FLOXAG is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below. (See DOSAGE AND ADMINISTRATION and Clinical Studies.)

Acute bacterial exacerbation of chronic bronchitis (ABECB) caused by Streptococcus pneumoniae, Haemophilus influenzae, Haemophilusparainfluenzae, or Moraxella catarrhalis.

Because fluoroquinolones, including FLOXAG, have been associated with serious adverse reactions (see WARNINGS) and for some patients ABECB is self-limiting, reserve FLOXAG for treatment of ABECB in patients who have no alternative treatment options.

Community-acquired pneumonia (of mild to moderate severity) caused by Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP])*, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae, or Klebsiella pneumoniae.

*MDRSP: multi-drug resistant Streptococcus pneumoniae, 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), 2nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

 To reduce the development of drug-resistant bacteria and maintain the effectiveness of FLOXAG and other antibacterial drugs, FLOXAG should be used only to treat 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.

DOSAGE AND ADMINISTRATION

FLOXAG can be taken with or without food and should be swallowed whole with a liberal amount of liquid.  The recommended dose of FLOXAG is 320 mg daily, according to the following table (Table 4).

Table 4. Recommended Dosage Regimen of FLOXAG  
The clinical decision regarding the use of a 5 day or 7 day regimen should be guided by results of the initial sputum culture.

*MDRSP: multi-drug resistant Streptococcus pneumoniae, 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), 2nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

The recommended dose and duration of FLOXAG should not be exceeded (see Table 2).

Use in Renally Impaired Patients

Dose adjustment in patients with creatinine clearance >40 mL/min is not required. Modification of the dosage is recommended for patients with creatinine  clearance ?40 mL/min. Table 5 provides dosage guidelines for use in patients with renal impairment.

Table 5. Recommended Doses for Patients with Renal Impairment

Patients requiring routine hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) should receive 160 mg every 24 hours.

When only the serum creatinine concentration is known, the following formula may be used to estimate creatinine clearance.

Use in Hepatically Impaired Patients

No dosage adjustment is recommended in patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.

Use in Elderly

No dosage adjustment is recommended.

WARNINGS

Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects

Fluoroquinolones, including FLOXAG have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting FLOXAG. Patients of any age or without pre-existing risk factors have experienced   these adverse reactions (See WARNINGS, Tendinitis and Tendon Rupture, Peripheral Neuropathy and Central Nervous System Effects)

Discontinue FLOXAG immediately at the first signs or symptoms of any serious adverse reaction.  In addition, avoid the use of fluoroquinolones, including FLOXAG, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

Tendinitis and Tendon Rupture

Fluoroquinolones, including FLOXAG, have been associated with an increased risk of tendinitis and tendon rupture in all ages.  This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur  within hours or days after starting FLOXAG, or as long as several months after completion of therapy. Tendinitis and tendon rupture can occur bilaterally.

The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous  tendon disorders such as rheumatoid arthritis.  Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Discontinue FLOXAGif  the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including FLOXAG, in patients who have a history of tendon disorders or have experienced  tendinitis or tendon rupture. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone  antimicrobial drug.

Peripheral Neuropathy

Fluoroquinolones, including FLOXAG, have been associated with an increased risk of peripheral neuropathy. 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 fluoroquinolones, including FLOXAG.  Symptoms may occur soon after initiation of FLOXAG and may be irreversible in some patients. Discontinue FLOXAG immediately if the patient experiences symptoms of peripheral neuropathy, including pain,  burning, tingling, numbness, and/or weakness or other alterations in sensations including light touch, pain, temperature, position sense, and vibratory sensation.

CNS Effects

Fluoroquinolones, including FLOXAG, have been associated with an increased risk of central nervous system (CNS) effects, including convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis. In clinical studies with FLOXAG, central nervous system (CNS) effects have been reported infrequently. As with other fluoroquinolones,     FLOXAG should be used with caution in patients with CNS diseases such as epilepsy or patients predisposed to convulsions.  CNS stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, insomnia, and rarely suicidal thoughts or acts may also be caused by other fluoroquinolones.  If these reactions occur in patients receiving FLOXAG, discontinue FLOXAG immediately and institute appropriate measures.

Exacerbation of Myasthenia Gravis

Fluoroquinolones, including FLOXAG, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis.  Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis.  Avoid FLOXAG in patients with known history of myasthenia gravis.  (See PATIENT INFORMATION and ADVERSE REACTIONS/Post-Marketing Adverse Reactions.)

THE SAFETY AND EFFECTIVENESS OF FLOXAG IN CHILDREN, ADOLESCENTS (LESS THAN 18 YEARS OF AGE), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED.  (See PRECAUTIONS: Pediatric Use, Pregnancy and Nursing Mothers subsections.)  

QT Effects

Fluoroquinolones may prolong the QT interval in some patients. FLOXAG should be avoided in patients with a history of prolongation of the QTc interval, patients with uncorrected  electrolyte disorders (hypokalemia or hypomagnesemia), and patients receiving Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents.

 Pharmacokinetic studies between gemifloxacin and drugs that prolong the QTc interval such as erythromycin, antipsychotics, and tricyclic antidepressantshave not been performed.  FLOXAG 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.  No cardiovascular morbidity or mortality attributable to QTc prolongation occurred with FLOXAG treatment in over 8119 patients, including 707 patients concurrently receiving drugs known to prolong the QTc interval and 7 patients with hypokalemia.

The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.  QTc prolongation may lead to an increased risk for ventricular arrhythmias including torsades de pointes. The maximal change in the QTc   interval occurs approximately 5-10 hours following oral administration of gemifloxacin.

Hypersensitivity Reactions

Serious hypersensitivity and/or anaphylactic reactions have been reported in patients receiving fluoroquinolone therapy, including FLOXAG. Hypersensitivity reactions  reported in patients receiving fluoroquinolone therapy have occasionally been fatal.  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.

FLOXAG should be discontinued immediately at the appearance of any sign of an immediate type I hypersensitivity skin rash or any other manifestation of a hypersensitivity reaction; the need for continued fluoroquinolone therapy should be evaluated.  As with other drugs, 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 and ADVERSE REACTIONS.)  Other serious and sometimes fatal adverse reactions, some due to hypersensitivity and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including FLOXAG.  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.

Discontinue FLOXAG immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and institute supportive measures (See PATIENT INFORMATION and ADVERSE REACTIONS).

Clostridium Difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including FLOXAG, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of    C. difficile.

 C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of  C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.  CDAD must be considered in all patients who present with diarrhea following antibiotic use.  Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

 If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.  Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Precautions

General

Prescribing FLOXAG in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drugresistant bacteria.

Rash

In clinical studies, rash occurred more often with FLOXAG than with therapy with comparator agents (2.7% vs. 0.6%).  Increasing incidence of rash was associated with younger age (especially below 40), female gender, use of hormone replacement therapy and longer durations of therapy (see Table 2). Urticarial reactions, some of which were not classified as rash, were more  common in FLOXAG patients than in comparator patients (0.6% vs. 0.2%).  FLOXAG should be discontinued in patients developing a rash or urticaria while on treatment.  (See ADVERSE REACTIONS and Clinical Studies.)

Table 2. Rash Incidence in FLOXAG Treated Patients from the Clinical Studies Population* by Gender, Age, and Duration of Therapy

*includes patients from studies of community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, and other indications **exceeds the recommended duration of therapy (see DOSAGE AND ADMINISTRATION)

The most common form of rash associated with FLOXAG was described as maculopapular and mild to moderate in severity. Eighty percent of rashes resolved within 14 days.  Approximately 10% of the rashes (0.5% of all patients) were described as of severe intensity and approximately 10% of those with rash were treated with systemic steroids.  There were no documented cases in the clinical trials of more serious skin reactions known to be associated with significant morbidity or mortality.

Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, Varea of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with use of quinolones after sun or UV light exposure. Therefore excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs. (See   ADVERSE REACTIONS and ADVERSE REACTIONS: Post-Marketing Adverse Reactions.)

Hepatic Effects

Liver enzyme elevations (increased ALT and/or AST) occurred at similar rates in patients receiving FLOXAG 320 mg daily relative to comparator antimicrobial agents (ciprofloxacin, levofloxacin, clarithromycin/cefuroxime axetil, amoxicillin/clavulanate potassium, and ofloxacin).  In patients who received gemifloxacin at doses of 480 mg per day or greater there was an increased incidence of elevations in liver enzymes.  (See ADVERSE REACTIONS.)

There were no clinical symptoms associated with these liver enzyme elevations.  The liver enzyme elevations resolved following cessation of therapy.  The recommended dose of FLOXAG 320 mg daily should not be exceeded and the recommended length of therapy should not be exceeded.  (See DOSAGE AND ADMINISTRATION.)

Renal Effects

Alteration of the dosage regimen is necessary for patientswith impairment of renal function (creatinine clearance ?40 mL/min). (See DOSAGE AND ADMINISTRATION.) Adequate hydration of patients receiving FLOXAG should be maintained to prevent the formation of a highly concentrated urine.

Information for Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

Serious Adverse Reactions

Advise patients to stop taking FLOXAG if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug.

Inform patients of the following serious adverse reactions that have been associated with FLOXAG or other fluoroquinolone use:

• Disabling and potentially irreversible serious adverse reactions that may occur together, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of FLOXAG and may occur together in the same patient. Inform patients to stop taking FLOXAG immediately if they experience an adverse reaction and to call their healthcare provider;
• Tendinitis and tendon rupture: instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue FLOXAG treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants;
• Peripheral neuropathies: Inform patients that peripheral neuropathies have been associated with the use of FLOXAG, that symptoms may occur soon after initiation of therapy and may be irreversible.  If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, patients should immediately discontinue FLOXAG and contact their physician;
• Central nervous system effects (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure): Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including FLOXAG.  Patients should notify their physician before taking FLOXAG if they have a history of convulsions, seizures, or epilepsy; Inform patients that other central nervous system problems such as tremors, restlessness, lightheadedness, confusion and hallucinations may occur rarely;   
• Exacerbation of Myasthenia Gravis: Inform patients that fluoroquinolones like FLOXAG may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems;  
• Hypersensitivity Reactions: Inform patients that FLOXAG may be associated with hypersensitivity reactions, including anaphylactic reactions, even following a single dose; patients should immediately discontinue the drug at the sign of a rash or other allergic reaction and seek medical care; Inform patients that FLOXAG has been associated with rash and hives.  Rash occurs more commonly in those under 40, especially women and in women on hormone replacement therapy.  The incidence of rash increases with duration more than 5 days and particularly longer than 7 days.  Patients should discontinue FLOXAG and call their healthcare provider if they develop a rash;
• Diarrhea: Inform patients that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued.  Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.  If this occurs, patients should contact their physician as soon as possible;
• Prolongation of the QT interval: inform patients of the following:
• that FLOXAG may cause changes in the electrocardiogram (QTc interval prolongation);  
• that FLOXAG should be avoided in patients receiving Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents;  
• that FLOXAG should be used with caution in patients receiving drugs that affect 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 hypokalemia, bradycardia, or recent myocardial ischemia;  
• to contact their physician if they experience palpitations or fainting spells while taking FLOXAG;  
• that FLOXAG may cause dizziness; if this occurs, patients should not operate an automobile or machinery or engage in activities requiring mental alertness or coordination;
• Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported in patients receiving quinolones.  Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones.  If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician.  If a sunburn-like reaction or skin eruption occurs, patients should contact their physician;

DRUG INTERACTIONS

Administration of repeat doses of FLOXAG had no effect on the repeat dose pharmacokinetics of theophylline, digoxin or an ethinylestradiol/levonorgestrol oral contraceptive product in healthy subjects.  (See CLINICAL PHARMACOLOGY: Drug-Drug Interactions.)

Concomitant administration of FLOXAG and calcium carbonate, cimetidine, omeprazole, or an estrogen/progesterone oral contraceptive produced minor changes in the pharmacokinetics of gemifloxacin, which were considered to be without clinical significance.  (See CLINICAL PHARMACOLOGY.)

Concomitant administration of FLOXAG with probenecid resulted in a 45% increase in systemic exposure to gemifloxacin.  (See CLINICAL PHARMACOLOGY.)

FLOXAG had no significant effect on the anticoagulant effect of warfarin in healthy subjects on stable warfarin therapy.  However, post-marketing reports of increases in the INR, or PT, and/or clinical episodes of bleeding in patients have been noted with the use of quinolones, including FLOXAG, and warfarin, or its derivatives.  In addition, infectious disease and its accompanying inflammatory process, age and general status of the patient are risk factors for increased anticoagulation activity.  Therefore, the PT, INR or other suitable coagulation test should be closely monitored if a quinolone antimicrobial, including FLOXAG, is administered concomitantly with warfarin or its derivatives.

Quinolones form chelates with alkaline earth and transition metals.  The absorption of oral gemifloxacin is significantly reduced by the concomitant administration of an antacid containing aluminum and magnesium. Magnesium-and/or aluminum-containing antacids, products containing ferrous sulfate(iron), multivitamin preparations containing zinc or other metal cations, or Videx (didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be taken within 3 hours before or 2 hours after FLOXAG.  Sucralfate should not be taken within 2 hours of FLOXAG. (See  CLINICAL PHARMACOLOGY.)

Pregnancy

Teratogenic Effects

Pregnancy Category C. Gemifloxacin treatment during organogenesis caused fetal growth retardation in mice (oral dosing at 450 mg/kg/day), rats (oral dosing at 600 mg/kg/day) and rabbits (IV dosing at 40 mg/kg/day) at AUC levels which were 2-, 4- and 3-fold those in women given oral doses of 320 mg.  In rats, this growth retardation appeared to be reversible in a pre- and postnatal development study (mice and rabbits were not studied for the reversibility of this effect).  Treatment of pregnant rats at 8-fold clinical exposure (based upon AUC  comparisons) caused fetal brain and ocular malformations in the presence of maternal toxicity.  The overall no-effect exposure level in pregnant animals was approximately 0.8 to 3-fold clinical exposure.

The safety of FLOXAG in pregnant women has not been established. FLOXAG should not be used in pregnant women unless the potential benefit to the mother outweighs the risk to  the fetus. There are no adequate and well-controlled studies in pregnant women.

Nursing Mothers

Gemifloxacin is excreted in the breast milk of rats. There is no information on excretion of gemifloxacin into human milk.   Therefore, FLOXAG should not be used in lactating women unless the potential benefit to the mother outweighs the risk.

FLOXAG can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how FLOXAG affects you. 

SIDE EFFECTS

In clinical studies, 8119 patients received daily oral doses of 320 mg FLOXAG.  In addition, 1797 healthy volunteers and 81 patients with renal or hepatic impairment received single or repeat doses of gemifloxacin in clinical pharmacology studies.  The majority of adverse reactions experienced by patients in clinical trials were considered to be of mild to moderate severity.

FLOXAG was discontinued because of an adverse event (determined by the investigator to be possibly or probably related to drug) in 2.0% of patients, primarily due to rash (0.8%), nausea (0.3%), diarrhea (0.3%), urticaria (0.2%) and vomiting (0.2%).  Comparator antibiotics were discontinued because of an adverse event at an overall comparable rate of 2.1%, primarily due to diarrhea (0.5%), nausea (0.4%), vomiting (0.3%), rash (0.3%), abdominal pain (0.2%) and vertigo (0.2%). The mostcommonly reported adverse events with a frequency of ?2% forpatients receiving 320 mg FLOXAG versus comparator drug (beta-lactam antibiotics, macrolides or other fluoroquinolones) are as follows: diarrhea 5.0% vs. 6.2%; rash 3.5% vs. 1.1%; nausea 3.7% vs. 4.5%; headache 4.2% vs. 5.2%; abdominal pain 2.2% vs. 2.2%; vomiting 1.6% vs. 2.0%; and dizziness 1.7% vs. 2.6%.  

Adverse Events with a Frequency of Less than 1%

Additional drug-related adverse events (possibly or probablyrelated) in the 8119 patients, with a frequency of >0.1% to ?1% included: abdominal pain, anorexia, constipation, dermatitis, dizziness, dry mouth, dyspepsia, fatigue, flatulence, fungal infection, gastritis, genital moniliasis, genital pruritus, hyperglycemia, increased alkaline phosphatase, increased ALT, increased AST, increased creatine phosphokinase, insomnia, leukopenia, pruritus, somnolence, taste perversion, thrombocythemia, urticaria, vaginitis, and vomiting.

Other adverse events reported from clinical trials which have potential clinical significance and which were considered to have a suspected relationship to the drug, that occurred in ?0.1% of patients were: abnormal urine, abnormal vision, anemia, arthralgia, asthenia, back pain, bilirubinemia, dyspnea, eczema, eosinophilia, facial edema, flushing, gastroenteritis, granulocytopenia, hot flashes, increased GGT, increased non-protein nitrogen, leg cramps, moniliasis, myalgia, nervousness, non-specified gastrointestinal disorder, pain, pharyngitis, photosensitivity/phototoxicity reactions, pneumonia, thrombocytopenia, tremor, vertigo. (See PRECAUTIONS.)

In clinical trials of acute bacterial exacerbation of chronic bronchitis (ABECB) and community acquired pneumonia (CAP), the incidences of rash were as follows (Table 3):

Table 3. Incidence of Rash by Clinical Indication in Patients Treated with FLOXAG

* insufficient number of patients in this category for a meaningful analysis (See PRECAUTIONS).

Laboratory Changes

The percentages of patients who received multiple doses of FLOXAG and had a laboratory abnormality are listed below. It is not known whether these abnormalities were  related to FLOXAG or an underlying condition.

Clinical Chemistry: increased ALT (1.7%), increased AST (1.3%), increased creatine phosphokinase (0.7%), increased alkaline phosphatase (0.4%), increased total bilirubin (0.4%), increased potassium (0.3%), decreased sodium (0.2%), increased blood urea nitrogen (0.3%), decreased albumin (0.3%), increased serum creatinine (0.2%), decreased calcium (0.1%), decreased total protein (0.1%), decreased potassium (0.1%), increased sodium (0.1%), increased lactate dehydrogenase (<0.1%) and increased calcium (<0.1%).

CPK elevations were noted infrequently: 0.7% in FLOXAG patients vs. 0.7% in the comparator patients.

Hematology: increased platelets (1.0%), decreased neutrophils (0.5%), increased neutrophils (0.5%), decreased hematocrit (0.3%), decreased hemoglobin(0.2%), decreased platelets (0.2%), decreased red blood cells (0.1%), increased hematocrit (0.1%), increased hemoglobin (0.1%), and increased red blood cells (0.1%).

In clinical studies, approximately 7% of the FLOXAG treated patients had elevated ALT values immediately prior to entry into the study. Of these patients, approximately 15% showed a  further elevation of their ALT at the on-therapy visit and 9% showed a further elevation at the end of therapy visit.  None of these patients demonstrated evidence of hepatocellular jaundice.  For the pooled comparators, approximately 6% of patients had elevated ALT values immediately prior to entry into the study.  Of these patients, approximately 7% showed a further elevation of their ALT at the on-therapy visit and 4% showed a further elevation at the end of therapy visit.

In a clinical trial where 638 patients received either a single 640 mg dose of gemifloxacin or 250 mg BID of ciprofloxacin for 3 days, there was an increased incidence of ALT elevations in the gemifloxacin arm (3.9%) vs. the comparator arm (1.0%).  In this study, two patients experienced ALT elevations of 8 to 10 times the upper limit of normal.  These elevations were asymptomatic and reversible.

Post-Marketing Adverse Reactions

The majority of the post-marketing adverse events reported were cutaneous and most of these were rash. Some of these cutaneous adverse events were  considered serious.  The majority of the rashes occurred in women and in patients under 40 years of age.

The following are additional adverse reactions reported during the post-marketing use of FLOXAG. Since these reactions are reported voluntarily from a population of uncertain size, it is impossible to reliably estimate their frequency or establish a causal relationship to FLOXAG exposure:

• Peripheral neuropathy that may be irreversible;
• Anaphylactic reaction, erythema multiforme, skin exfoliation, facial swelling;
• Exacerbation of myasthenia gravis;
• Hemorrhage, increased international normalized ratio (INR), retinal hemorrhage;
• Peripheral edema;
• Renal failure;
• Prolonged QT, supraventricular tachycardia, syncope, transient ischemic attack;
• Photosensitivity/phototoxicity reaction (See PRECAUTIONS.);
• Antibiotic-associated colitis;  
• Tendon rupture.

   The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662 o Call NPC at +966-11-2038222, Exts: 2317-2356-2340. o Reporting hotline: 19999 o E-mail: npc.drug@sfda.gov.sa o Website: www.sfda.gov.sa/npc

Any signs or symptoms of overdosage should be treated symptomatically.  No specific antidote is known.  In the event of acute oral overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage; the patient should be carefully observed and treated symptomatically with appropriate hydration maintained.  Hemodialysis removes approximately 20 to 30% of an oral dose of gemifloxacin from plasma.

Mortality occurred at oral gemifloxacin doses of 1600 mg/kg in rats and 320 mg/kg in mice. The minimum lethal intravenous doses in these species were 160 and 80 mg/kg, respectively.  Toxic signs after administration of a single high oral dose (400 mg/kg) of gemifloxacin to rodents included ataxia, lethargy, piloerection, tremor, and clonic convulsions.

Microbiology

Gemifloxacin has in vitro activity against a wide range of Gram-negative and Gram-positive microorganisms.  Gemifloxacin is bactericidal with minimum bactericidal concentrations (MBCs) generally within one dilution of the minimum inhibitory concentrations (MICs).  Gemifloxacin acts by inhibiting DNA synthesis through the inhibition of both DNA gyrase and topoisomerase IV (TOPO IV), which are essential for bacterial growth.  Streptococcus pneumoniaeshowing mutations in both DNA gyrase and TOPO IV (double mutants) are resistant to most fluoroquinolones.  Gemifloxacin has the ability to inhibit both enzyme systems at therapeutically relevant drug levels in S. pneumoniae (dual targeting), and has MIC values that are still in the susceptible range for some of these double mutants.  However, the presence of double mutants was not evaluated in clinical trials; therefore, the clinical significance of these in vitrodata are unknown.

The mechanism of action of quinolones, including gemifloxacin, is different from that of macrolides, beta-lactams, aminoglycosides, or tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to gemifloxacin and other quinolones.  There is no known cross-resistance between gemifloxacin and the above mentioned classes of antimicrobials.

The main mechanism of fluoroquinolone resistance is due to mutations in DNA gyrase and/or TOPO IV.  Resistance to gemifloxacin develops slowly via multistep mutations and efflux in a manner similar to other fluoroquinolones.  The frequency of spontaneous mutation is low (10-7 to <10-10). Although cross-resistance has been observed between gemifloxacin and other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to gemifloxacin.

Gemifloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic Gram-Positive Microorganisms

Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP])*

*MDRSP: multi-drug resistant Streptococcus pneumoniae, 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), 2nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

Aerobic Gram-Negative Microorganisms

Haemophilus influenzae
Haemophilusparainfluenzae
Klebsiella pneumoniae (many strains are only moderately susceptible) Moraxella catarrhalis

Other Microorganisms

Chlamydia pneumoniae
Mycoplasma pneumoniae

The following data are available, but their clinical significance is unknown.

Gemifloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 0.25 µg/mL or less against most (?90%)strains of the following microorganisms; however, the safety and effectiveness of gemifloxacin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials:

Aerobic Gram-Positive Microorganisms

Staphylococcus aureus (methicillin-susceptible strains only)
Streptococcus pyogenes

Aerobic Gram-Negative Microorganisms

Acinetobacter lwoffii
Klebsiellaoxytoca
Legionella pneumophila
Proteus vulgaris

Susceptibility Tests

Dilution techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to  antimicrobial compounds.  The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method 1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of gemifloxacin powder.  The MICs should be interpreted according to the following criteria:

For testing Klebsiella pneumoniae:

For testing Haemophilus influenzae and Haemophilusparainfluenzaea: 

aThis interpretive standard is applicable only to broth microdilution susceptibility testing with Haemophilus influenzae and Haemophilusparainfluenzae using Haemophilus Test Medium (HTM)1.

The current absence of data on resistant strains precludes defining any results other than susceptible.  Strains yielding MIC results suggestive of a nonsusceptiblecategory should be submitted to a reference laboratory for further testing.  

For testing Streptococcus pneumoniae:

bThese interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.

A report of Susceptibleindicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable.  A report of Intermediateindicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated.  This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used.  This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation.  A report of Resistantindicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.  Standard gemifloxacin powder should provide the following MIC values:

cThis quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using Haemophilus Test Medium (HTM)1.
dThis quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a broth microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds.  One such standardized procedure2 requires the use of standardized inoculum concentrations.  This procedure uses paper disks impregnated with 5 µg gemifloxacin to test the susceptibility of microorganisms to gemifloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 µg gemifloxacin disk should be interpreted according to the following criteria:

For testing Klebsiella pneumoniae:  

For testing Haemophilus influenzae and Haemophilusparainfluenzae:

This interpretive standard is applicable only to disk diffusion susceptibility testing with Haemophilus influenzae and Haemophilusparainfluenzae using Haemophilus Test Medium (HTM).2

The current absence of data on resistant strains precludes defining any results other than Susceptible.  Strains yielding zone diameter results suggestive of a nonsusceptible category should be submitted to a reference laboratory for further testing.

For testing Streptococcus pneumoniae:

^f These zone diameter standards apply only to tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood incubated in 5% CO2.

Interpretation should be as stated above for results using dilution techniques.  Interpretation involves correlation of the diameter obtained in the disk test with the MIC for gemifloxacin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures.  For the diffusion technique, the 5 µg gemifloxacin disk should provide the following zone diameters in these laboratory quality control strains:

This quality control range is applicable to only H. influenzae ATCC 49247 tested by a disk diffusion procedure using Haemophilus Test Medium (HTM)2.
hThis quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood and incubated in 5% CO2.

Clinical Studies

Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB)

FLOXAG (320 mg once daily for 5 days) was evaluated for the treatment of acute bacterial exacerbation of chronic bronchitis in three pivotal double-blind, randomized, actively-controlled clinical trials (studies 068, 070, and 212). The primary efficacy parameter in these studies was the clinical response at follow-up (day 13 to 24). The results of the clinical response at follow-up for the    principal ABECB studies demonstrate that FLOXAG 320 mg PO once daily for 5 days was at least as good as the comparators given for 7 days.  The results are shown in Table 6 below.

Table 6. Clinical Response at Follow-Up (Test of Cure): Pivotal ABECB Studies

Community Acquired Pneumonia (CAP)

5 Day Treatment Regimen

To evaluate the safety and efficacy of a 5-day course of FLOXAG, 510 outpatient and hospitalized adults with clinically and radiologically determined mild to moderate community-acquired pneumonia were clinically evaluated in a double-blind, randomized, prospective, multicenter study comparing FLOXAG 320 mg for five days to FLOXAG 320 mg for seven days (Study OP-634-001). Clinical success rates in the clinically evaluable population were 95.0% in the 5 day group and 92.1% in the 7 day group.

Table 7. Clinical Response at Follow-Up (Test of Cure): Study OP-634-001

The microbiological efficacy of the 5-day regimen was documented for pathogens listed in Table 8 below.

Table 8. Bacterial Eradication by Pathogen for Patients Treated with FLOXAG in Study OP-634-001

7 Day Treatment Regimen

Previous clinical studies evaluated the efficacy of FLOXAG in a 7-day treatment of CAP in adults.  This clinical program consisted of three double-blind, randomized, actively-controlled clinical studies (studies 011, 012, and 049) and one open-label, actively-controlled study (study 185).  In addition, two uncontrolled studies (studies 061 and 287) were conducted.  Three of the studies, controlled study 011 and the uncontrolled studies, had a fixed 7-day duration of treatment for FLOXAG. Controlled study 011 compared a 7-day course of FLOXAG with a 10-day treatment course of  amoxicillin/clavulanate (1g/125 mg TID) and clinical success rates were similar between treatment arms.  The results of comparative studies 049, 185, and 012 were supportive although treatment duration could have been 7 to 14 days.  The results of the clinical studies with a fixed 7-day duration of FLOXAG are shown in Table 9.

Table 9. Clinical Response at Follow-Up (Test of Cure): CAP Studies with a Fixed 7-day Duration of Treatment

*For uncontrolled studies, the 95% CI around the success rate is shown

The combined bacterial eradication rates for patients treated with a fixed 7-day treatment regimen of FLOXAG are shown in Table 10.

Table 10. Bacterial Eradication by Pathogen for Patients Treated with FLOXAG in Studies with a Fixed 7-day Duration of Treatment

7 Day Treatment Regimen of Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus Pneumoniae (MDRSP)

FLOXAG was also effective in the treatment of CAP due to multi-drug resistant Streptococcus pneumoniae (MDRSP*).  Of 35 patients with MDRSP treated for 7 days, 29 (82.9%) achieved clinical and bacteriological success at follow-up.  The clinical and bacteriological success for the 35 patients with MDRSP isolates are shown in Table 11.  

*MDRSP: multi-drug resistant Streptococcus pneumoniae, 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), 2nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

Table 11. Clinical and Bacteriological Success for 35 Patients Treated with FLOXAG in CAP Studies with a 7-day Duration of Treatment for MDRSP

Not all isolates were resistant to all antimicrobial classes tested.  Success and eradication rates are summarized in Table 12 below.

Table 12. Resistant Streptococcus pneumoniae Clinical Success and Bacteriological Eradication Rates

Clinical Safety Study of Rash

To further characterize gemifloxacin-associated rash, which in early clinical studies appeared to be associated with age less than 40 and female gender, a clinical pharmacology study was conducted.  The study enrolled 1,011 healthy female volunteers less than 40 years of age.  Subjects were randomized in a 5:1 ratio to receive either FLOXAG 320 mg PO daily (819 subjects) or ciprofloxacin 500 mg PO twice daily for 10 days (164 subjects). This study was designed to enroll subjects at a high risk for rash (women <40 years of age and dosing beyond the recommended duration of therapy for  FLOXAG [10 days]) and over estimates the risk to patients taking FLOXAG as prescribed.  Subjects who received FLOXAG were 7 times more likely to develop rash than those who received ciprofloxacin.  Of the 260 rashes in subjects receiving FLOXAG, the majority of rashes were maculopapular and of mild to moderate severity; 7% of the rashes were reported as severe, and severity appeared to correlate with the extent of the rash. In 68% of the subjects reporting a severe rash and approximately 25% of all those reporting rash, >60% of the body surface area was involved; the characteristics of the rash were otherwise indistinguishable from those subjects reporting a mild rash.  The histopathology was consistent with the clinical observation of uncomplicated exanthematous morbilliform eruption.  Approximately 11% of the rashes were described as being urticaria-like.  There were no documented cases of hypersensitivity syndrome or findings suggestive of angioedema or other serious cutaneous reactions.

The majority of rashes (81.9%) occurred on days 8 through 10 of the planned 10 day course of FLOXAG; 2.7% of rash events occurred within one day of the start of dosing. The median duration of rash was 6 days.  The rash resolved without treatment in the majority of subjects.  Approximately 19% received antihistamines and 5% received steroids, although the therapeutic benefit of these therapies is uncertain.

In the second part of this study after a 4 to 6 week wash out period, subjects developing a rash on FLOXAG were treated with ciprofloxacin (n=136) or placebo (n=50); 5.9% developed rash when treated with ciprofloxacin and 2.0% developed rash when treated with placebo.  The cross sensitization rate to other fluoroquinolones was not evaluated in this clinical study.  There was no evidence of sub-clinical sensitization to FLOXAG on a second exposure (i.e., subjects who had not developed a rash to FLOXAG in the first part of the study were not at higher risk of developing a rash to FLOXAG with a second exposure).

There was no relationship between the incidence of rash and systemic exposure (Cmax and AUC) to either gemifloxacin or its major metabolite, N-acetyl gemifloxacin.

Pharmacokinetics

The pharmacokinetics of gemifloxacin are approximately linear over the dose range from 40 mg to 640 mg.  There was minimal accumulation of gemifloxacin following multiple oral doses up to 640 mg a day for 7 days (mean accumulation <20%).  Following repeat oral administration of 320 mg gemifloxacin once daily, steady-state is achieved by the third day of dosing.

Absorption and Bioavailability

Gemifloxacin, given as an oral tablet, is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations of gemifloxacin were observed between 0.5 and 2 hours following oral tablet  administration and the absolute bioavailability of the 320 mg tablet averaged approximately 71% (95% CI 60%-84%). Following repeat oral doses of 320 mg to healthy subjects, the mean  ±  SD maximal gemifloxacin plasma concentrations (Cmax) and systemic drug exposure (AUC (0-24)) were 1.61 ±  0.51 µg/mL (range 0.70-2.62 µg/mL) and 9.93 ±  3.07 µg•hr/mL (range 4.71-20.1 µg•hr/mL), respectively. In patients with respiratory and urinary tract infections (n=1423), similar estimates of systemic drug exposure were determined using a population pharmacokinetics analysis (geometric mean AUC (0-24), 8.36 µg•hr/mL; range 3.2 to 47.7 µg•hr/mL).

The pharmacokinetics of gemifloxacin were not significantly altered when a 320 mg dose was administered with a high-fat meal.  Therefore FLOXAG tablets may be administered without regard to meals.

Distribution

In vitro binding of gemifloxacin to plasma proteins in healthy subjects is approximately 60 to 70% and is concentration independent. After repeated doses, the in vivo plasma protein binding in healthy elderly and young subjects ranged from 55% to 73% and was unaffected by age. Renal impairment does not significantly affect the protein binding of gemifloxacin.  The blood-to-plasma concentration ratio of gemifloxacin was 1.2:1.  The geometric mean for Vdss/F is 4.18 L/kg (range, 1.66 “ 12.12 L/kg).

Gemifloxacin is widely distributed throughout the body after oral administration.  Concentrations of gemifloxacin in bronchoalveolar lavage fluid exceed those in the plasma.  Gemifloxacinpenetrates well into lung tissue and fluids.  After five daily doses of 320 mg gemifloxacin, concentrations in plasma, bronchoalveolar macrophages, epithelial lining fluid and bronchial mucosa at approximately 2 hours were as in Table 1.

Table 1. Gemifloxacin Concentrations in Plasma and Tissues (320 mg Oral Dosing)

Metabolism

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

Excretion

Gemifloxacin and its metabolites are excreted via dual routes of excretion.  Following oral administration of gemifloxacin to healthy subjects, a mean (±  SD) of 61 ± 9.5% of the dose was excreted in the feces and 36 ± 9.3% in the urine as unchanged drug and metabolites.  The mean (±  SD) renal clearance following repeat doses of 320 mg was approximately 11.6 ± 3.9 L/hr (range 4.6-17.6 L/hr), which indicates active secretion is involved in the renal excretion of gemifloxacin.  The mean (±  SD) plasma elimination half-life at steady state following 320 mg to healthy subjects was approximately 7 ± 2 hours (range 4-12 hours). 

Special Populations

Pediatric: The pharmacokinetics of gemifloxacin in pediatric subjects have not been studied.

Geriatric: In adult subjects, the pharmacokinetics of gemifloxacin are not affected by age.

Gender: There are no significant differences between gemifloxacin pharmacokinetics in males and females when differences in body weight are taken into account.  Population pharmacokinetic studies indicated that following administration of 320 mg gemifloxacin, AUC values were approximately 10% higher in healthy female patients compared to males.  Males and females had mean AUC values of 7.98 µg•hr/mL (range, 3.21 “42.71 µg•hr/mL) and 8.80 µg•hr/mL (range, 3.33 to 47.73 µg•hr/mL), respectively.  No gemifloxacin dosage adjustment based on gender is necessary.

Hepatic Insufficiency: The pharmacokinetics following a single 320 mg dose of gemifloxacin were studied in patients with mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) liver disease.

There was a mean increase in AUC (0-inf) of 34% and a mean increase in Cmax of 25% in these patients with hepatic impairment compared to healthy volunteers.

The pharmacokinetics of a single 320 mg dose of gemifloxacin were also studied in patients with severe hepatic impairment (Child-Pugh Class C).  There was a mean increase in AUC (0-inf) of 45% and a mean increase in Cmax of 41% in these subjects with hepatic impairment compared to healthy volunteers.

These average pharmacokinetic increases are not considered to be clinically significant.  There was no significant change in plasma elimination half-life in the mild, moderate or severe

hepatic impairment patients.  No dosage adjustment is recommended in patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. (See DOSAGE AND ADMINISTRATION.)

Renal Insufficiency: Results from population pharmacokinetic and clinical pharmacology studies with repeated 320 mg doses indicate the clearance of gemifloxacin is reduced and the plasma elimination is prolonged, leading to an average increase in AUC values of approximately 70% in patients with renal insufficiency. In the pharmacokinetic studies, gemifloxacin Cmax was not significantly altered in subjects with renal insufficiency. Dose adjustment in patients with creatinine clearance >40 mL/min is not required.  Modification of the dosage is recommended for patients  with creatinine clearance ?40 mL/min. (See DOSAGE AND ADMINISTRATION.)

Hemodialysis removes approximately 20 to 30% of an oral dose of gemifloxacin from plasma.

Photosensitivity Potential

In a study of the skin response to ultraviolet and visible radiation conducted in 40 healthy volunteers, the minimum erythematous dose (MED) was assessed following administration of either gemifloxacin 160 mg once daily, gemifloxacin 320 mg once daily, ciprofloxacin 500 mg BID, or placebo for 7 days.  At 5 of the 6 wavelengths tested (295-430 nm), the photosensitivity potential of gemifloxacin was not statistically different from placebo.  At 365 nm (UVA region), gemifloxacin showed a photosensitivity potential similar to that of ciprofloxacin 500 mg BID and the photosensitivity potential for both drugs were statistically greater than that of placebo.  Photosensitivity reactions were reported rarely in clinical trials with gemifloxacin (0.039%).  (See ADVERSE REACTIONS.)

It is difficult to ascribe relative photosensitivity/phototoxicity among various fluoroquinolones during actual patient use because other factors play a role in determining a subject™s susceptibility to this adverse event such as: a patient™s skin pigmentation, frequency and duration of sun and artificial ultraviolet light (UV) exposure, wearing of sun screen and protective clothing, the use of other concomitant drugs and the dosage and duration of fluoroquinolone therapy. (See ADVERSE REACTIONS and ADVERSE REACTIONS: Post-Marketing Adverse Reactions.)

See (5.1 pharmacodynamic properties&5.2 Pharmacokinetic properties)

Avicel PH101

Crospovidone NF

Croscarmellose Sodium type A

Sodium Lauryl Sulphate

Povidone 30

Ethanol Absolute

Avicel PH 102

Magnesium Stearate

Coating:

Hydroxypropyle methylcellulose

Titanium dioxide pharma grade

Purified talc

Polyethylene glycol MW 6000

Purified water

None known.

Do not store above 30°C

A white to off-white color, oblong shaped, biconvex, film-coated tablet, engraved with “517” on one side and break line on the other side.

Each carton contains 5 or 7 Film-Coated tablets in Aluminum thin soft temper plain strips.

Not all pack sizes may be marketed

None.