Gatifloxacin

Dosage Forms And Strengths

Six (6) mL bottle containing 2.5 mL of a 0.5% sterile topical ophthalmic solution.

Storage and Handling

Gatifloxacin ophthalmic solution, 0.5% is supplied sterile in a white, low density polyethylene (LDPE) bottle with a controlled dropper tip, and a tan cap in the following sizes:

2.5 mL in 6 mL bottle

Storage: Store at 20°-25°C (68°-77°F). Protect from freezing.

Manufactured by: Hi-Tech Pharmacal Co., Inc. Amityville, NY 11701, Revised: July 2013

INDICATIONS

TEQUIN (gatifloxacin) is indicated for the treatment of infections due to susceptible strains of the designated microorganisms in the conditions listed below (see DOSAGE AND ADMINISTRATION).

Acute bacterial exacerbation of chronic bronchitis due to Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Staphylococcus aureus.

Acute sinusitis due to Streptococcus pneumoniae or Haemophilus influenzae.

Community-acquired pneumonia due to Streptococcus pneumoniae (including multidrug-resistant strains [MDRSP])*, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Staphylococcus aureus, Mycoplasma pneumoniae, Chlamydia pneumoniae, or Legionella pneumophila. (See Clinical Studies.)

Uncomplicated skin and skin structure infections (ie, simple abscesses, furuncles, folliculitis, wound infections, and cellulitis) due to Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.

NOTE: An insufficient number of patients with the diagnosis of impetiginous lesions were available for evaluation.

Uncomplicated urinary tract infections (cystitis) due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis.

Complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis.

Pyelonephritis due to Escherichia coli.

Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Acute, uncomplicated rectal infections in women due to Neisseria gonorrhoeae (see WARNINGS).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of TEQUIN (gatifloxacin (removed from us market - may 2006)) and other antibacterial drugs, TEQUIN (gatifloxacin (removed from us market - may 2006)) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

*Multidrug-resistant Streptococcus pneumoniae (MDRSP) includes isolates previously known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin (MIC 2 µg/mL), 2^nd generation cephalosporins (eg, cefuroxime), macrolides, tetracyclines, and trimethoprim/ sulfamethoxazole.

DOSAGE AND ADMINISTRATION

The recommended dosage for TEQUIN (gatifloxacin (removed from us market - may 2006)) Tablets or TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection is described in Table 4. Doses of TEQUIN (gatifloxacin (removed from us market - may 2006)) are administered once every 24 hours. These recommendations apply to all patients with a creatinine clearance ³40 mL/min. For patients with a creatinine clearance < 40 mL/min, see the Impaired Renal Function subsection.

TEQUIN (gatifloxacin (removed from us market - may 2006)) can be administered without regard to food, including milk and dietary supplements containing calcium.

Oral doses of TEQUIN (gatifloxacin (removed from us market - may 2006)) should be administered at least 4 hours before the administration of ferrous sulfate, dietary supplements containing zinc, magnesium, or iron (such as multivitamins), aluminum/magnesium-containing antacids, or VIDEX^â (didanosine) buffered tablets or pediatric powder for oral solution.

TEQUIN (gatifloxacin (removed from us market - may 2006)) can be administered without regard to gender or age (³18 years). Consideration should be given to the possibility that the elderly may have impaired renal function (see PRECAUTIONS: Geriatric Use).

When switching from intravenous to oral dosage administration, no dosage adjustment is necessary. Patients whose therapy is started with TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection may be switched to TEQUIN (gatifloxacin (removed from us market - may 2006)) Tablets when clinically indicated at the discretion of the physician.

TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection should be administered by INTRAVENOUS infusion only. It is not intended for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.

Single-use vials require dilution prior to administration (see Preparation of Gatifloxacin for Intravenous Administration.)

TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection should be administered by intravenous infusion over a period of 60 minutes. CAUTION: RAPID OR BOLUS INTRAVENOUS INFUSION SHOULD BE AVOIDED.

Since gatifloxacin is eliminated primarily by renal excretion, a dosage modification of TEQUIN (gatifloxacin (removed from us market - may 2006)) is recommended for patients with creatinine clearance <40 mL/min, including patients on hemodialysis and on CAPD. The recommended dosage of TEQUIN (gatifloxacin) is:

Administer TEQUIN (gatifloxacin (removed from us market - may 2006)) after a dialysis session for patients on hemodialysis.

Single 400-mg dose TEQUIN (gatifloxacin (removed from us market - may 2006)) regimen (for the treatment of uncomplicated urinary tract infections and gonorrhea) and 200 mg once daily for 3 days TEQUIN (gatifloxacin (removed from us market - may 2006)) regimen (for the treatment of uncomplicated urinary tract infections) require no dosage adjustment in patients with impaired renal function.

The following formula may be used to estimate creatinine clearance:

Women: 0.85 x the value calculated for men.

No adjustment in the dosage of TEQUIN (gatifloxacin (removed from us market - may 2006)) is necessary in patients with moderate hepatic impairment (Child-Pugh Class B). There are no data in patients with severe hepatic impairment (Child-Pugh Class C) (see CLINICAL PHARMACOLOGY).

TEQUIN (gatifloxacin (removed from us market - may 2006)) solution in single-use vials: TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection is supplied in single-use 40 mL vials (10 mg/mL) containing a concentrated solution of gatifloxacin in 5% dextrose (400 mg of gatifloxacin). THESE TEQUIN (gatifloxacin (removed from us market - may 2006)) INJECTION SINGLE-USE VIALS MUST BE FURTHER DILUTED WITH AN APPROPRIATE SOLUTION PRIOR TO INTRAVENOUS ADMINISTRATION. The concentration of the resulting diluted solution should be 2 mg/mL prior to administration.

Compatible intravenous solutions: 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 PRECAUTIONS). Any of the following intravenous solutions may be used to prepare a 2 mg/mL gatifloxacin solution: 5% Dextrose Injection, USP

0.9% Sodium Chloride Injection, USP

5% Dextrose and 0.9% Sodium Chloride Injection, USP

Lactated Ringer’s and 5% Dextrose Injection, USP

5% Sodium Bicarbonate Injection, USP

Plasma-Lyte^Ò 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP)

M/6 Sodium Lactate Injection, USP

Gatifloxacin solutions at 2 mg/mL also have been shown to be compatible with 20 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP.

This intravenous drug product should be inspected visually for particulate matter prior to dilution and administration. Samples containing visible particles should be discarded. Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparation of the final intravenous solution. Since the vials are for single-use only, any unused portion remaining in the vial should be discarded.

Since only limited data are available on the compatibility of gatifloxacin intravenous injection with other intravenous substances, additives or other medications should not be added to TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection in single-use vials or infused simultaneously through the same intravenous line.

If the same intravenous line is used for sequential infusion of different drugs, the line should be flushed before and after infusion of TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection with an infusion solution compatible with TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection and with any other drug(s) administered via this common line.

If TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each drug.

TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection premix in single-use flexible containers: TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection is also available in ready-to-use 100- and 200-mL flexible bags containing a dilute solution of 200 or 400 mg gatifloxacin in 5% dextrose. NO FURTHER DILUTION OF THIS PREPARATION IS NECESSARY.

This intravenous drug product should be inspected visually for particulate matter prior to administration. Samples containing visible particles should be discarded.

Since the premix flexible bags are for single use only, any unused portion should be discarded.

Since only limited data are available on the compatibility of gatifloxacin intravenous injection with other intravenous substances, additives or other medications should not be added to TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection in flexible containers or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of different drugs, the line should be flushed before and after infusion of TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection with an infusion solution compatible with TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection and with any other drug(s) administered via this common line.

To open:

1. Tear outer wrap at the notch and remove solution container.

2. Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution, as the sterility may be compromised.

3. Use only if solution is clear and light yellow to greenish-yellow in color.

4. Use sterile equipment.

Do not use flexible containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Preparation for administration:

1. Close flow control clamp of administration set.

2. Remove cover from port at bottom of container.

3. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated.

4. Suspend container from hanger.

5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection premix in flexible containers.

6. Open flow control clamp to expel air from set. Close clamp.

7. Regulate rate of administration with flow control clamp.

When stored under recommended conditions, TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection, as supplied in 40-mL vials and in 100-mL and 200-mL flexible containers, is stable through the expiration date printed on the label.

TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection, when diluted in a compatible intravenous fluid to a concentration of 2 mg/mL, is stable for 14 days when stored between 20° C to 25° C or when stored under refrigeration between 2° C to 8° C.

TEQUIN (gatifloxacin (removed from us market - may 2006)) Injection, when diluted to a concentration of 2 mg/mL in a compatible intravenous fluid EXCEPT FOR 5% SODIUM BICARBONATE INJECTION, USP, may be stored for up to 6 months at -25° C to -10° C (-13° F to 14° F). Frozen solutions may be thawed at controlled room temperature. Solutions that have been thawed are stable for 14 days after removal from the freezer when stored between 20° C to 25° C or when stored under refrigeration between 2° C to 8°C. Solutions should not be refrozen.

HOW SUPPLIED

TEQUIN^â (gatifloxacin) Tablets are available as 200-mg and 400-mg white, film-coated tablets. The tablets are almond shaped and biconvex and contain gatifloxacin sesquihydrate equivalent to either 200 mg or 400 mg gatifloxacin.

TEQUIN (gatifloxacin (removed from us market - may 2006)) Tablets are packaged in bottles, unit dose blister strips, and multidose blister packs of 5 tablets (TEQUIN (gatifloxacin (removed from us market - may 2006)) Teq-Paqä) in the following configurations:

200 mg tablets—color: white; shape: biconvex; debossing: "BMS" on one side and "TEQUIN (gatifloxacin (removed from us market - may 2006)) " and "200" on the other.

Bottles of 30 (NDC 0015-1117-50)

Blister pack of 100 (NDC 0015-1117-80)

400 mg tablets—color: white; shape: biconvex; debossing: "BMS" on one side and "TEQUIN (gatifloxacin (removed from us market - may 2006)) " and "400" on the other.

Bottles of 50 (NDC 0015-1177-60)

Blister pack of 100 (NDC 0015-1177-80)

Carton of 3 TEQUIN (gatifloxacin (removed from us market - may 2006)) Teq-PaqsÔ (5 tablets each) (NDC 0015-1177-21)

Store at 25° C (77° F); excursions permitted to 15° to 30° C (59° to 86° F).

TEQUIN^â (gatifloxacin) Injection is available for intravenous administration in the following configuration:

Single-use vials containing a clear, light yellow to greenish-yellow solution at a concentration of 10 mg/mL gatifloxacin.

10 mg/mL (400 mg), 40-mL vials (NDC 0015-1179-80)

Store at 25° C (77° F); excursions permitted to 15° to 30° C (59° to 86° F).

TEQUIN (gatifloxacin (removed from us market - may 2006)) ^â (galifloxacin in 5% dextrose) Injection is available in ready-to-use flexible bags containing a dilute solution of 200 mg or 400 mg of gatifloxacin in 5% dextrose. Premix bags are manufactured by Abbott Laboratories in North Chicago, IL.

2 mg/mL (200 mg), 100-mL flexible container (NDC 0015-1180-80)

Carton of 24 (NDC 0015-1180-79)

2 mg/mL (400 mg), 200-mL flexible container (NDC 0015-1181-80)

Carton of 24 (NDC 0015-1181-79)

Store at 25° C (77° F); excursions permitted to 15° to 30° C (59° to 86° F). Do not freeze.

In three animal species (rats, beagle dogs, and cynomolgus monkeys) given oral gatifloxacin doses approximately 1.0- to 19-times the approved human dose (based on body surface area) from one to six months, electron microscopy showed vesiculation of rough endoplasmic reticulum and decreased secretory granules in pancreatic b-cells of all three species. These ultrastructural changes correlated with vacuolation of pancreatic b-cells seen by light microscopy in dogs given a dose level for one or six months that was approximately equivalent to the human dose (based upon body surface area and plasma AUC). Following a 4-week recovery period without gatifloxacin, partial recovery from these pancreatic changes was seen in the rat and complete recovery was evident in beagle dogs and cynomolgus monkeys (see WARNINGS and CLINICAL PHARMACOLOGY).

In contrast to some other quinolone antibacterials, there was no evidence of phototoxicity when gatifloxacin was evaluated in the hairless mouse or guinea pig models using simulated sunlight or UVA radiation, respectively.

Unlike some other members of the quinolone >While some quinolone antibacterials have proconvulsant activity that is exacerbated with concomitant use of nonsteroidal anti-inflammatory drugs (NSAID), gatifloxacin did not produce an increase in seizure activity when administered intravenously to mice at doses up to 100 mg/kg in combination with the NSAID fenbufen.

Quinolone antibacterials have been shown to cause arthropathy in immature animals. There is no evidence of arthropathy in fully mature rats and dogs given gatifloxacin for 6 months at doses of 240 or 24 mg/kg, respectively (approximately 1.5 times the maximum human dose in both species based on systemic exposure). Arthropathy and chondrodysplasia were observed in immature dogs given 10 mg/kg gatifloxacin orally for 7 days (approximately equal to the maximum human dose based upon systemic exposure). The relevance of these findings to the clinical use of gatifloxacin is unknown.

Some members of the quinolone >CIPRO^â (ciprofloxacin) is a registered trademark of the Bayer Corporation.

LEVAQUIN^â (levofloxacin) is a registered trademark of Ortho-McNeil Pharmaceutical, Inc.

Bristol-Myers Squibb Company Princeton, NJ 08543 USA, Licensed from Kyorin Pharmaceutical Company, Limited, Tokyo, Japan, 117880DIM-XX 51-008627-XX 1099993BX

Gatifloxacin ophthalmic solution, 0.5% is indicated for the treatment of bacterial conjunctivitis caused by susceptible strains of the following organisms:

Aerobic Gram-Positive Bacteria

Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus mitis group*
Streptococcus oralis*
Streptococcus pneumoniae

Aerobic Gram-Negative Bacteria

Haemophilus influenzae

*Efficacy for this organism was studied in fewer than 10 infections.

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.

None

OVERDOSE

Gatifloxacin 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).

CONTRAINDICATIONS

TEQUIN is contraindicated in persons with a history of hypersensitivity to gatifloxacin or any member of the quinolone class of antimicrobial agents.

WARNINGS

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 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.

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.

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.

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.

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.

PRECAUTIONS

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).

(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.

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]).

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.

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 (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

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Topical Ophthalmic Use Only

Gatifloxacin ophthalmic solution should not be introduced directly into the anterior chamber of the eye.

Growth of Resistant Organisms with Prolonged Use

As 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 Wear

Patients 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 Fertility

There 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 C

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.

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 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 Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

SIDE EFFECTS

Clinical Studies Experience

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 INTERACTIONS

Specific drug interaction studies have not been conducted with gatifloxacin ophthalmic solution.

SIDE EFFECTS

Over 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.

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.

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 INTERACTIONS

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).

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).

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).

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).

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).

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.

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).

There are no reported laboratory test interactions.

Pregnancy Category C

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.

Clinical Studies Experience

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.

No information provided.

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.