No information provided.
None
Overdosage & Contraindications OVERDOSEGatifloxacin exhibits a low potential for acute toxicity in animal studies. The minimum lethal oral doses in rats and dogs were greater than 2000 mg/kg and 1000 mg/kg, respectively. The minimum lethal intravenous dose was 144 mg/kg in rats and greater than 45 mg/kg in dogs. Clinical signs observed included decreased activity and respiratory rate, vomiting, tremors, and convulsions.
In the event of acute oral overdose, the stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully observed (including ECG monitoring) and given symptomatic and supportive treatment. Adequate hydration should be maintained. Gatifloxacin is not efficiently removed from the body by hemodialysis (approximately 14% recovered over 4 hours) or by chronic ambulatory peritoneal dialysis (CAPD) (approximately 11% recovered over 8 days).
CONTRAINDICATIONSTEQUIN is contraindicated in persons with a history of hypersensitivity to gatifloxacin or any member of the quinolone class of antimicrobial agents.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
In clinical studies with gatifloxacin, the most frequently reported adverse reactions occurring in ? 1 % of patients in the gatifloxacin study population (N=717) were: worsening of the conjunctivitis, eye irritation, dysgeusia, and eye pain. Additional adverse events reported with other formulations of gatifloxacin ophthalmic solution include chemosis, conjunctival hemorrhage, dry eye, eye discharge, eyelid edema, headache, increased lacrimation, keratitis, papillary conjunctivitis, and reduced visual acuity.
Gatifloxacin ophthalmic solution, 0.5% is indicated for the treatment of bacterial conjunctivitis caused by susceptible strains of the following organisms:
Aerobic Gram-Positive BacteriaStaphylococcus aureus
Staphylococcus epidermidis
Streptococcus mitis group*
Streptococcus oralis*
Streptococcus pneumoniae
Haemophilus influenzae
*Efficacy for this organism was studied in fewer than 10 infections.
Gatifloxacin ophthalmic solution 0.3% or 0.5% was administered to one eye of 6 healthy male subjects each in an escalated dosing regimen starting with a single 2 drop dose, then 2 drops 4 times daily for 7 days, and finally 2 drops 8 times daily for 3 days. At all time points, serum gatifloxacin levels were below the lower limit of quantification (5 ng/mL) in all subjects.
Teratogenic Effects:
There were no teratogenic effects observed in rats or rabbits following oral gatifloxacin doses up to 50 mg/kg/day (approximately 1000-fold higher than the maximum recommended ophthalmic dose). However, skeletal/craniofacial malformations or delayed ossification, atrial enlargement, and reduced fetal weight were observed in fetuses from rats given ?150 mg/kg/day (approximately 3000-fold higher than the maximum recommended ophthalmic dose). In a perinatal/postnatal study, increased late postimplantation loss and neonatal/perinatal mortalities were observed at 200 mg/kg/day (approximately 4000-fold higher than the maximum recommended ophthalmic dose). Because there are no adequate and well-controlled studies in pregnant women, gatifloxacin ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
THE SAFETY AND EFFECTIVENESS OF GATIFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (LESS THAN 18 YEARS OF AGE), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED (see PRECAUTIONS: Pediatric Use, Pregnancy, and Nursing Mothers).
QTc Interval Prolongation
Gatifloxacin has the potential to prolong the QTc interval of the electrocardiogram in some patients. QTc prolongation may lead to an increased risk for ventricular arrhythmias including torsades de pointes. Rare cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving quinolones, including gatifloxacin. Nearly all of these rare cases were associated with one or more of the following factors: age over 60, female gender, underlying cardiac disease, and/or use of multiple medications. No cardiovascular morbidity or mortality attributable to QTc prolongation has occurred in over 44,000 patients treated with gatifloxacin in clinical trials; these include 118 patients concurrently receiving drugs known to prolong the QTc interval and 139 patients known to have uncorrected hypokalemia (ECG monitoring was not performed). Gatifloxacin should be avoided in patients with known prolongation of the QTc interval, patients with uncorrected hypokalemia, and patients receiving >Pharmacokinetic and pharmacodynamic studies between gatifloxacin and drugs that prolong the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants have not been performed. Gatifloxacin should be used with caution when given concurrently with these drugs, as well as in patients with ongoing proarrhythmic conditions, such as clinically significant bradycardia or acute myocardial ischemia.
The magnitude of QTc prolongation increases with increasing concentrations of the drug (see CLINICAL PHARMACOLOGY: Electrocardiogram); therefore, the recommended dose and the recommended intravenous infusion rate should not be exceeded (see DOSAGE AND ADMINISTRATION for dosing recommendations for patients with or without renal impairment).
Disturbances in Blood Glucose
Disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with TEQUIN (gatifloxacin (removed from us market - may 2006)) , usually in diabetic patients. Therefore, careful monitoring of blood glucose is recommended when TEQUIN (gatifloxacin (removed from us market - may 2006)) is administered to patients with diabetes (see CLINICAL PHARMACOLOGY, PRECAUTIONS: Information for Patients and Drug Interactions, and ANIMAL PHARMACOLOGY).
Studies conducted in non-infected patients with type 2 diabetes mellitus controlled on oral hypoglycemic agents have demonstrated that TEQUIN (gatifloxacin (removed from us market - may 2006)) is associated with disturbances in glucose homeostasis including an increase in serum insulin and decrease in serum glucose usually following administration of initial doses (ie, first 2 days of treatment), and sometimes associated with symptomatic hypoglycemia. Increases in fasting serum glucose were also observed, usually after the third day of TEQUIN (gatifloxacin (removed from us market - may 2006)) administration, continuing throughout the duration of treatment, and returning to baseline by 28 days after the cessation of gatifloxacin treatment in most patients.
During the postmarketing period, there have been reports of serious disturbances of glucose homeostasis in patients being treated with TEQUIN (gatifloxacin (removed from us market - may 2006)). Hypoglycemic episodes, in some cases severe, have been reported in patients with diabetes mellitus treated with either sulfonylurea or non-sulfonylurea oral hypoglycemic medications. These events frequently occurred on the first day of therapy and usually within 3 days following the initiation of TEQUIN (gatifloxacin (removed from us market - may 2006)). Hyperglycemic episodes, in some cases severe and associated with hyperosmolar non-ketotic hyperglycemic coma, were reported in diabetic patients, mostly between 4 and 10 days following the initiation of TEQUIN (gatifloxacin (removed from us market - may 2006)) therapy. Some of the hyperglycemic and hypoglycemic events were life-threatening and many required hospitalization, although these events were reversible when appropriately managed. Many of these patients had other underlying medical problems and were receiving concomitant medications that may have contributed to the glucose abnormality. Episodes of hyperglycemia, including hyperosmolar non-ketotic hyperglycemic coma, also occurred in patients not previously diagnosed with diabetes mellitus. Elderly patients who may have unrecognized diabetes, age-related decrease in renal function, underlying medical problems, and/or are taking concomitant medications associated with hyperglycemia may be at particular risk for serious hyperglycemia.
The dose of TEQUIN should be adjusted based on underlying renal function (see DOSAGE AND ADMINISTRATION). When TEQUIN (gatifloxacin (removed from us market - may 2006)) is used in diabetic patients, blood glucose should be closely monitored. Signs and symptoms of hypoglycemia should be monitored, especially during the first 3 days of therapy, and signs and symptoms of hyperglycemia should be monitored in diabetics and patients who may be at risk for hyperglycemia, especially with continued treatment with TEQUIN (gatifloxacin (removed from us market - may 2006)) beyond 3 days. If signs and symptoms of either hypoglycemia or hyperglycemia occur in any patient being treated with TEQUIN (gatifloxacin (removed from us market - may 2006)) , appropriate therapy must be initiated immediately and TEQUIN (gatifloxacin (removed from us market - may 2006)) should be discontinued.
Tendon Effects
Ruptures of the shoulder, hand, and Achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including gatifloxacin. Postmarketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly. Gatifloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been excluded. Tendon rupture can occur during or after therapy with quinolones, including gatifloxacin.
Peripheral Neuropathy
Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones.
Other
As with other members of the quinolone >Convulsions, increased intracranial pressure, and psychosis have been reported in patients receiving quinolones. Quinolones may also cause central nervous system (CNS) stimulation, which may lead to tremors, restlessness, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, and insomnia. These reactions may occur following the first dose. If these reactions occur in patients receiving gatifloxacin, the drug should be discontinued and appropriate measures instituted (see ADVERSE REACTIONS).
As with other quinolones, TEQUIN (gatifloxacin (removed from us market - may 2006)) should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral atherosclerosis, epilepsy, and other factors that predispose to seizures.
Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with quinolones. These reactions may occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions.
TEQUIN (gatifloxacin (removed from us market - may 2006)) should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated (see PRECAUTIONS).
Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have been reported in patients receiving antibacterial therapy. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash or severe dermatologic reactions (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome); vasculitis, arthralgia, myalgia, serum sickness; allergic pneumonitis, interstitial nephritis; acute renal insufficiency or failure; hepatitis, jaundice, acute hepatic necrosis or failure; anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including TEQUIN (gatifloxacin (removed from us market - may 2006)) , and may range in severity from mild to life-threatening. It is important, therefore, to consider this diagnosis in patients who present with diarrhea subsequent to the administration of any antibacterial agent.
Treatment with antibacterial agents alters the flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is the primary cause of "antibiotic-associated colitis."
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis.
Gatifloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis.
PRECAUTIONSGeneral
Prescribing TEQUIN (gatifloxacin (removed from us market - may 2006)) in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Quinolones may cause central nervous system (CNS) events including nervousness, agitation, insomnia, anxiety, nightmares, or paranoia (see WARNINGS and PRECAUTIONS: Information for Patients).
Administer gatifloxacin with caution in the presence of renal insufficiency. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of gatifloxacin may be reduced. In patients with impaired renal function (creatinine clearance 40 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of gatifloxacin due to decreased clearance (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Because a hypotonic solution results, Water for Injection should not be used as a diluent when preparing a 2 mg/mL solution from the concentrated solution of gatifloxacin (10 mg/mL) (see DOSAGE AND ADMINISTRATION).
Disturbances of blood glucose homeostasis have been reported during the postmarketing period (see CLINICAL PHARMACOLOGY, WARNINGS, and ANIMAL PHARMACOLOGY).
Information for Patients(See Patient Information section.)
To assure safe and effective use of TEQUIN (gatifloxacin (removed from us market - may 2006)) , the following information and instructions should be communicated to the patient when appropriate.
Patients should be advised:
· that antibacterial drugs including TEQUIN (gatifloxacin (removed from us market - may 2006)) should only be used to treat bacterial infections. They do not treat viral infections (eg, the common cold). When TEQUIN (gatifloxacin (removed from us market - may 2006)) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by TEQUIN (gatifloxacin (removed from us market - may 2006)) or other antibacterial drugs in the future;
· that TEQUIN (gatifloxacin (removed from us market - may 2006)) may cause changes in the electrocardiogram (QTc interval prolongation);
· that TEQUIN (gatifloxacin (removed from us market - may 2006)) should be avoided in patients receiving class IA (eg, quinidine, procainamide) or class III (eg, amiodarone, sotalol) antiarrhythmic agents;
· that TEQUIN (gatifloxacin (removed from us market - may 2006)) should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants;
· to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia;
· to discontinue treatment and contact their physician if symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop;
· that disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with TEQUIN (gatifloxacin (removed from us market - may 2006)) , usually in diabetic patients or in patients at risk for hyperglycemia. If a hypoglycemic reaction or symptoms of hyperglycemia occur, patients should initiate appropriate therapy immediately, discontinue TEQUIN, and contact their physician (see CLINICAL PHARMACOLOGY and WARNINGS);
· to inform their physician of any other medications when taken concurrently with TEQUIN (gatifloxacin (removed from us market - may 2006)) , including over-the-counter medications;
· to contact their physician if they experience palpitations or fainting spells while taking TEQUIN (gatifloxacin (removed from us market - may 2006)) ;
· that TEQUIN (gatifloxacin (removed from us market - may 2006)) Tablets may be taken with or without meals;
· that TEQUIN (gatifloxacin (removed from us market - may 2006)) Tablets should be taken 4 hours before any aluminum- or magnesium-based antacids (see PRECAUTIONS: Drug Interactions);
· that TEQUIN (gatifloxacin (removed from us market - may 2006)) Tablets should be taken at least 4 hours before the administration of ferrous sulfate or dietary supplements containing zinc, magnesium, or iron (such as multivitamins) (see PRECAUTIONS: Drug Interactions);
· that TEQUIN (gatifloxacin (removed from us market - may 2006)) should be taken 4 hours before VIDEX (didanosine) buffered tablets or pediatric powder for oral solution;
· that TEQUIN (gatifloxacin (removed from us market - may 2006)) may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, difficulty in swallowing or breathing, any swelling suggesting angioedema (eg, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction (see WARNINGS and ADVERSE REACTIONS);
· to discontinue treatment; rest and refrain from exercise; and inform their physician if they experience pain, inflammation, or rupture of a tendon;
· that TEQUIN (gatifloxacin (removed from us market - may 2006)) may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination;
· that phototoxicity has been reported in patients receiving certain quinolones. There was no phototoxicity seen with TEQUIN (gatifloxacin (removed from us market - may 2006)) at the recommended dose. In keeping with good medical practice, avoid excessive sunlight or artificial ultraviolet light (eg, tanning beds). If sunburn-like reaction or skin eruptions occur, contact their physician (see CLINICAL PHARMACOLOGY: Photosensitivity Potential);
· that convulsions have been reported in patients receiving quinolones, and they should notify their physician before taking this drug if there is a history of this condition.
Carcinogenesis, Mutagenesis, Impairment of Fertility
B6C3F1 mice given gatifloxacin in the diet for 18 months at doses with an average intake of up to 81 mg/kg/day in males and 90 mg/kg/day in females showed no increases in neoplasms. These doses are approximately 0.13 and 0.18 times the maximum recommended human dose based upon daily systemic exposure (AUC).
In a 2-year dietary carcinogenicity study in Fischer 344 rats, no increases in neoplasms were seen in males given doses up to 47 mg/kg/day and females given up to 139 mg/kg/day. These doses are approximately 0.36 (males) and 0.81 (females) times the maximum recommended human dose based upon daily systemic exposure. A statistically significant increase in the incidence of large granular lymphocyte (LGL) leukemia was seen in males treated with a high dose of 100 mg/kg/day (approximately 0.74 times the maximum recommended human dose based upon daily systemic exposure) versus controls. Although Fischer 344 rats have a high spontaneous background rate of LGL leukemia, the incidence in high-dose males slightly exceeded the historical control range established for this strain. The findings in high-dose males are not considered a concern with regard to the safe use of gatifloxacin in humans.
In genetic toxicity tests, gatifloxacin was not mutagenic in several strains of bacteria used in the Ames test; however, it was mutagenic to Salmonella strain TA102. Gatifloxacin was negative in four in vivo assays that included oral and intravenous micronucleus tests in mice, an oral cytogenetics test in rats, and an oral DNA repair test in rats. Gatifloxacin was positive in in vitro gene-mutation assays in Chinese hamster V-79 cells and in vitro cytogenetics assays in Chinese hamster CHL/IU cells. These findings were not unexpected; similar findings have been seen with other quinolones and may be due to the inhibitory effects of high concentrations on eukaryotic type II DNA topoisomerase.
There were no adverse effects on fertility or reproduction in rats given gatifloxacin orally at doses up to 200 mg/kg/day (approximately equivalent to the maximum human dose based on systemic exposure [AUC]).
Pregnancy Category C
There were no teratogenic effects observed in rats or rabbits at oral gatifloxacin doses up to 150 or 50 mg/kg, respectively (approximately 0.7 and 1.9 times the maximum human dose based on systemic exposure). However, skeletal malformations were observed in fetuses from rats given 200 mg/kg/day orally or 60 mg/kg/day intravenously during organogenesis. Developmental delays in skeletal ossification, including wavy ribs, were observed in fetuses from rats given oral doses of ³150 mg/kg or intravenous doses of ³30 mg/kg daily during organogenesis, suggesting that gatifloxacin is slightly fetotoxic at these doses. Similar findings have been seen with other quinolones. These changes were not seen in rats or rabbits given oral doses of gatifloxacin up to 50 mg/kg (approximately 0.2 and 1.9 times the maximum human dose, respectively, based on systemic exposure).
When rats were given oral doses of 200 mg/kg of gatifloxacin beginning in late pregnancy and continuing throughout lactation, late postimplantation loss increased, as did neonatal and perinatal mortalities. These observations also suggest fetotoxicity. Similar findings have been seen with other quinolones.
Because there are no adequate and well-controlled studies in pregnant women, TEQUIN (gatifloxacin (removed from us market - may 2006)) should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Nursing Mothers
Gatifloxacin is excreted in the breast milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when gatifloxacin is administered to a nursing woman.
Pediatric Use
The safety and effectiveness of gatifloxacin in pediatric populations ( 18 years of age) have not been established. Quinolones, including gatifloxacin, cause arthropathy and osteochondrotoxicity in juvenile animals (rats and dogs).
Geriatric Use
During the postmarketing period, serious disturbances of glucose homeostasis have been reported in elderly patients being treated with TEQUIN (see WARNINGS, PRECAUTIONS: Drug Interactions and ANIMAL PHARMACOLOGY).
In multiple-dose clinical trials of gatifloxacin (n=2891), 22% of patients were ³65 years of age and 10% were ³75 years of age. No overall differences in safety or efficacy were observed in clinical trials between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION).
Warnings & Precautions WARNINGSIncluded as part of the PRECAUTIONS section.
PRECAUTIONS Topical Ophthalmic Use OnlyGatifloxacin ophthalmic solution should not be introduced directly into the anterior chamber of the eye.
Growth of Resistant Organisms with Prolonged UseAs with other anti-infectives, prolonged use of gatifloxacin ophthalmic solution, 0.5% may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit lamp biomicroscopy and where appropriate, fluoroscein staining.
Avoidance of Contact Lens WearPatients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis or during the course of therapy with gatifloxacin ophthalmic solution (see PATIENT INFORMATION).
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of FertilityThere was no increase in neoplasms among B6C3F1 mice given gatifloxacin in the diet for 18 months at doses averaging 81 mg/kg/day in males and 90 mg/kg/day in females. These doses are approximately 1600-fold and 1800-fold higher, respectively, than the maximum recommended ophthalmic dose of 0.05 mg/kg/day in a 50 kg human.
There was no increase in neoplasms among Fischer 344 rats given gatifloxacin in the diet for 2 years at doses averaging 47 mg/kg/day in males and 139 mg/kg/day in females (900- and 2800-fold higher, respectively, than the maximum recommended ophthalmic dose). A statistically significant increase in the incidence of large granular lymphocyte (LGL) leukemia was seen in males treated with a high dose of approximately 2000-fold higher than the maximum recommended ophthalmic dose. Fischer 344 rats have a high spontaneous background rate of LGL leukemia and the incidence in high-dose males only slightly exceeded the historical control range established for this strain.
In genetic toxicity tests, gatifloxacin was positive in 1 of 5 strains used in bacterial reverse mutation assays: Salmonella strain TA102. Gatifloxacin was positive in in vitro mammalian cell mutation and chromosome aberration assays. Gatifloxacin was positive in in vitro unscheduled DNA synthesis in rat hepatocytes but not human leukocytes. Gatifloxacin was negative in in vivo micronucleus tests in mice, cytogenetics test in rats, and DNA repair test in rats. The findings may be due to the inhibitory effects of high concentrations on eukaryotic type II DNA topoisomerase.
There were no adverse effects on fertility or reproduction in rats given gatifloxacin orally at doses up to 200 mg/kg/day (approximately 4000-fold higher than the maximum recommended ophthalmic dose for gatifloxacin).
Use In Specific Populations Pregnancy Pregnancy Category CTeratogenic Effects:
There were no teratogenic effects observed in rats or rabbits following oral gatifloxacin doses up to 50 mg/kg/day (approximately 1000-fold higher than the maximum recommended ophthalmic dose). However, skeletal/craniofacial malformations or delayed ossification, atrial enlargement, and reduced fetal weight were observed in fetuses from rats given ?150 mg/kg/day (approximately 3000-fold higher than the maximum recommended ophthalmic dose). In a perinatal/postnatal study, increased late postimplantation loss and neonatal/perinatal mortalities were observed at 200 mg/kg/day (approximately 4000-fold higher than the maximum recommended ophthalmic dose). Because there are no adequate and well-controlled studies in pregnant women, gatifloxacin ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing MothersGatifloxacin is excreted in the breast milk of rats. It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when gatifloxacin is administered to a nursing woman.
Pediatric UseThe safety and effectiveness of gatifloxacin in infants below one year of age have not been established. Gatifloxacin has been demonstrated in clinical trials to be safe and effective for the treatment of bacterial conjunctivitis in pediatric patients one year or older (see Clinical Studies).
Geriatric UseNo overall differences in safety or effectiveness have been observed between elderly and younger patients.
Patients 1 year of age or older: Instill one drop every two hours in the affected eye(s) while awake, up to 8 times on Day 1. Instill one drop two to four times daily in the affected eye(s) while awake on Days 2 through 7.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
In clinical studies with gatifloxacin, the most frequently reported adverse reactions occurring in ? 1 % of patients in the gatifloxacin study population (N=717) were: worsening of the conjunctivitis, eye irritation, dysgeusia, and eye pain. Additional adverse events reported with other formulations of gatifloxacin ophthalmic solution include chemosis, conjunctival hemorrhage, dry eye, eye discharge, eyelid edema, headache, increased lacrimation, keratitis, papillary conjunctivitis, and reduced visual acuity.
DRUG INTERACTIONSSpecific drug interaction studies have not been conducted with gatifloxacin ophthalmic solution.
Side Effects & Drug Interactions SIDE EFFECTSOver 5000 patients have been treated with gatifloxacin in single- and multiple-dose clinical efficacy trials worldwide.
In gatifloxacin studies, the majority of adverse reactions were described as mild in nature. Gatifloxacin was discontinued for adverse events thought related to drug in 2.7% of patients.
Drug-related adverse events >³3% in patients receiving gatifloxacin in single- and multiple-dose clinical trials are as follows: nausea 8%, vaginitis 6%, diarrhea 4%, headache 3%, dizziness 3%.
In patients who were treated with either intravenous gatifloxacin or with intravenous followed by oral therapy, the incidence of adverse events was similar to those who received oral therapy alone. Local injection site reactions (redness at injection site) were noted in 5% of patients.
Additional drug-related adverse events (possibly, probably, or definitely related) considered clinically relevant that occurred in ³0.1% to 3% of patients receiving gatifloxacin in single- and multiple-dose clinical trials are as follows:
Body as a Whole: allergic reaction, asthenia, back pain, chest pain, chills, face edema, fever
Cardiovascular System: hypertension, palpitation
Digestive System: abdominal pain, anorexia, constipation, dyspepsia, flatulence, gastritis, glossitis, mouth ulcer, oral moniliasis, stomatitis, vomiting
Metabolic/Nutritional System: hyperglycemia, peripheral edema, thirst
Musculoskeletal System: arthralgia, leg cramp
Nervous System: abnormal dream, agitation, anxiety, confusion, insomnia, nervousness, paresthesia, somnolence, tremor, vasodilatation, vertigo
Respiratory System: dyspnea, pharyngitis
Skin/Appendages: dry skin, pruritus, rash, sweating
Special Senses: abnormal vision, taste perversion, tinnitus
Urogenital System: dysuria
Additional drug-related adverse events considered clinically relevant that occurred in 0.1% (rare adverse events) of patients receiving gatifloxacin in single- and multiple-dose clinical trials are as follows: abnormal thinking, alcohol intolerance, arthritis, asthma (bronchospasm), ataxia, bone pain, bradycardia, breast pain, cheilitis, colitis, convulsion, cyanosis, depersonalization, depression, diabetes mellitus, dysphagia, ear pain, ecchymosis, edema, epistaxis, euphoria, eye pain, eye photosensitivity, gastrointestinal hemorrhage, generalized edema, gingivitis, halitosis, hallucination, hematemesis, hematuria, hostility, hyperesthesia, hypertonia, hyperventilation, hypoglycemia, lymphadenopathy, maculopapular rash, metrorrhagia, migraine, mouth edema, myalgia, myasthenia, neck pain, panic attack, paranoia, parosmia, photophobia, pseudomembranous colitis, psychosis, ptosis, rectal hemorrhage, stress, substernal chest pain, tachycardia, taste loss, tongue edema, vesiculobullous rash.
Laboratory Changes
Clinically relevant changes in laboratory parameters, without regard to drug relationship, occurred in fewer than 1% of TEQUIN (gatifloxacin (removed from us market - may 2006)) -treated patients. These included the following: neutropenia, increased ALT or AST levels, alkaline phosphatase, bilirubin, serum amylase, and electrolytes abnormalities. It is not known whether these abnormalities were caused by the drug or the underlying condition being treated.
Postmarketing Adverse Event Reports
The following events have been reported during postapproval use of TEQUIN (gatifloxacin (removed from us market - may 2006)). Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Abnormal renal function (including acute renal failure), acute allergic reaction including anaphylactic reaction and angioneurotic edema, hepatitis, hypotension, increased International Normalized Ratio (INR)/prothrombin time, pancreatitis, severe hyperglycemia (including hyperosmolar nonketotic hyperglycemia), severe hypoglycemia (including hypoglycemic coma), Stevens-Johnson syndrome, syncope, tendon rupture, thrombocytopenia, and torsades de pointes.
DRUG INTERACTIONSTEQUIN (gatifloxacin) can be taken 4 hours before ferrous sulfate, dietary supplements containing zinc, magnesium, or iron (such as multivitamins), or aluminum/magnesium-containing antacids without any significant pharmacokinetic interactions (see CLINICAL PHARMACOLOGY).
Milk, calcium carbonate, cimetidine, theophylline, warfarin, or midazolam
No significant interactions have been observed when administered concomitantly with TEQUIN (gatifloxacin (removed from us market - may 2006)). No dosage adjustments are necessary when these drugs are administered concomitantly with TEQUIN (see CLINICAL PHARMACOLOGY).
Antidiabetic Agents
Pharmacodynamic changes in glucose homeostasis have been seen with concomitant glyburide use. However, no significant pharmacokinetic interactions have been observed when glyburide was administered concomitantly with TEQUIN (see CLINICAL PHARMACOLOGY: Glucose Homeostasis and WARNINGS).
Digoxin
Concomitant administration of TEQUIN and digoxin did not produce significant alteration of the pharmacokinetics of gatifloxacin; however, an increase in digoxin concentrations was observed for 3 of 11 subjects. Patients taking digoxin should therefore be monitored for signs and/or symptoms of toxicity. In patients who display signs and/or symptoms of digoxin intoxication, serum digoxin concentrations should be determined, and digoxin dosage should be adjusted as appropriate (see CLINICAL PHARMACOLOGY).
Probenecid
The systemic exposure of TEQUIN (gatifloxacin (removed from us market - may 2006)) is significantly increased following the concomitant administration of TEQUIN and probenecid (see CLINICAL PHARMACOLOGY).
Warfarin
In subjects receiving warfarin, no significant change in clotting time was observed when gatifloxacin was coadministered. However, because some quinolones have been reported to enhance the effects of warfarin or its derivatives, prothrombin time or other suitable anticoagulation test should be monitored closely if a quinolone antimicrobial is administered with warfarin or its derivatives.
Nonsteroidal anti-inflammatory drugs (NSAIDS)
Although not observed with gatifloxacin in preclinical and clinical trials, the concomitant administration of nonsteroidal anti-inflammatory drugs with a quinolone may increase the risks of CNS stimulation and convulsions (see WARNINGS).
Laboratory Test Interactions
There are no reported laboratory test interactions.
