Gemifloxacin

389.39

389.38

DTXSID3048495

Off-white, amorphous solid from chloroform-ethanol

J - Antiinfectives for systemic use

2933990090

123.04000

0.38

1'+-.0.1 g/cm3(Predicted)

235-237°

638.9±65.0 °C(Predicted)

340.2±34.3 °C

1.735

In water, 1.31X10+4 mg/L at 25 °C (est)

1.04 mm Hg at 25 °C (est)

Henry's Law constant = 1.03X10-23 atm-cu m/mol at 25 °C (est)

pKa1 = 6.4 /COOH/; pKa2 = 9.0 /NH2/

White to light brown solid. Freely soluble at neutral pH (350 ug/mL at 37 °C, pH 7.0) /Gemifloxacin mesylate/|Hydroxyl radical reaction rate constant = 5.53X10-11 cu cm/molec-sec at 25 °C (est)|Ozone radical reaction rate constant = 1.75X10-18 cu cm/molec-sec at 25 °C (est)

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including gemifloxacin mesylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Gemifloxacin mesylate/

Gemifloxacin (jem" i flox' a sin), like other fluoroquinolones, is associated with a low rate (1% to 7%) of serum enzyme elevations during therapy, although this rate may be slightly higher than occurs with placebo or comparative agents. These abnormalities are generally mild, asymptomatic and transient, resolving even with continuation of therapy. Too few cases of hepatotoxicity due to gemifloxacin have been reported to provide a reliable description of its clinical features and course. However, the liver injury due to the fluoroquinolones appears to be a class effect, and gemifloxacin injury appears to share these characteristics. It is a far less common cause of liver injury than ciprofloxacin, levofloxacin or moxifloxacin, but cases have been reported. In general, fluoroquinone hepatotoxicity is marked by a short time to onset (a few days to 3 weeks); often presenting abruptly with marked nausea, fatigue, abdominal pain and jaundice. The pattern of serum enzyme elevations can be either hepatocellular or cholestatic, and cases with the shorter times to onset are usually more hepatocellular with markedly elevated ALT levels, and occasionally, with rapid worsening of prothrombin time and signs of hepatic failure. The onset of illness may occur a few days after the medication is stopped. Many (but not all) cases have had allergic manifestations with fever, rash and eosinophilia. Autoantibodies are usually not present.

Possible pharmacologic interaction /with warfarin/ (increased prothrombin time (PT), international normalized ratio (INR), and/or bleeding). Consider that infectious disease and its accompanying inflammatory process, age, and general status of the patient also are risk factors for increased anticoagulation activity. Closely monitor PT, INR, or other suitable coagulation test.|Pharmacokinetic interaction (decreased absorption of gemifloxacin). Gemifloxacin should be taken at least 2 hours before sucralfate.|Pharmacokinetic interaction /with probenecid/ (decreased clearance of gemifloxacin).|Pharmacokinetic interaction (decreased absorption of gemifloxacin). Dietary supplements containing metal cations such as zinc, magnesium, or iron (e.g., multivitamins, ferrous sulfate) should be taken at least 3 hours before or 2 hours after gemifloxacin.|For more Interactions (Complete) data for Gemifloxacin (11 total), please visit the HSDB record page.

Avoid Factive in patients with known history of myasthenia gravis.|Fluoroquinolones may prolong the QT interval in some patients. FACTIVE should be avoided in patients with a history of prolongation of the QTc interval, patients with uncorrected electrolyte disorders (hypokalemia or hypomagnesemia), ... .|Concomitant use of corticosteroids increases the risk of severe tendon disorders (e.g., tendinitis, tendon rupture), especially in geriatric patients older than 60 years of age.|Rash has been reported in approximately 2.7% of patients receiving gemifloxacin in clinical studies. Urticarial reactions (some not classified as rash) were reported in approximately 0.6% of patients receiving gemifloxacin in clinical studies. The most common form of rash associated with gemifloxacin appears to be mild to moderate maculopapular rash; approximately 10% of rash cases are described as severe. Histologic examination confirmed presence of an uncomplicated exanthematous skin reaction and revealed no evidence of phototoxicity, vasculitis, or necrosis. In clinical studies, 80% of rashes resolved within 14 days; approximately 10% of the rashes (0.5% of patients) were described as severe and 10% of those with rashes were treated with corticosteroids. Rash occurred most frequently in patients younger than 40 years of age (especially females), in women receiving hormone replacement therapy, and in patients who received gemifloxacin for longer than 7 days (although this was not evident in men 40 years of age and older); the reason for this observation has not been clearly elucidated. Although no morbidity or mortality attributable to severe skin reactions has been reported with gemifloxacin in clinical trials, the manufacturer states that gemifloxacin should be discontinued at the first appearance of a rash or any other sign of hypersensitivity.|Seizures, increased intracranial pressure, psychoses, and CNS stimulation, which may lead to tremor, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, insomnia, and rarely, suicidal thoughts or acts, have been reported in patients receiving fluoroquinolones. These reactions have not been reported to date in clinical trials with gemifloxacin. Gemifloxacin should be used with caution in patients with known or suspected CNS disorders (e.g., seizure disorders) or other risk factors predisposing to seizures. If CNS effects occur, gemifloxacin should be discontinued and appropriate measures instituted.

While data specific to gemifloxacin were not located(SRC, 2012), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soils(1).

Gemifloxacin is a fourth generation, oral fluoroquinolone antibiotic used in the therapy of mild-to-moderate respiratory tract infections caused by susceptible organisms. Gemifloxacin has been linked to rare instances of acute liver injury.

Antiinfective Agents

Anti-Bacterial Agents|Gemifloxacin is used for the treatment of acute bacterial exacerbation of chronic bronchitis caused by susceptible Streptococcus pneumoniae, Haemophilus influenzae, H. parainfluenzae, or Moraxella catarrhalis. /Included in US product label/|Gemifloxacin is used for the treatment of community-acquired pneumonia (CAP) of mild to moderate severity caused by susceptible S. pneumoniae (including multidrug-resistant strains), H. influenzae, M. catarrhalis, Mycoplasma pneumoniae, Chlamydophila pneumoniae (formerly Chlamydia pneumoniae), or Klebsiella pneumoniae. /Included in US product label/

/BOXED WARNING/ WARNING: Fluoroquinolones, including Factive, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart and lung transplants.|/BOXED WARNING/ WARNING: Fluoroquinolones, including Factive, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid Factive in patients with known history of myasthenia gravis|Fluoroquinolones, including gemifloxacin, cause arthropathy and osteochondrosis in immature animals of various species. The relevance of these adverse effects in immature animals to use in humans is unknown.|Fluoroquinolones, including gemifloxacin, are associated with increased risk of tendinitis and tendon rupture in all age groups. This risk is further increased in older adults (usually those older than 60 years of age), individuals receiving concomitant corticosteroids, and kidney, heart, or lung transplant recipients. Other factors that may independently increase risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have been reported in patients receiving fluoroquinolones who did not have any of these risk factors. Fluoroquinolone-associated tendinitis and tendon rupture most frequently involve the Achilles tendon and may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (shoulder), hand, biceps, thumb, and other tendon sites also reported. Tendon rupture can occur during or following fluoroquinolone therapy and has been reported up to several months after completion of therapy. Advise patients to rest and refrain from exercise and contact a clinician at the first sign of tendinitis or tendon rupture (e.g., pain, swelling, or inflammation of a tendon or weakness or inability to use a joint). Discontinue gemifloxacin if pain, swelling, inflammation, or rupture of a tendon occurs.|For more Drug Warnings (Complete) data for Gemifloxacin (21 total), please visit the HSDB record page.

Compounds that inhibit the activity of DNA TOPOISOMERASE II. Included in this category are a variety of ANTINEOPLASTIC AGENTS which target the eukaryotic form of topoisomerase II and ANTIBACTERIAL AGENTS which target the prokaryotic form of topoisomerase II. (See all compounds classified as Topoisomerase II Inhibitors.)|Substances that inhibit the growth or reproduction of BACTERIA. (See all compounds classified as Anti-Bacterial Agents.)

Gemifloxacin, given as an oral tablet, is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations of gemifloxacin were observed between 0.5 and 2 hours following oral tablet administration and the absolute bioavailability of the 320 mg tablet averaged approximately 71% (95% CI 60%-84%). Following repeat oral doses of 320 mg to healthy subjects, the mean + or - SD maximal gemifloxacin plasma concentrations (Cmax) and systemic drug exposure (AUC (0-24)) were 1.61 + or - 0.51 ug/mL (range 0.70-2.62 ug/mL) and 9.93 + or - 3.07 ug.hr/mL (range 4.71-20.1 ug.hr/mL), respectively. In patients with respiratory and urinary tract infections (n=1423), similar estimates of systemic drug exposure were determined using a population pharmacokinetics analysis (geometric mean AUC (0-24), 8.36 ug.hr/mL; range 3.2 -47.7 ug.hr/mL).|In vitro binding of gemifloxacin to plasma proteins in healthy subjects is approximately 60 to 70% and is concentration independent. After repeated doses, the in vivo plasma protein binding in healthy elderly and young subjects ranged from 55% to 73% and was unaffected by age. Renal impairment does not significantly affect the protein binding of gemifloxacin. The blood-to-plasma concentration ratio of gemifloxacin was 1.2:1. The geometric mean for Vdss/F is 4.18 L/kg (range, 1.66 - 12.12 L/kg). Gemifloxacin is widely distributed throughout the body after oral administration. Concentrations of gemifloxacin in bronchoalveolar lavage fluid exceed those in the plasma. Gemifloxacin penetrates well into lung tissue and fluids.|Gemifloxacin and its metabolites are excreted via dual routes of excretion. Following oral administration of gemifloxacin to healthy subjects, a mean (+ or - SD) of 61 + or - 9.5% of the dose was excreted in the feces and 36 + or - 9.3% in the urine as unchanged drug and metabolites. The mean (+ or - SD) renal clearance following repeat doses of 320 mg was approximately 11.6 + or - 3.9 L/hr (range 4.6-17.6 L/hr), which indicates active secretion is involved in the renal excretion of gemifloxacin. The mean (+ or - SD) plasma elimination half-life at steady state following 320 mg to healthy subjects was approximately 7 + or - 2 hours (range 4-12 hours).

Gemifloxacin is metabolized to a limited extent by the liver. The unchanged compound is the predominant drug-related component detected in plasma (approximately 65%) up to 4 hours after dosing. All metabolites formed are minor (<10% of the administered oral dose); the principal ones are N-acetyl gemifloxacin, the E-isomer of gemifloxacin and the carbamyl glucuronide of gemifloxacin. Cytochrome P450 enzymes do not play an important role in gemifloxacin metabolism, and the metabolic activity of these enzymes is not significantly inhibited by gemifloxacin.

Gemifloxacin has an elimination half life of about 7 hours.

Like other fluoroquinolone anti-infective agents, gemifloxacin inhibits DNA synthesis in susceptible organisms via inhibition of type II DNA topoisomerases (DNA gyrase, topoisomerase IV). However, unlike many other fluoroquinolones, gemifloxacin targets both DNA gyrase and topoisomerase IV in susceptible S. pneumoniae. Although cross-resistance can occur between gemifloxacin and other fluoroquinolones, gemifloxacin may be active against some strains of S. pneumoniae resistant to ciprofloxacin and other fluoroquinolones.|The fluroquinolone gemifloxacin was examined for its capacity to modulate secretion of cytokines by human monocytes stimulated with lipopolysaccharide (LPS). Monocytes from six male and two female healthy volunteers were stimulated with LPS, exposed to gemifloxacin and the amounts of secreted IL-1 alpha, IL-1 beta, IL-6, IL-10 and TNF-alpha measured at 3, 6 and 24 h. The results revealed that LPS alone increased secretion of each cytokine significantly. Treatment of the LPS-stimulated monocytes with gemifloxacin resulted in a significant inhibition (p < 0.01) of secretion of each of the cytokines from monocytes of the eight volunteers. Nuclear extracts of the human monocyte cell line, THP-1, were used in the electrophoretic mobility shift assay to determine whether gemifloxacin affects nuclear factor-kappa B (NF-kappa B) activation. In addition, RNA from THP-1 cells was used in Northern blots to determine whether inhibition of secretion of IL-1 beta and TNF-alpha by gemifloxacin occurred at the transcription or translation level. Whereas LPS induced a rapid increase in NF-kappa B activation, gemifloxacin alone did not. Gemifloxacin did not affect the kinetics or decrease the extent of activation. Northern blots indicated that the inhibitory activity of gemifloxacin occurred post-transcription. Thus, gemifloxacin may modulate the immune response by altering secretion of cytokines by human monocytes. Although the concentrations of gemifloxacin used were higher than those observed in the serum of human volunteers treated with the dose under clinical development, it should be taken into consideration that concentrations at tissue and intracellular levels may be considerably higher than serum concentrations.|Fluoroquinolones prolong the QT interval by blocking voltage-gated potassium channels, especially the rapid component of the delayed rectifier potassium current I(Kr), expressed by HERG (the human ether-a-go-go-related gene). According to the available case reports and clinical studies, moxifloxacin carries the greatest risk of QT prolongation from all available quinolones in clinical practice and it should be used with caution in patients with predisposing factors for Torsades de pointes (TdP).

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Emergency and supportive measures: Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, anaphylaxis, and hemolysis if they occur. replace fluid losses resulting from gastroenteritis with IV crystalloids. ... /Antibacterial agents/|For more Antidote and Emergency Treatment (Complete) data for Gemifloxacin (6 total), please visit the HSDB record page.

/CASE REPORTS/ ... Fluoroquinolones are associated with various neuropsychiatric side effects, such as seizures, insomnia, confusion, lightheadedness, psychosis, paranoia and hallucinations. ... A case of a 36-year-old woman given gemifloxacin for an upper respiratory tract infection who developed acute dystonia on the third day following therapy initiation /is reported/.|/CASE REPORTS/ A 67-year-old woman presented to the emergency department with an acute alteration in mental status. Twenty-four hours earlier she had taken one 320 mg tablet of her husband's gemifloxacin prescription to treat symptoms of a mild upper respiratory infection. During her initial evaluation at our institution, the woman was dysphasic, unable to follow commands, and agitated, suggesting encephalopathy. A thorough diagnostic investigation did not reveal any structural, metabolic, or infectious etiology. Her mental status returned to normal within 2 days without any definitive treatment. Fluoroquinolone-associated neurotoxicity may manifest as encephalopathy, seizures, confusion, or toxic psychosis. To date, none of these adverse effects, specifically encephalopathy, has been reported with gemifloxacin. An objective causality assessment revealed that encephalopathy was probably associated with gemifloxacin use. Seizures, either convulsive or nonconvulsive, may have contributed to our patient's presentation, but she denied seizures prior to this event and did not suffer a seizure in the 18 months following her discharge. However, her second electroencephalograph revealed an underlying predisposition to seizures, which gemifloxacin may have unmasked. This report illustrates that severe central nervous system adverse effects associated with some fluoroquinolones may also occur with gemifloxacin. Gemifloxacin and other fluoroquinolones should be considered in the etiologic evaluation of patients with acute encephalopathy.

7-(3-aminomethyl-4-methoxyimino-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-(1,8)-naphthyridine-3-carboxylic acid

Oral: Tablets, film-coated: 320 mg (of gemifloxacin) Factive (Oscient). /Gemifloxacin mesylate/

A sensitive electroanalytical method for determination of gemifloxacin in pharmaceutical formulation has been investigated on the basis of the enhanced electrochemical response at multi-walled carbon nanotubes modified glassy carbon electrode in the presence of CTAB /cetyltrimethyl ammonium bromide/. Solubilized system of different surfactants including SDS, Tween-20 and CTAB were taken for the study of electrochemical behaviour of gemifloxacin at modified electrode. The reduction peak current increases in the presence of CTAB while other surfactants show opposite effect. The modified electrode exhibits catalytic activity, high sensitivity, stability and is applicable over wide range of concentration for the determination of gemifloxacin. The mechanism of electrochemical reduction of gemifloxacin has been proposed on the basis of CV /voltametric behavior/, SWV /square wave voltammetry/, DPV /differential pulse voltammetry/ and coulometeric techniques. The proposed squarewave voltammetric method shows linearity over the concentration range 2.47-15.5 ug/mL. The achieved limits of detection (LOD) and quantification (LOQ) are 0.90 ng/mL and 3.0 ng/mL respectively.

... /A/ high-performance liquid chromatographic method with fluorescence detection was developed and validated for the determination of gemifloxacin (GEM) in rat plasma using furosemide as internal standard (I.S.). Plasma samples were pretreated by direct deproteinization and all samples and standard solutions were chromatographed at 45 °C using triethylamine solution (0.5%, v/v, pH 3.0 + or - 0.1), methanol and acetonitrile (63:30:7, v/v/v) as the mobile phase. Chromatographic resolution was achieved using a RP-C(18) column (Atlantis, Waters, 150 mm x 4.6 mm, 5 um) at a flow rate of 1.0 mL min(-1) and an injection volume of 30 uL. The analytes were measured by fluorescence detection with excitation and emission wavelengths of 344 nm and 399 nm, respectively. The retention times for GEM and I.S. were approximately 7.5 and 12.6 min, respectively. The lower limit of quantitation (LLOQ) was 20 ng mL(-1) and the calibration curves were linear over a concentration range of 20-5000 ng mL(-1).|Two new, sensitive and selective spectrofluorimetric methods have been developed for the determination of gemifloxacin (GFX) in tablets and spiked plasma samples. Gemifloxacin, as a primary amine compound, reacts with 7-chloro-4-nitrobenzofurazon (NBD-Cl) (for method A) and fluorescamine (for method B) which are a highly sensitive fluorogenic reagents used in many investigations. For method A, the reaction product was measured spectrofluorimetrically at 516 nm with excitation at 451 nm. The reaction proceeded quantitatively at pH 8.5, 80 °C in 7 min. For method B, the method was based on the reaction between GFX and fluorescamine in borate buffer solution of pH 8.5 to give highly fluorescent derivatives that were measured at 481 nm using an excitation wavelength of 351 nm. The fluorescence intensity was directly proportional to the concentration over the range 40-200 ng mL(-1) and 100-1,200 ng mL(-1) for method A and B, respectively. Successful applications of the developed methods, for the drug determination in pharmaceutical preparations and spiked plasma samples, were performed.|A highly selective, sensitive and rapid high performance liquid chromatographic method has been developed and validated to quantify gemifloxacin in human plasma. The gemifloxacin and internal standard (ciprofloxacin) were extracted by ultrafiltration technique followed by injection into chromatographic system. Chromatographic separation was achieved on a reversed phase C(18) column with a mobile phase of acetonitrile:0.1% trifluoroacetic acid (20:80, v/v) using isocratic elution (at flow rate 1 mL min(-1)). The analytes were detected at 269 and 393 nm for excitation and emission, respectively. The assay exhibited a linear range of 25-5000 ng mL(-1) for gemifloxacin in human plasma. The lower limit of detection was 10 ng mL(-1).|Two simple, rapid, sensitive and economic chromatographic methods have been developed for determination of gemifloxacin mesylate in human plasma by using internal standard. First method depends on reverse phase high performance liquid chromatography. The plasma sample was extracted using chloroform:acetic acid (5.4:0.1, v/v). A concentration range from 30 to 600 ng/mL was used for calibration curve. The percent recovery of gemifloxacin mesylate was found to be 80.06-84.88. The mobile phase used consist of methanol:sodium acetate (1%):ortho phosphoric acid (65:35:0.5, v/v/v) with pH 2.1 and flow rate 0.8 mL/min in isocratic mode. The separation was carried out by UV-detector at wavelength 263 nm. Second method depends on high performance thin layer chromatography. The plasma sample was extracted using chloroform:acetic acid (5.9:0.1, v/v). A concentration range from 50 to 600 ng/spot was used for calibration curve. The percent recovery of gemifloxacin mesylate was found to be 80.01-86.17. The mobile phase used consists of ethyl acetate:methanol:ammonia (8.0:4.0:3.0, v/v/v). Densitometric analysis was carried out at wavelength 254 nm. The R(f) values for gemifloxacin mesylate and linezolide were 0.33+/-0.03 and 0.69+/-0.03 respectively. The stability of gemifloxacin mesylate in plasma was confirmed during three freeze-thaw cycles (-20 degrees C), on bench during 12 hr. The proposed method was validated statistically and by performing recovery study for determination of gemifloxacin mesylate in human plasma. /Gemifloxacin mesylate/|HPLC-tandem MS determination in human plasma.