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).
PROLONGATION OF THE QTC INTERVAL
GATIFLOXACIN HAS THE POTENTIAL TO PROLONG THE QTc INTERVAL OF THE ELECTROCARDIOGRAM IN SOME PATIENTS. DUE TO THE LACK OF CLINICAL EXPERIENCE IN PATIENTS WITH KNOWN PROLONGATION OF THE QTc INTERVAL, PATIENTS WITH UNCORRECTED HYPOKALEMIA, AND PATIENTS RECEIVING CLASS IA (E.G., QUINIDINE, PROCAINAMIDE) OR CLASS III (E.G., AMIODARONE, SOTALOL) ANTIARRHYTHMIC AGENTS, GATIFLOXACIN SHOULD BE AVOIDED IN THESE PATIENT POPULATIONS.
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; 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). QTc prolongation may lead to an increased risk for ventricular arrhythmias including torsades de pointes (see CLINICAL PHARMACOLOGY: Electrocardiogram).
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). During postmarketing surveillance, rare cases of torsades de pointes have been reported in patients taking gatifloxacin. These cases have occurred primarily in elderly patients with underlying medical problems for which they were receiving concomitant medications known to prolong the QTc interval; the contribution, if any, of gatifloxacin to the development of torsades de pointes in these patients is unknown.
DISTURBANCES IN BLOOD GLUCOSE
Disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with TEQUIN, usually in diabetic patients. Therefore, careful monitoring of blood glucose is recommended when TEQUIN 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) is associated with disturbances in glucose homeostasis including an increase in serum insulin and decrease in serum glucose usually following administration of initial doses (i.e., 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 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. 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. 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 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 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 beyond 3 days. If signs and symptoms of either hypoglycemia or hyperglycemia occur in any patient being treated with TEQUIN, appropriate therapy must be initiated immediately and TEQUIN should be discontinued.
As with other members of the quinolone class, gatifloxacin has caused arthropathy and/or chondrodysplasia in immature dogs. The relevance of these findings to the clinical use of gatifloxacin is unknown (see ANIMAL PHARMACOLOGY).
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) 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 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 (e.g., 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, 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.
Ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. TEQUIN (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 confidently excluded. Tendon rupture can occur during or after therapy with quinolones.
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.
Prescribing TEQUIN 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, the following information and instructions should be communicated to the patient when appropriate.
Patients should be advised:
that antibacterial drugs including TEQUIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When TEQUIN 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 or other antibacterial drugs in the future;
that TEQUIN may produce changes in the electrocardiogram (QTc interval prolongation);
that TEQUIN should be avoided in patients receiving Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents;
that TEQUIN should be used with caution in patients receiving drugs that may effect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants;
to inform their physician of any personal or family history of QTc prolongation or proarrhythmic conditions such as recent hypokalemia, significant bradycardia, or recent myocardial ischemia;
that disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with TEQUIN (gatifloxacin), 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, including over-the-counter medications;
to contact their physician if they experience palpitations or fainting spells while taking TEQUIN;
that TEQUIN Tablets may be taken with or without meals;
that TEQUIN Tablets should be taken 4 hours before any aluminum- or magnesium-based antacids (see PRECAUTIONS: Drug Interactions);
that TEQUIN 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 should be taken 4 hours before VIDEX® (didanosine) buffered tablets or pediatric powder for oral solution;
that TEQUIN 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 (e.g., 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 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 gatifloxacin at the recommended dose. In keeping with good medical practice, avoid excessive sunlight or artificial ultraviolet light (e.g., 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.
TEQUIN (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. 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 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.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
B6C3F1 mice given gatifloxacin in the diet for 18 months at doses with an average intake 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 >/=150 mg/kg or intravenous doses of >/=30 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) should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
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.
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).
During the postmarketing period, serious disturbances of glucose homeostasis have been reported in elderly patients being treated with TEQUIN (gatifloxacin) (see WARNINGS, PRECAUTIONS: Drug Interactions and ANIMAL PHARMACOLOGY).
In multiple-dose clinical trials of gatifloxacin (n = 2891), 22% of patients were >/=65 years of age and 10% were >/=75 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).