Tarivid is a broad-spectrum antibacterial agent of pyridonecarboxylic acid derivative originated in Daiichi Pharmaceutical Co., Ltd. Tarivid shows more potent antibacterial activities against gram-negative bacteria eg, E. coli, K. pneumoniae, Serratia and Proteus spp, P. aeruginosa and H. influenzae than the other formerly developed derivatives of pyridonecarboxylic acid. Moreover, ofloxacin has antibacterial activities against gram-positive bacteria eg, Staphylococcus sp, Streptococcus hemolyticus and Enterococcus sp. Tarivid, which is transferred rapidly to each tissue in high concentrations without being accumulated there, is mostly excreted in the urine almost unchanged. It shows clinical effects on respiratory tract, genitourinary tract, biliary tract, intestinal tract infections and other various infections in the gynecological, dermatological, otorhinolaryngological, ophthalmological and oral surgery fields.
Pharmacology: Mechanism of Action: Ofloxacin is considered to specifically inhibit DNA synthesis in microorganism. Its antibacterial activity is bactericidal and causes bacteriolysis at MIC.
Nonclinical Studies: Absorption and Distribution: 14C-Ofloxacin, when administered orally to rats at a dose of 20 mg/kg, was absorbed primarily from the small intestine and the maximum tissue concentrations were reached 2 hrs after administration. Except for the levels in the central nervous system, the drug concentrations in all tissues of the body were higher than the blood level (2.59 mcg/mL), demonstrating the ready transference to tissues. Regarding the drug concentrations in the main organs, the maximal level of 14 mcg/g in the kidney was followed by 8.2 mcg/g in the liver and 3.3 mcg/g in the lung. Also, following 2-week oral administration to beagle dogs at a dose of 20 mg/kg, levofloxacin, the optically active (-)S-form of racemate ofloxacin, was distributed in high concentrations in the iris, ciliary body, choroid and pigmented layer of retina, those eye tissues containing melanin pigments. Concentrations were decreased to 20-30% one week after the termination of drug administration. On the other hand, drug distribution to retina excluding pigmentated layer was minimal.
Single-Dose Toxicity: LD50 values after oral administration were 5450 mg/kg in mice, 3590 mg/kg in rats, >200 mg/kg in dogs and 500-1000 mg/kg in monkeys.
Repeated-Dose Toxicity: Following 4-week administration to rats, no changes were observed up to 90 mg/kg in general condition, hematology, urinalysis and histology. At a dose of 270 mg/kg or more, rats showed roughened fur, soft stool and depression of body weight gain. In addition to these changes, rarefaction of articular cartilage matrix was observed in rats given 810 mg/kg. When dogs were orally administered for 4 weeks, no noticeable changes were observed at a dose of 12.5 mg/kg. However, at 50 and 200 mg/kg, vomiting, salivation and blister or erosion of the articular cartilage were observed.
Following 6-month administration to rats, no noticeable changes were observed up to 30 mg/kg. At 90 and 270 mg/kg, salivation, soft stool, of enhancement spontaneous lesions in the cartilage and of lipid deposition in cortical cells of the adrenal glands were observed.
Reproductive and Developmental Toxicity: Administration Prior to and in the Early Stage of Pregnancy: No effects were observed on fertility of both sexes and on the fetuses after administration of 360 mg/kg to rats.
Administration During the Period of Organogenesis: In rats, growth retardation in the fetuses at a dose of ≥90 mg/kg and skeletal variations in the fetuses at a dose of 810 mg/kg were observed. However, no teratogenesis was observed up to 810 mg/kg. In rabbits, no teratogenesis was observed up to 160 mg/kg.
Administration During the Perinatal and Lactation Periods: No effects were observed in the female parturition and on pups after administration of 360 mg/kg to rats.
Antigenicity: No antigenicity was suggested from the systematic anaphylaxis test, PCA reaction, hemagglutination reaction and precipitation reactions in guinea pigs, from the PCA reaction and hemagglutination reaction in rabbits and from the detection test of specific IgE antibody in mice.
Mutagenicity: The sister chromatid exchange test, unscheduled DNA synthesis test, reverse mutation test, chromosomal aberration test (in vitro and in vivo), micronucleus test and dominant lethal test showed no mutagenic potential of the drug.
Effects on Kidney: Following oral administration to rabbits for 10 days, no abnormalities were observed in renal functional parameters and morphological studies up to 200 mg/kg.
Effects on Eye: Following oral administration to rats for 4 weeks, no abnormalities were observed in ophthalmological tests and morphological studies up to 100 mg/kg.
Effects on Articulation: When ofloxacin was administered orally to juvenile rats (4 weeks) or juvenile dogs (3-4 months) for 7 days, blisters or erosions occurred in the articular cartilage in rats on 300 mg/kg or more and in dogs on 10 mg/kg or more. After termination of administration, however, it was confirmed that these symptoms tended to subside gradually without showing any sign of deterioration. In mature rats (8-10 weeks) and mature dogs (12-13 months), repeated administration did not cause any change.
Others: Animal studies have shown that ofloxacin may produce arthropathy in juvenile dogs and juvenile rats.
Clinical Studies: Clinical Efficacy: The results of the clinical trials carried out in Japan in cases of various infections of each field and those of the double-blind comparative studies are summarized in the following: Respiratory Tract Infections: Clinical efficacy rate was 80.7% (668/828) in patients with respiratory tract infections eg, pharyngolaryngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis with infection, diffuse panbronchiolitis, secondary infections of chronic respiratory diseases and pneumonia. The main causative organisms were Staphylococcus and Streptococcus spp, S. pneumoniae, K. pneumoniae, P. aeruginosa and H. influenzae. Most of the patients received a daily dose of 300-600 mg. Moreover, usefulness of the drug in acute lacunar tonsillitis, chronic respiratory tract infections and pneumonia and bronchitis were confirmed by respective double-blind comparative studies.
Urinary Tract Infections: Clinical efficacy rate was 85.6% (1339/1564) in patients with urinary tract infections eg, pyelonephritis, cystitis, prostatitis, gonococcal urethritis, nongonococcal urethritis. The main causative organisms were Staphylococcus sp, S. faecalis, E. coli, Citrobacter sp, K. pneumoniae, Enterobacter, Serratia and Proteus spp, P. aeruginosa and N. gonorrhoeae. Most of the patients received a daily dose of either 300 or 400 mg. Moreover, usefulness of ofloxacin in acute simple cystitis and in complicated urinary tract infections has been confirmed by respective double-blind comparative studies.
Gynecological Field Infections: Clinical efficacy rate was 92.7% (140/151) in patients with gynecological field infections eg, uterine adnexitis, intrauterine infection and bartholinitis. The main causative organisms were E. coli and Peptostreptococcus sp. Most of the patients received a daily dose of either 300 or 600 mg. Moreover, usefulness of ofloxacin in these infections has been confirmed by a double-blind comparative study.
Chlamydial Urethritis and Cervicitis: Clinical efficacy rates were 82.6% (300/363), 90.2% (166/184) in patients with male urethritis or cervicitis, respectively. The main causative organism was Chlamydia trachomatis. Most of the patients received a daily dose of 600 mg.
Soft Skin Tissue Infections: Clinical efficacy rate was 85.7% (323/377) in patients with soft skin tissue infections eg, folliculitis, furuncle, phlegmon, felon, subcutaneous abscess and infectious atheroma. The main causative organism was Staphylococcus sp. Most of the patients received a daily dose of 300 mg. Moreover, usefulness of the drug in these infections has been confirmed by a double-blind comparative study.
Infections in the Field of Surgery and Orthopedics: Clinical efficacy rate was 75.8% (72/95) in patients with surgical and orthopedical infections eg, secondary infections of trauma, burn and surgical trauma. The main causative organism was Staphylococcus sp. Most of the patients received a daily dose of either 300 or 400 mg.
Biliary Tract Infections: Clinical efficacy rate was 73.9% (68/92) in patients with biliary tract infections eg, cholecystitis and cholangitis. The main causative organisms were E. coli, K. pneumoniae and Enterobacter sp. Most of the patients received a daily dose of either 300 or 600 mg.
Infections in the Field of Otorhinolaryngology: Clinical efficacy rate was 71.7% (76/106) in patients with otorhinolaryngological infections eg, otitis media and sinusitis. The main causative organism was Staphylococcus sp. Most of the patients received a daily dose of 600 mg. Moreover, usefulness of the drug in otitis media has been confirmed by a double-blind comparative study.
Infections in the Field of Ophthalmology: Clinical efficacy rate was 94.6% (141/149) in patients with ophthalmological infections eg, hordeolum, dacryocystitis, tarsadenitis and keratohelcosis. The main causative organism was Staphylococcus sp. Most of the patients received a daily dose of 400 mg.
Infectious Enteritis: Clinical efficacy rate was 99.1% (107/108) in patients with infectious enteritis, eg bacillary dysentery and colitis. The main causative organisms were Shigella and Campylobacter spp. Most of the patients received a daily dose of either 400 or 600 mg. Moreover, usefulness of the drug in these infections has been confirmed by a double-blind comparative study.
Infections in the Field of Dental Surgery: Clinical efficacy rate was 80.9% (212/262) in patients with dental surgical infections eg, periodontitis, pericoronitis and gnathitis.
The main causative organism was Peptostreptococcus sp. Most of the patients received a daily dose of either 300 or 600 mg. Moreover, usefulness of the drug in these infections has been confirmed by a double-blind comparative study.
Adverse Reactions and Abnormal Laboratory Findings: A total of 6514 cases were treated with ofloxacin and adverse reactions were observed in 239 cases (3.7%). The major adverse reactions were gastrointestinal system disorders (159 cases; 2.4%) eg, abdominal pain, diarrhea, nausea and anorexia, psychoneurologic symptoms (48 cases; 0.7%) eg, insomnia and dizziness, hypersensitivity (33 cases; 0.5%) eg, rash. The major changes in the laboratory values were increase in GOT (2%; 63/3221), GPT (2.2%; 70/3168), BUN (0.8%; 23/2965), eosinophiles (2%; 46/2281) and decrease in leucocytes (0.5%; 18/3418).
In drug use investigation after approval, total 17,670 cases were treated with the drug, and adverse reactions were observed in 248 cases (1.4%).
Pharmacokinetics: Blood Concentration: The serum concentration of Tarivid increases dose-dependently when orally administered to healthy adults in a single dose.
When Tarivid was administered orally after meals at doses of 100, 200 and 300 mg, the maximal serum levels (1, 1.65 and 2.8 mcg/mL, respectively) were reached 2 or 3 hrs after administration. Its biological half-life at each dose was 3.6, 4.5 and 5.5 hrs, respectively.
Distribution: When a single dose of 200 mg of ofloxacin was administered to healthy adults or patients, the drug transferred to the following tissues in high concentrations: Sputum (3.08 mcg/mL 1 hr later), saliva (1.96 mcg/mL 2 hrs later), palatal tonsil (4.58 mcg/g approximately 1 hr later), prostate (6.25 mcg/g 2 hrs later), prostatic fluid (1.66 mcg/mL 2 hrs later), endometrium (4.76 mcg/g approximately 3 hrs later), oviduct (3.83 mcg/g approximately 3 hrs later), skin (2.24 mcg/g 2 hrs later), bile (2.57 mcg/mL 4 hrs later), gallbladder (2.3 mcg/g 4 hrs later), otorrhea, maxillary sinus mucosa and tears (1.36 mcg/mL 2 hrs later) and gingiva. The drug is also transferred to milk.
Metabolism and Excretion: The urinary concentration increased dose-dependently, when orally administered to healthy adults in a single dose. When 100 mcg of ofloxacin was administered after meal, the urinary concentration peaked at 115 mcg/mL in 2-4 hrs and declined to 36 mcg/mL in 12-24 hrs after administration. The majority of the drug is not metabolized in the body. More than 90% of the administered dose is excreted into the urine as an unchanged form and approximately 4% in the feces by 48 hrs after administration. When a single dose of 200 mg of ofloxacin was administered orally, the cumulative urinary excretion rates during the first 12 hrs after administration were 68% in the subjects with normal renal function [creatinine clearance (CrCl) ≥70], 43% in those in the middle level of renal impairment (50>CrCl ≥30) and 14% in those in the severe stage of renal impairment (CrCl<30), demonstrating the decreasing urinary excretion rate relative to the decreasing renal function.
Microbiology: Ofloxacin has a wide range of antibacterial spectrum against various gram-positive and gram-negative bacteria. Antibacterial activities of ofloxacin are 2- to 4-fold stronger than those of norfloxacin against Staphylococcus sp, hemolytic streptococci and enterococci. Meanwhile, ofloxacin has excellent activities as those of norfloxacin against Enterobacteriaceae, including E. coli, K. pneumoniae, Serratia and Proteus spp, glucose nonfermentative gram-negative rods, including P. aeruginosa, H. influenzae and N. gonorrhoeae. Especially, it has excellent effects against nalidixic acid-resistant Enterobacteriaceae, ABPC-resistant N. gonorrhoeae and gentamicin-resistant P. aeruginosa. Furthermore, it has excellent effects against anaerobic Peptostreptococcus sp. The effective doses (ED50) of ofloxacin in experimentally produced infectious diseases in mice were between ¼ and ½ of norfloxacin and between 1/40 and 1/8 of pipemidic acid, thus indicating an excellent effect of this drug in the prevention of infections.