Gemifloxacin

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.

/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.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

gemifloxacin

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Acute Exposure/Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent that exhibits potent activity against most Gram-negative and Gram-positive organisms, and has a comparatively low chondrotoxic potential in immature animals. This study examined the effects of gemifloxacin on the Achilles tendons in immature Sprague-Dawley rats treated by oral intubation once daily for 5 consecutive days from postnatal week 4 onward at doses of 0 (vehicle), and 600 mg/kg body weight. Ofloxacin or ciprofloxacin were used for comparison. The Achilles tendon specimens were examined by electron microscopy. In comparison with the vehicle-treated controls, there were ultrastructural changes in all samples from the gemifloxacin-, ofloxacin-, and ciprofloxacin-treated rats. Degenerative changes were observed in the tenocytes, and the cells that detached from the extracellular matrix were recognizable. The degree of degenerative changes and the number of degenerated cells in the Achilles tendon were significantly higher in the treated group than in the control group. Moreover, among the quinolone-treated groups, these findings were most significant in the ofloxacin-treated group, and least significant in the gemifloxacin-treated group. It is unclear what these findings mean with respect to the possible risk in juvenile patients treated with gemifloxacin or other quinolones. However, these results show that gemifloxacin causes less changes in the connective tissue structures.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Dogs given 192 mg/kg/day (about 6 times the systemic exposure at the clinical dose) for 28 days, or 24 mg/kg/day (approximately equivalent to the systemic exposure at the clinical dose) for 13 weeks showed reversible increases in plasma ALT activities and local periportal liver changes associated with blockage of small bile ducts by crystals containing gemifloxacin.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Quinolones have been shown to cause arthropathy in immature animals. Degeneration of articular cartilage occurred in juvenile dogs given at least 192 mg/kg/day gemifloxacin in a 28-day study (producing about 6 times the systemic exposure at the clinical dose), but not in mature dogs. There was no damage to the articular surfaces of joints in immature rats given repeated doses of up to 800 mg/kg/day.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The purpose of this study was to investigate the potential toxicity of gemifloxacin by 28-day repeated oral dose in Wistar albino rats. The test article, was administered daily by gavage to male and female rats at dose levels of 0, 50, 100, 200 mg/kg/day. At the end of treatment period, 12 rats/sex/group was sacrificed, while six extra rats/sex in the vehicle control and highest dose groups sacrificed after 14 days recovery period. During the treatment and recovery periods, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, phototoxicity, hematology, serum biochemistry, synovial fluid biochemistry, electrocardiogram (ECG), gross findings, organ weights, microscopic examination of synovial fluid, and histopathology were examined. Hematological and serum biochemical investigations revealed a dose-dependent increase in the total white blood cell (WBC), total bilirubin (T-BIL), glucose (GLU), alanine aminotransferase (ALT) and significant decreases in total protein (TP) were observed in both sexes at the same dose, at the end of treatment period, but the levels returned toward normal during the recovery period. Histopathology of talar joint showed that erosion of the articular surface of that joint in both sexes at the end of treatment period at the dose level of 200 mg/kg/day. Degenerative changes in tendinocytes were observed in Achilles tendon of both sexes at the high dose level at the end of treatment period. In histopathological study shows partial effacement of liver architecture and focal ulceration in gastric mucosa at the high dose level at the end of treatment period. Based on these results, it was concluded that 28 days repeated oral dose of gemifloxacin caused increases in the liver weight, WBC count, T-BIL, glucose level, ALT, decreasing the TP, cause chronic hepatitis and acute gastritis, erosion of the articular surface of joint and histopathologic changes in Achilles tendon in rats at the dose level of 200 mg/kg/day.

For more Non-Human Toxicity Excerpts (Complete) data for Gemifloxacin (6 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).

/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.

7 (± 2) hours

Gemifloxacin has an elimination half life of about 7 hours.

Gemifloxacin is metabolized to a limited extent by the liver. 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.

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.

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GEMIFLOXACIN

Established Pharmacologic Class [EPC] - Quinolone Antimicrobial

Chemical Structure [CS] - Quinolones

Gemifloxacin is a Quinolone Antimicrobial.

Substances that inhibit the growth or reproduction of BACTERIA.

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.

Rapidly absorbed from the gastrointestinal tract. The absolute bioavailability averages approximately 71%.

Gemifloxacin and its metabolites are excreted via dual routes of excretion.Following oral administration of gemifloxacin to healthy subjects, a mean (± SD) of 61 ± 9.5% of the dose was excreted in the feces and 36 ± 9.3% in the urine as unchanged drug and metabolites. The mean (± SD) renal clearance following repeat doses of 320 mg was approximately 11.6 ± 3.9 L/hr (range 4.6-6 L/hr), which indicates active secretion is involved in the renal excretion of gemifloxacin.

1.66 to 12.12 L/kg

renal cl=11.6+/- 3.9 L/hr [Healthy subjects receiving repeat doses of 320 mg orally]

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.