following patients: Patients with a history of hypersensitivity to any ingredients of Gracevit Tab 50 or other quinolones.
Pregnant women or women suspected of being pregnant (see Use in Pregnancy & Lactation).
Pediatric patients (see Pharmacology: Toxicology: Preclinical Safety Data under Actions): The safety of Gracevit Tab 50 in low birth weight infants, newborn infants, infants and toddlers, children and adolescents has not been established.

Careful Administration (Gracevit Tab 50 should be administered with caution in the following patients): Patients with renal impairment [Persistent increased serum sitafloxacin concentration has been reported in patients with renal impairment (See Pharmacology: Pharmacokinetics under Actions)].
Patients with convulsive diseases such as epilepsy or with a history of convulsive diseases [Convulsion in association with the use of the other quinolones has been reported].
Patients with myasthenia gravis [Exacerbation of myasthenia gravis in associated with the use of the other quinolones has been reported].
Patients complicated with aortic aneurysm or aortic dissection, or patients who have a previous history, positive family history, or risk factors (Marfan syndrome/Loeys-Dietz syndrome) of aortic aneurysm or aortic dissection [The increased risk of aortic aneurysm and dissection after intake of fluoroquinolones have been reported in overseas epidemiologic studies (see Important Precautions as follows and Clinically significant adverse reactions under Adverse Reactions)].
Important Precautions: Aortic aneurysm or aortic dissection may occur; therefore, patients should be carefully observed and instructed to seek medical attention immediately if they experience symptoms, e.g., in case of pain in the abdomen, chest, or back. Imaging assessment should be considered if necessary for patients complicated with aortic aneurysm or aortic dissection, or patients who have a previous history, positive family history, or risk factors of aortic aneurysm or aortic dissection (see Careful Administration as previously mentioned and Clinically significant adverse reactions under Adverse Reactions).
Precautions concerning use: Precaution regarding dispensing: When Gracevit Tab 50 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 such as mediastinitis.)
Effects on Ability to Drive and Use Machines: Some undesirable effects (e.g. dizziness or vertigo), which may affect the ability to drive or operate machinery, have been reported uncommonly (less than 1.0%).
Sitafloxacin may have some influence on the ability to drive and use machine.
Use in the Elderly: Elderly patients [It has been reported that tendon disorders are more likely to occur since elderly patients generally have reduced physiological function, Gracevit Tab 50 should be used with caution while closely observation of the patient's condition (see Pharmacology: Pharmacokinetics under Actions)].

Gracevit Tab 50 must not be used in pregnant women or women suspected of being pregnant. [The safety of the product in these populations has not been established.]
Nursing mothers must be guided to avoid the breast-feeding during treatment with Gracevit Tab 50. [Preclinical studies showed that sitafloxacin is excreted into milk in rats.]

The following adverse reactions may appear, so observe thoroughly and if abnormalities are observed, appropriate measures such as discontinuing administration should be taken.
Clinically significant adverse reactions: Shock (frequency unknown), anaphylaxis (frequency unknown).
If any abnormality is observed, such as blood pressure reductions, dyspnea, rash, or angioedema, administration should be discontinued and appropriate measures should be taken.
Toxic epidermal necrolysis (TEN) (frequency unknown), mucocutaneous ocular syndrome (Stevens-Johnson syndrome) (frequency unknown), erythema multiforme (frequency unknown).
Acute renal failure (frequency unknown).
Hepatic function disorders (frequency unknown), jaundice (frequency unknown).
Disorders, such as increased AST and increased ALT, may occur.
Pancytopenia (frequency unknown), agranulocytosis (frequency unknown), hemolytic anemia (frequency unknown), thrombocytopenia (frequency unknown).
Pseudomembranous colitis (frequency unknown).
If such symptoms as abdominal pain and frequent diarrhea are noted, administration should be discontinued and appropriate measures should be taken.
Hypoglycemia (frequency unknown).
Some cases of hypoglycemic coma have been reported. Hypoglycemia is more likely to occur in patients with diabetes mellitus, patients with impaired renal function and the elderly.
Psychiatric symptoms such as confusion (frequency unknown), delirium (frequency unknown) and hallucination (frequency unknown).
Aortic aneurysm, aortic dissection (frequency unknown) (see Important Precautions under Precautions).
Tendon disorders such as Achilles tendonitis and tendon rupture (frequency unknown).
If symptoms such as pain, edema, and redness around the tendon are observed, administration should be discontinued and appropriate measures should be taken.
Convulsion (frequency unknown).
QT prolongation (frequency unknown), ventricular tachycardia (including Torsade de pointes) (frequency unknown).
Interstitial pneumonia (frequency unknown).
Rhabdomyolysis (frequency unknown).
Other Adverse Reactions: See Table 11.

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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 the other quinolones. Therefore, careful monitoring of patients being treated with Gracevit Tab 50 is recommended. The drug should be discontinued if any abnormal symptoms related to the events occur, and appropriate therapies should be initiated immediately.
Toxic epidermal necrolysis (TEN); Convulsions; QT prolongation, ventricular tachycardia (including Torsade de pointes); Jaundice; Interstitial pneumonia; Rhabdomyolysis; Tendon disorders; Agranulocytosis; Pancytopenia; Hemolytic anemia; Exacerbation of myasthenia gravis.

Gracevit Tab 50 should be co-administered with care when administered with the following drugs (see Table 12).

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Incompatibilities: Not applicable.

Shelf Life: 48 months.
Special Precaution for Storage: Store below 30°C.

Quinolones

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

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