Factive

FACTIVE (gemifloxacin mesylate) is available as white to off-white, oval, film-coated tablets with breaklines and GE 320 debossed on both faces.  Each tablet contains gemifloxacin mesylate equivalent to 320 mg of gemifloxacin.

320 mg Unit of Use (CR*) 5's   NDC 44001-321-05
320 mg Unit of Use (CR*) 7's   NDC 44001-321-07

*Child Resistant

Storage

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

Manufactured for: Merus Labs International, Inc. Toronto, ON M5K 1H1  CANADA. Licensed from LG Life Sciences, Ltd. Seoul, Korea. Revised: May 2016

FACTIVE 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, Haemophilus parainfluenzae, or Moraxella catarrhalis.

Because fluoroquinolones, including FACTIVE, have been associated with serious adverse reactions (see WARNINGS) and for some patients ABECB is self-limiting, reserve FACTIVE 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 FACTIVE and other antibacterial drugs, FACTIVE 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.

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

Table 4. Recommended Dosage Regimen of FACTIVE  
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 FACTIVE 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.

FACTIVE is contraindicated in patients with a history of hypersensitivity to gemifloxacin, fluoroquinolone antibiotic agents, or any of the product components.

WARNINGS

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

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

Tendinitis and Tendon Rupture

Fluoroquinolones, including FACTIVE, 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 FACTIVE, 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 FACTIVE if  the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including FACTIVE, 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 FACTIVE, 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 FACTIVE.  Symptoms may occur soon after initiation of FACTIVE and may be irreversible in some patients. Discontinue FACTIVE 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 FACTIVE, 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 FACTIVE, central nervous system (CNS) effects have been reported infrequently. As with other fluoroquinolones,     FACTIVE 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 FACTIVE, discontinue FACTIVE immediately and institute appropriate measures.

Exacerbation of Myasthenia Gravis

Fluoroquinolones, including FACTIVE, 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 FACTIVE in patients with known history of myasthenia gravis.  (See PATIENT INFORMATION and ADVERSE REACTIONS/Post-Marketing Adverse Reactions.)

THE SAFETY AND EFFECTIVENESS OF FACTIVE 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. FACTIVE 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 antidepressants have not been performed.  FACTIVE 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 FACTIVE 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 FACTIVE. 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.

FACTIVE 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 FACTIVE.  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 FACTIVE 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 FACTIVE, 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 FACTIVE 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 FACTIVE 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 FACTIVE patients than in comparator patients (0.6% vs. 0.2%).  FACTIVE should be discontinued in patients developing a rash or urticaria while on treatment.  (See ADVERSE REACTIONS and Clinical Studies.)

Table 2. Rash Incidence in FACTIVE 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 FACTIVE 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, “V” area 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 FACTIVE 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 FACTIVE 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 FACTIVE 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 FACTIVE 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 FACTIVE 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 FACTIVE and may occur together in the same patient. Inform patients to stop taking FACTIVE 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 FACTIVE 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 FACTIVE, 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 FACTIVE 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 FACTIVE.  Patients should notify their physician before taking FACTIVE 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 FACTIVE 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 FACTIVE 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 FACTIVE 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 FACTIVE 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 FACTIVE may cause changes in the electrocardiogram (QTc interval prolongation);  
• that FACTIVE should be avoided in patients receiving Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents;  
• that FACTIVE 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 FACTIVE;  
• that FACTIVE 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; (See CLINICAL PHARMACOLOGY: Photosensitivity Potential).

Other Information

Advise Patients:

• that increases of the International Normalized Ratio (INR), or prothrombin time (PT), and/or clinical episodes of bleeding have been noted with concurrent administration of warfarin or its derivatives, and FACTIVE.  Patients should notify their physicians if they are taking warfarin or its derivatives;
• to inform their physician of any other medications when taken concurrently with FACTIVE, including over-the-counter medications and dietary supplements;  •  that FACTIVE may be taken with or without meals;
• to drink fluids liberally;
• not to take antacids containing magnesium and/or aluminum or 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 within 3 hours before or 2 hours after taking FACTIVE tablets;   
• that FACTIVE should be taken at least 2 hours before sucralfate;
• that antibacterial drugs including FACTIVE should only be used to treat bacterial infections.  They do not treat viral infections (e.g., the common cold).  When FACTIVE 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 effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by FACTIVE or other antibacterial drugs in the future.  

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long term studies in animals to determine the carcinogenic potential of gemifloxacin have not been conducted.

Photocarcinogenesis

Gemifloxacin did not shorten the time to development of UVR-induced skin tumors in hairless albino (Skh-1) mice; thus, it was not photocarcinogenic in this model.  These mice received oral gemifloxacin and concurrent irradiation with simulated sunlight 5 days per week for 40 weeks followed by a 12-week treatment-free observation period.  The daily dose of UV radiation used in this study was approximately 1/3 of the minimal dose of UV radiation that would induce erythema in Caucasian humans.  The median time to the development of skin tumors in the hairless mice was similar in the vehicle control group (36 weeks) and those given up to 100 mg/kg gemifloxacin daily (39 weeks). Following repeat doses of 100 mg/kg gemifloxacin per day, the mice had  skin gemifloxacin concentrations of approximately 7.4 µg/g. Plasma levels following this dose were approximately 1.4 µg/mL in the mice around the time of irradiation. There are no data on  gemifloxacin skin levels in humans, but the mouse plasma gemifloxacin levels are in the expected range of human plasma Cmax levels (0.7-2.6 µg/mL, with an overall mean of about 1.6 µg/mL) following multiple 320 mg oral doses.

Mutagenesis

Gemifloxacin was not mutagenic in 4 bacterial strains (TA 98, TA 100, TA 1535, TA 1537) used in an Ames    Salmonella reversion assay. It did not induce micronuclei in the bone  marrow of mice following intraperitoneal doses of up to 40 mg/kg and it did not induce unscheduled DNA synthesis in hepatocytes from rats which received oral doses of up to 1600 mg/kg.  Gemifloxacin was clastogenic in vitro in the mouse lymphoma and human lymphocyte chromosome aberration assays.  It was clastogenic in vivo in the rat micronucleus assay at oral and intravenous dose levels (?800 mg/kg and ?40 mg/kg, respectively) that producedbone marrow toxicity.  Fluoroquinolone clastogenicity is apparently due to inhibition of mammalian topoisomerase activity which has threshold implications.

Impairment of Fertility

Gemifloxacin did not affect the fertility of male or female rats at AUC levels following oral administration (216 and 600 mg/kg/day) that were approximately 3- to 4-fold higher  than the AUC levels at the clinically recommended dose.

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 FACTIVE in pregnant women has not been established. FACTIVE 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, FACTIVE should not be used in lactating women unless the potential benefit to the mother outweighs the risk.

Pediatric Use

Safety and effectiveness in children and adolescents less than 18 years of age have not been established. Fluoroquinolones, including gemifloxacin, cause arthropathy and osteochondrosis in immature animals.  (See WARNINGS.)

Geriatric Use

Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as FACTIVE. This risk is further increased in patients receiving concomitant corticosteroid therapy.  Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing FACTIVE to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue FACTIVE and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (See BOXED WARNING, WARNINGS, and ADVERSE REACTIONS/Post-Marketing Adverse Event Reports).

Of the total number of subjects in clinical studies of FACTIVE, 29% (2314) were 65 and over, while 11% (865) were 75 and over.  No overall difference in effectiveness was observed between these subjects and younger subjects; the adverse event rate for this group was similar to or lower than that for younger subjects with the exception that the incidence of rash was lower in geriatric patients compared to patients less than 40 years of age.

Elderly patients may be more susceptible to drug-associated effects on the QT interval.  Therefore, FACTIVE should be avoided in patients taking drugs that can result in prolongation of the QT interval (e.g., Class IA or Class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QT prolongation, uncorrected hypokalemia).

SIDE EFFECTS

In clinical studies, 8119 patients received daily oral doses of 320 mg FACTIVE.  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.

FACTIVE 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 FACTIVE 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 FACTIVE

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

Laboratory Changes

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

DRUG INTERACTIONS

Administration of repeat doses of FACTIVE 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 FACTIVE 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 FACTIVE with probenecid resulted in a 45% increase in systemic exposure to gemifloxacin.  (See CLINICAL PHARMACOLOGY.)

FACTIVE 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 FACTIVE, 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 FACTIVE, 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 FACTIVE.  Sucralfate should not be taken within 2 hours of FACTIVE. (See  CLINICAL PHARMACOLOGY.)

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 FACTIVE in pregnant women has not been established. FACTIVE 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.

In clinical studies, 8119 patients received daily oral doses of 320 mg FACTIVE.  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.

FACTIVE 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 FACTIVE 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 FACTIVE

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

Laboratory Changes

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

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.

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.