Darflox

Darflox

prulifloxacin

Manufacturer:

Meiji

Distributor:

DKSH
Full Prescribing Info
Contents
Prulifloxacin.
Description
Each tablet contains prulifloxacin 132.1 mg equivalent to ulifloxacin 100 mg. Ulifloxacin is the active form of prulifloxacin.
Prulifloxacin is (1RS)-6-fluoro-1-methyl-4-oxo-7-(piperazin-1-yl)-4H[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid.
Action
Pharmacology: Mechanism of Action: Ulifloxacin is transferred into bacterial cells in high concentration and shows antibacterial activity by inhibiting the activity of DNA gyrase.
In vitro Antibacterial Activity: Ulifloxacin has a broad antibacterial spectrum against gram-positive and gram-negative bacteria. Especially, it shows potent antibacterial activity against gram-negative bacteria eg, Pseudomonas aeruginosa, Serratia marcescens and Enterobacter sp, etc. Ulifloxacin has a prompt and potent bactericidal activity and the minimum inhibitory concentration (MIC) value is nearly equal to the minimal bactericidal concentration (MBC) value; even in sub-MIC, it shows bactericidal activity.
Therapeutic Effect on Experimental Infections: In mice, prulifloxacin showed an excellent protective effect in experimental systemic infections and a good therapeutic effect on experimental infections eg, respiratory and urinary tract infections, etc, caused by Pseudomonas aeruginosa, etc.
Clinical Studies: The results of clinical studies, including comparative and open studies are summarized as follows. The usefulness of prulifloxacin in the treatment of patients with respiratory tract infections (secondary infections in chronic respiratory lesion, pneumonia) and complicated urinary tract infections (pyelonephritis, cystitis) was confirmed in double-blind comparative studies. (See Table 1.)

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Microbiology: Susceptible Bacteria: Ulifloxacin-susceptible strains of Staphylococcus sp, Streptococcus sp, Streptococcus pneumoniae, Enterococcus sp, Moraxella (Branhamella) catarrhalis, Escherichia coli, Shigella sp, Salmonella sp (excluding Salmonella typhi and Salmonella paratyphi), Citrobacter sp, Klebsiella sp, Enterobacter sp, Serratia sp, Proteus sp, Vibrio cholerae, Haemophilus influenzae, Pseudomonas aeruginosa and Peptostreptococcus sp.
Pharmacokinetics: Blood Concentration:
Prulifloxacin is a prodrug type of antibacterial agent that is absorbed in the upper small intestine after oral administration. It is hydrolyzed in intestinal tissue, portal vein, blood and liver, and distributed throughout the body as an active form, ulifloxacin. Table 2 shows pharmacokinetic parameters obtained after single oral administration of prulifloxacin 132.1, 264.2 or 528.4 mg (the approved single dose of prulifloxacin is 264.2-396.3 mg) to healthy adults at fasting. (See Table 2.)

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Protein Binding: Binding rates to human serum protein determined by ultrafiltration method were 50.9-52.1% in a ulifloxacin concentration range of 0.1-10 mcg/mL (in vitro).
Distribution: After oral administration of prulifloxacin 264.2 mg to patients, the maximum ulifloxacin concentrations in prostate, gallbladder, female genitalia, skin tissue, otorhinolaryngological tissue, ocular tissue and sputum were 1.21-8.25 mcg/g (mL) and the ratios to the serum concentrations were 1.79-58.2. Good transfer to body fluid and tissue was confirmed.
Metabolism and Excretion: Prulifloxacin was metabolized mainly to ulifloxacin in intestinal tissue, portal vein blood and liver. The metabolites of ulifloxacin included modified piperazinyl group and glucuronide were observed in plasma and urine. The cumulative urinary ulifloxacin excretion rates (0-24 hrs) in healthy adults administered with prulifloxacin 132.1 or 264.2 mg were 43.1% and 36.2%, respectively. No accumulation was observed after repeated administration of prulifloxacin.
Patients with Renal Function Disorder and Elderly: The pharmacokinetic parameters in patients with renal function disorder and elderly patients administered a single oral dose of prulifloxacin 264.2 mg after a meal are shown in Tables 3 and 4, respectively. As compared with healthy adults, prolonged half-life of serum ulifloxacin concentration, increased AUC and reduced cumulative urinary ulifloxacin excretion rates were observed. (See Tables 3 and 4.)

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Indications/Uses
Superficial skin and deep skin infections, chronic pyoderma, secondary infections in traumas, burns or surgical wounds, etc, perianal abscess, pharyngitis/laryngitis, tonsillitis, acute bronchitis, pneumonia, secondary infections in chronic respiratory lesion, cystitis, pyelonephritis, prostatitis (acute, chronic), cholecystitis, cholangitis, infectious enteritis, cholera, intrauterine infection, uterine adnexitis, hordeolum, otitis media, sinusitis.
Dosage/Direction for Use
Adults: Usual Dose: Prulifloxacin 264.2 mg (200 mg as an active form) orally twice a day. The dosage may be adjusted according to the symptoms. The maximum dosage is limited to prulifloxacin 396.3 mg (300 mg as an active form) at one time.
Pneumonia or Secondary Infections in Chronic Respiratory Lesion: Prulifloxacin 396.3 mg (300 mg as an active form) orally twice a day.
Contraindications
Patients with a history of hypersensitivity to any of the ingredients of Darflox. Patients receiving treatment with fenbufen, flurbiprofen axetil or flurbiprofen (see Interactions).
Use in Pregnancy & Lactation: Darflox should not be used in pregnant women or women who may possibly be pregnant. (The safety of prulifloxacin in pregnant women has not been established.)
In the teratogenicity study (30, 300 and 3000 mg/kg) in rats, inhibited fetal development was observed at the higher dose, while in the teratogenicity study (10, 30 and 100 mg/kg) in rabbits, increased frequency of premature delivery and fetal death in late pregnancy were noted. However, teratogenic action was not found in these studies. It is advisable to avoid using prulifloxacin in lactating mothers. If use of this product is judged to be essential, breastfeeding must be discontinued during treatment.
[It has been reported that prulifloxacin is excreted in breast milk in animal studies (rats).]
Use in Children: Since the safety of prulifloxacin in low birth weight infants, newborns, suckling infants, infants and children has not been established, this product should not be administered to pediatric patients.
Special Precautions
Careful Administration (Darflox should be administered with care in the following patients): Patients with severe renal disorder [since high blood concentration persists, the dose should be reduced or dosing intervals should be prolonged (see Pharmacokinetics under Actions)]; patients with convulsive disorders eg, epilepsy or with a history thereof (convulsions may occur); elderly.
Dysarthrosis has been observed in animal studies (juvenile dogs: Dose 20 and 80 mg/kg/day for 7 consecutive days).
In the animal study using monkeys, accumulation of ulifloxacin has been observed in the eyes (choroid, pigment epithelium) after long-term administration for 52 weeks.
In the case of patients with a remarkably low stomach acid state eg, achlorhydria, it is considered that the absorption of Darflox is decreased by the elevated pH in the stomach and the decreased solubility of Darflox.
Carcinogenicity: In the medium-term carcinogenicity study in rats (0.15%, 0.5% and 1.5% in diet), prulifloxacin slightly increased the generation of GST-P positive hepatocellular foci in the liver at the higher dose, but this was regarded as a very minor change in view of the high dose at which it occurred as well as its minor level. Moreover, no neoplastic lesion was found by the histopathological examination.
Mutagenicity: In the chromosomal aberration test using in vitro CHL cells, prulifloxacin increased the frequency of occurrence of cells with structural chromosome aberrations. However, no mutagenicity was detected in the reverse mutation test in bacteria, chromosomal aberration tests in human peripheral blood lymphocytes and in micronucleus test in mice.
Use in the elderly: Because pharmacokinetic studies in elderly patients have shown prolonged half-life of prulifloxacin and high blood concentration may persist, Darflox should be administered with care eg, reduction of the dose or prolonging dosing intervals (see Pharmacokinetics under Actions).
Use In Pregnancy & Lactation
Darflox should not be used in pregnant women or women who may possibly be pregnant. (The safety of prulifloxacin in pregnant women has not been established.)
In the teratogenicity study (30, 300 and 3000 mg/kg) in rats, inhibited fetal development was observed at the higher dose, while in the teratogenicity study (10, 30 and 100 mg/kg) in rabbits, increased frequency of premature delivery and fetal death in late pregnancy were noted. However, teratogenic action was not found in these studies. It is advisable to avoid using prulifloxacin in lactating mothers. If use of this product is judged to be essential, breastfeeding must be discontinued during treatment.
[It has been reported that prulifloxacin is excreted in breast milk in animal studies (rats).]
Adverse Reactions
In a total of 2936 patients evaluated for the safety Darflox, 172 episodes of adverse reactions were observed in 131 patients (4.46%). The main adverse reactions were abdominal pain, diarrhea and nausea, etc. In a total of 2584 patients, 240 changes in laboratory values were observed in 148 patients (5.73%). The main changes were increased AST (GOT) and increased ALT (GPT) etc.
Clinically Significant Adverse Reactions: Shock or anaphylactoid reaction (incidence unknown) may occur. Patients should be carefully monitored and if any symptoms eg, dyspnea, decreased blood pressure, generalized redness, urticaria or face edema occur, administration should be discontinued and appropriate measures should be taken.
Rhabdomyolysis (<0.1%) which is characterized by myalgia, feelings of weakness, increased CK (CPK) and increased myoglobin in blood or urine and is accompanied by abrupt aggravation of renal function may occur. Patients should be carefully monitored and if any abnormality is observed, administration should be discontinued and appropriate measures should be taken.
Hypoglycemia (incidence unknown) may occur. (Hypoglycemia is more frequently observed in elderly patients, patients with renal disorder or diabetes mellitus.) Patients should be carefully monitored and if any symptoms eg, depressed level of consciousness, convulsion or general malaise occur, administration should be discontinued and appropriate measures should be taken.
Clinically Significant Adverse Reactions (Similar Drugs): The following clinically significant adverse reactions (<0.1%) have been reported in patients treated with other new quinolones. Patients should be carefully monitored and if any abnormality is observed, administration should be discontinued and appropriate measures should be taken. Muco-cutaneo-ocular syndrome (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome); pancytopenia, agranulocytosis, hemolytic anemia, thrombocytopenia; serious renal disorder eg, acute renal failure; hepatic function disorder, jaundice; ventricular tachycardia (including Torsades de pointes), QT prolongation; tendon disorder eg, Achilles tendonitis or tendon rupture (symptoms: Pain in the periphery of tendons, edema); serious colitis with bloody stool eg, pseudomembranous colitis (symptoms: Abdominal pain, frequent diarrhea, etc); interstitial pneumonia (symptoms: Fever, cough, dyspnea, abnormal chest X-ray, eosinophilia, etc) (treatment: Administration of adrenocortical hormones); convulsion; psychiatric symptoms eg, confusion, depression, etc; vasculitis.
Others: The following adverse reactions may occur. If any abnormalities are observed, appropriate measures eg, discontinuation of administration should be taken according to the symptoms.
Hypersensitivity: <5%, ≥0.1%: Rash. <0.1%: Eczema, itching, urticaria. Incidence Unknown: Edema, photosensitivity.
Renal: <5%, ≥0.1%: Increased BUN and creatinine, hematuria.
Hepatic: <5%, ≥0.1%: Increased AST (GOT), ALT (GPT), Al-P, LDH, γ-GTP, LAP and bilirubin.
Gastrointestinal: <5%, ≥0.1%: Abdominal pain, diarrhea, nausea, vomiting, anorexia, dyspepsia, stomatitis. <0.1%: Constipation, angular stomatitis.
Hematologic: <5%, ≥0.1%: Leucopenia, thrombocytopenia, eosinophilia.
Psychoneurologic: <5%, ≥0.1%: Headache, dizziness. <0.1%: Insomnia, sleepiness.
Others: <5%, ≥0.1%: Chest pain, feelings of weakness, increased CK (CPK). <0.1%: Fever, tinnitus, dyspnea, palpitation, myalgia, malaise, hot flush, conjunctival hyperaemia.
Drug Interactions
Darflox should not be co-administered with the following drugs: Fenbufen, Flurbiprofen axetil, Flurbiprofen: Signs, Symptoms and Treatment: Convulsions may occur. If any symptom is observed, appropriate measures eg, discontinuation of both drugs should be taken.
Mechanism and Risk Factors: It is considered that the inhibitory action of prulifloxacin against GABAA receptor binding may be enhanced by co-administration and as a result convulsions may be induced.
Darflox should be administered with care when co-administered with the following drugs: Theophylline, Aminophylline, etc: Signs, Symptoms and Treatment: Blood concentration of theophylline may be increased and effects of theophylline may be enhanced. In case of co-administration, appropriate measures eg, reducing the dose of theophylline should be taken.
Mechanism and Risk Factors: It is considered that theophylline metabolism in the liver is inhibited by slight inhibitory action of prulifloxacin against CYP1A and blood concentration of theophylline is increased as a result. Careful attention should be particularly paid to elderly patients and patients with renal disorder.
Nonsteroidal Anti-Inflammatory Drugs of Phenylacetic Acid Derivatives (Fenbufen is contraindicated for co-administration): Diclofenac, etc; Propionic Acid Derivatives (Flurbiprofen axetil and flurbiprofen are contraindicated for co-administration): Ketoprofen, etc: Signs, Symptoms and Treatment: Convulsions may occur. If any symptom is observed, appropriate measures eg, discontinuation of both drugs should be taken.
Mechanism and Risk Factors: It is considered that the inhibitory action of prulifloxacin against GABAA receptor binding may be enhanced by co-administration and convulsions may be induced as a result. Careful attention should be particularly paid to patients with convulsive disorders eg, epilepsy, patients with a history of such disorders, elderly and patients with renal disorder.
Antacids Containing Aluminum or Magnesium, Iron Preparations, Preparations Containing Calcium: Signs, Symptoms and Treatment: The effect of prulifloxacin may be reduced. Careful attention should be paid to administration of these drugs. For example, these drugs should be administered at intervals of >2 hrs after administration of prulifloxacin.
Mechanism and Risk Factors: It is considered that the absorption of prulifloxacin is inhibited by the chelate formation with metal ion of these drugs.
H2-Receptor Antagonist eg, Cimetidine, etc; Proton Pump Inhibitor eg, Omeprazole, etc: Signs, Symptoms and Treatment: The effect of prulifloxacin may be reduced.
Mechanism and Risk Factors: It is considered that the absorption of prulifloxacin is decreased, as a result of the elevated pH in the stomach by these drugs and the decreased solubility of Darflox.
Caution For Usage
Precaution for Dispensing: In the case of press-through packages (PTP), the patient must be instructed to remove Darflox from the package prior to use. (If the PTP sheet is swallowed, its sharp corners may penetrate the esophageal mucosa, leading to serious complications eg, mediastinitis.)
Storage
Store below 25°C.
MIMS Class
ATC Classification
J01MA17 - prulifloxacin ; Belongs to the class of fluoroquinolones. Used in the systemic treatment of infections.
Presentation/Packing
Tab 100 mg x 100's.
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