Ofloxacin is (±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido [1,2,3,-de][1,4]benzoxazine-6-carboxylic acid.
Ofloxacin has a molecular formula of C18H20FN3O4, molecular weight of 361.37 and melting point of 260-270°C (decomposition). Ofloxacin occurs as pale yellowish-white to light yellowish-white crystals or crystalline powder, is odorless and has a bitter taste. It is freely soluble in glacial acetic acid, sparingly soluble in chloroform, slightly soluble in water, methanol, ethanol and acetone and very slightly soluble in ethyl acetate. It is slowly colorized by light and has no specific rotation.
pH: 6-7. Osmotic pressure ratio (respect to physiological saline) 1-1.2.
Tarivid Otic Solution also contains benzalkonium chloride as inactive ingredient.
Pharmacology: Tarivid otic solution is an antibacterial otic preparation containing ofloxacin, quinoline derivative, originating from Daiichi Pharmaceutical Co., Ltd.
Tarivid otic solution has a wide range of antibacterial spectrum against various gram-positive and gram-negative bacteria. MIC80 of ofloxacin against clinical isolates including Staphylococcus sp, Streptococcus sp, Pseudomonas aeruginosa and Haemophilus influenzae in otitis media and otitis externa was ¼ of cefmenoxime and 1/64 of fosfomycin, thus indicating an excellent antibacterial effect. Especially, MIC80 of ofloxacin against Staphylococcus aureus and Pseudomonas aeruginosa, major causal bacteria, in otitis media and otitis externa, were ¼ and 1/8 of cefmenoxime and 1/64 and 1/32, respectively.
Tarivid otic solution shows excellent effects on otitis media and otitis externa by eardrop and maintenance in the ear. It is a stable and convenient solution preparation.
Mechanism of Action: Ofloxacin is considered to specifically act on bacterial DNA gyrase and thus, inhibit DNA synthesis in microorganisms. Its antibacterial activity is bactericidal and causes bacteriolysis at MIC.
Clinical Studies: Clinical Efficacy: Otitis Media: In the general clinical trials in patients with tympanitis when the drug is instilled once or twice a day, clinical efficacy rate was 86.6% (175/202 cases) in patients with otitis media. Among these, the efficacy rate was 88.2% (142/161 cases) in patients administered twice a day. On the other hand, the efficacy rate was 91.75 (66/72 cases) in children (<15 years). Moreover, its efficacy has been confirmed in a double-blind comparative study in patients with tympanitis using oral cefalexin as a basal medication and a placebo as a control.
Otitis Externa: In general clinical trials on otitis externa, when the drug was instilled once or twice a day, clinical efficacy rate was 80.2% (65/81 cases) in patients with otitis externa, Among these, the efficacy rate was 81.7% (49/60 cases) in patients when administered twice a day. The efficacy rate was 84.2% (16/19 cases) in children (<15 years).
Bacterial Eradication: In general clinical trials on tympanitis and otitis externa, bactericidal efficacy rate by instillation of Tarivid otic solution once or twice a day were 97.8% (89/91 strains) for Staphylococcus aureus and 92.6% (63/68 strains) for coagulase-negative Staphylococci. All 18 strains of Streptococcus sp, including Streptococcus pyogenes (3 strains) and Streptococcus pneumoniae (4 strains), were eradicated. Proteus vulgaris (2 strains) was completely eradicated. The eradication rate was 83.3% (5/6 strains) for Proteus mirabilis, while 32 strains of Pseudomonas and 6 strains of Haemophilus influenzae were all eradicated.
Adverse Reaction: In a general clinical trial and double-blind comparative study on otitis media or otitis externa, adverse reactions were reported in 2 patients (0.5%), earaches (0.5%, 2 cases) and itching (0.2%, 1 case) in 424 patients including 110 children (<15 years). No adverse reactions were observed in the children. Laboratory examinations were performed in 52 patients, revealing no abnormal changes. In addition, audiometry was also performed in 100 patients and no cases of hearing reducing were observed.
Non-Clinical Studies: Absorption and Distribution: When a single dose of 0.3% ofloxacin solution was administered into the cavity of the middle ear of guinea pigs at 1 mg/kg, the intracerebral concentration reached its peak level in proportion to the serum concentration 15 min after administration, and its concentration ratio to serum concentration ranged from 1/5-1/10 until 8 hrs later, revealing a low value. Moreover, when this agent was administered orally, the ratio similarly ranged from 1/3-1/10, suggesting ofloxacin has diffused into the brain through the blood circulatory system after administration into the cavity of the middle ear. Thus, the fact that ofloxacin diffused into the lymphatic system but not directly into the brain has been confirmed by the finding of cranial autoradiogram when 0.3% 14C-ofloxacin solution was administered as a single dose into the cavity of the middle ear.
Pharmacokinetics: Blood Concentration: When 0.3% ofloxacin solution was instilled and allowed to stand in the middle ear cavity at 10 drops per administration twice a day for 7 days (total of 14 times) in adult patients, the serum concentration 30 min after administration ranged from 0.009-0.012 mcg/mL, showing a low value. Furthermore, when a single administration of ofloxacin solution at 5 drops per administration was instilled and allowed to stand in the cavity of the middle ear in children, the serum concentration 120 min after administration was ≤0.013 mcg/mL, similarly showing a low value.
Distribution: When 0.3% ofloxacin solution was instilled and allowed to maintain in the middle ear cavity at 10 drops per administration twice a day for 10 days (total of 19 times) in adult patients, the concentration in the mucosa of the middle ear 90 min after administration was 20 mcg/g, and when a single administration of 0.1% ofloxacin solution at 10 drops was instilled, the concentration in the otorrhea in 30 min after administration ranged from 107-610 mcg/mL, showing a high value.
Toxicology: 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 a 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, rats showed roughened fur, soft stool and depression of body weight gain. In addition to these changes, rare fraction 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.
Chronic Toxicity: Following a 6-month administration to rats, no noticeable changes were observed up to 30 mg/kg. At 90 and 270 mg/kg, salivation, soft stool, enhancement of spontaneous lesions in the cartilage and enhancement of lipid deposition in cortical cells of the adrenal glands were observed.
Ototoxicity: No significant changes associated with acoustic brainstem reaction, or no impairments of the mucosa of middle ear or cochlear hair cells were observed when 0.5% ofloxacin solution was administered into the cavity of the middle ear of guinea pigs once a day for 7-10 days.
Antigenicity: No antigenicity was suggested from the systemic 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 antibodies 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.
Treatment of the following infections caused by ofloxacin-susceptible strains of Staphylococcus, Streptococcus and Proteus spp, Pseudomonas aeruginosa and Haemophilus influenzae.
Adults: 6-10 drops of Tarivid Otic Solution are usually instilled into the ear twice daily. The ear drops should be maintained in the ear for about 10 min.
The frequency of administration should be adjusted to individuals depending on the severity of symptoms. The dosage should be reduced appropriately for children.
As a general rule, the duration of administration of Tarivid Otic Solution should be limited to the minimum period required for the treatment of the patient's condition, after susceptibility of the microorganism to the drug has been confirmed, in order to prevent the emergence of drug-resistant microorganisms.
Patients with a history of hypersensitivity to ofloxacin.
As a general rule, the duration of treatment with Tarivid Otic Solution should be 4 weeks as a standard. Continuing administration after 4 weeks should not be desultory and drug administration should be done with caution.
Route of Administration: Use only for instillation into ear.
Method of Treatment: Topical therapy by the instillation of Tarivid Otic Solution is generally applicable when inflammation is localized in the mucosa of the middle ear in patients with tympanitis. When inflammation is extended into the region around the tympanum, systemic therapy with oral agents should be considered in combination with topical therapy.
Administration: If the solution is cold, dizziness may occur. Thus, use Tarivid Otic Solution at temperature as similar to that of the body temperature as possible.
Co-administration of the oral administration of ofloxacin with nonsteroidal anti-inflammatory drugs of phenylacetic/propionic acid derivatives may possibly cause convulsions. However, when Tarivid Otic Solution was topically instilled and allowed to stand in the ear, the peak blood concentration was 1/100 compared to oral administration. Therefore, there is practically no possibility that concomitant use with these anti-inflammatory analgesics may induce convulsions.
Oral administration of ofloxacin is contraindicated in children since the safety in children has not been established and animal studies have shown that ofloxacin may produce arthropathy in juvenile animals. However, when Tarivid Otic Solution was topically instilled and allowed to stand in the ear, the peak blood concentration was 1/100 compared to oral administration. Safety has been confirmed in the clinical trials in children, and it is possible to use this drug for children.
If hypersensitivity symptoms are observed, discontinue Tarivid Otic Solution.
Application Site (0.1% to <5%):
Substituted microbism may occur infrequently (0.1% to <5%).
Store at room temperature (below 25°C).
Shelf-Life: 5 years.
S02AA16 - ofloxacin ; Belongs to the class of antiinfectives used in the treatment of ear infections.
Ear soln 3 mg/mL (pale yellow to light yellow, clear) aseptic preparation x 5 mL x 1's, 10's.