İHALE DÜNYASI
İHALE DÜNYASI
FACTIVE (gemifloxacin mesylate) is a synthetic broad-spectrum antibacterial agent for oral administration. Gemifloxacin, a compound related to the fluoroquinolone class of antibiotics, is available as the mesylate salt in the sesquihydrate form. Chemically, gemifloxacin is (R,S )-7-[(4Z)-3-(aminomethyl)-4-(methoxyimino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. The mesylate salt is a white to light brown solid with a molecular weight of 485.49. Gemifloxacin is considered freely soluble at neutral pH (350 ?g/mL at 37ºC, pH 7.0). Its empirical formula is C 18 H 20 FN 5 O 4 *CH 4 O 3 S and its chemical structure is: Each white to off-white, oval, film-coated FACTIVE tablet has breaklines and GE 320 debossed on both faces and contains gemifloxacin mesylate equivalent to 320 mg gemifloxacin. The inactive ingredients are crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, and titanium dioxide. Gemifloxacin Mesylate
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 ?g/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 or 7 day regimen should be guided by results of the initial sputum culture. INDICATION DOSE / DURATION Acute bacterial exacerbation of chronic bronchitis One 320 mg tablet daily for 5 days Community-acquired pneumonia (of mild to moderate severity) due to known or suspected S. pneumoniae, H. influenzae, M. pneumoniae, or C. pneumoniae infection One 320 mg tablet daily for 5 days due to known or suspected MDRSP*, K. pneumoniae, or M. catarrhalis infection One 320 mg tablet daily for 7 days *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 Creatinine Clearance (mL/min) Dose >40 See Usual Dosage 40 160 mg every 24 hours 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. Creatinine Clearance Formula Women: 0.85 x the value calculated for men 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. Creatinine Clearance Formula
FACTIVE is contraindicated in patients with a history of hypersensitivity to gemifloxacin, fluoroquinolone antibiotic agents, or any of the product components.
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 most commonly reported adverse events with a frequency of ?2% for patients 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 probably related) 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 ABECB (5 days) N = 2284 CAP (5 days) N = 256 CAP (7 days) N = 643 n/N % n/N % n/N % Totals 27/2284 1.2 1/256 0.4 26/643 4.0 Females, < 40 years NA* 1/37 2.7 8/88 9.1 Females, ? 40 years 16/1040 1.5 0/73 0 5/214 2.3 Males, < 40 years NA* 0/65 0 5/101 5.0 Males, ? 40 years 11/1203 0.9 0/81 0 8/240 3.3 * 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.
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 PRECAUTIONS/Information for Patients 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 reqactions, 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 instituted (See PRECAUTIONS: Information for Patients 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. --- BOXED WARNING: WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS Fluoroquinolones, including FACTIVE (R) , have been associated with with disabling and potentially irreversible serious adverse reactions that have occurred together (See WARNINGS ) including: Tendinitis and tendon rupture Peripheral neuropathy Central nervous system effects Discontinue FACTIVE immediately and avoid the use of fluoroquinolones, including FACTIVE, in patients who experience any of these serious adverse reactions (See WARNINGS ). Fluoroquinolones, including FACTIVE, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid FACTIVE in patients with known history of myasthenia gravis (See WARNINGS ). Because fluoroquinolones, including FACTIVE, have been associated with serious adverse reactions (See WARNINGS ), reserve FACTIVE for use in patients who have no alternative treatment options for acute bacterial exacerbation of chronic bronchitis (See INDICATIONS AND USAGE ).
Drug-Drug Interactions Antacids/Di- and Trivalent Cations : The systemic availability of gemifloxacin is significantly reduced when an aluminum- and magnesium- containing antacid is concomitantly administered (AUC decreased 85%; Cmax decreased 87%). Administration of an aluminum- and magnesium- containing antacid or ferrous sulfate (325 mg) at 3 hours before or at 2 hours after gemifloxacin did not significantly alter the systemic availability of gemifloxacin. Therefore, aluminum- and/or magnesium- containing antacids, ferrous sulfate (iron), multivitamin preparations containing zinc or other metal cations, or Videx (R) (didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be taken within 3 hours before or 2 hours after taking FACTIVE tablets. Calcium carbonate (1000 mg) given either 2 hr before or 2 hr after gemifloxacin administration showed no notable reduction in gemifloxacin systemic availability. Calcium carbonate administered simultaneously with gemifloxacin resulted in a small, not clinically significant, decrease in gemifloxacin exposure [AUC (0-inf) decreased 21% and Cmax decreased]. Sucralfate : When sucralfate (2 g) was administered 3 hours prior to gemifloxacin, the oral bioavailability of gemifloxacin was significantly reduced (53% decrease in AUC; 69% decrease in Cmax). When sucralfate (2 g) was administered 2 hours after gemifloxacin, the oral bioavailability of gemifloxacin was not significantly affected; therefore FACTIVE should be taken at least 2 hours before sucralfate. (See PRECAUTIONS . ) In Vitro Metabolism : Results of in vitro inhibition studies indicate that hepatic cytochrome P450 (CYP450) enzymes do not play an important role in gemifloxacin metabolism. Therefore gemifloxacin should not cause significant in vivo pharmacokinetic interactions with other drugs that are metabolized by CYP450 enzymes. Theophylline : Gemifloxacin 320 mg at steady-state did not affect the repeat dose pharmacokinetics of theophylline (300 to 400 mg BID to healthy male subjects). Digoxin : Gemifloxacin 320 mg at steady-state did not affect the repeat dose pharmacokinetics of digoxin (0.25 mg once daily to healthy elderly subjects). Oral Contraceptives : The effect of an oral estrogen/progesterone contraceptive product (once daily for 21 days) on the pharmacokinetics of gemifloxacin (320 mg once daily for 6 days) in healthy female subjects indicates that concomitant administration caused an average reduction in gemifloxacin AUC and Cmax of 19% and 12%. These changes are not considered clinically significant. Gemifloxacin 320 mg at steady-state did not affect the repeat dose pharmacokinetics of an ethinylestradiol/levonorgestrol oral contraceptive product (30 ?g/150 ?g once daily for 21 days to healthy female subjects). Cimetidine : Co-administration of a single dose of 320 mg gemifloxacin with cimetidine 400 mg four times daily for 7 days resulted in slight average increases in gemifloxacin AUC(0-inf) and Cmax of 10% and 6%, respectively. These increases are not considered clinically significant. Omeprazole : Co-administration of a single dose of 320 mg gemifloxacin with omeprazole 40 mg once daily for 4 days resulted in slight average increases in gemifloxacin AUC(0-inf) and Cmax of 10% and 11%, respectively. These increases are not considered clinically significant. Warfarin : Administration of repeated doses of gemifloxacin (320 mg once daily for 7 days) to healthy subjects on stable warfarin therapy had no significant effect on warfarin-induced anticoagulant activity (i.e., International Normalized Ratios for Prothrombin Time). (See PRECAUTIONS: Drug Interactions. ) Probenecid : Administration of a single dose of 320 mg gemifloxacin to healthy subjects who also received repeat doses of probenecid (total dose = 4.5 g) reduced the mean renal clearance of gemifloxacin by approximately 50%, resulting in a mean increase of 45% in gemifloxacin AUC (0-inf) and a prolongation of mean half-life by 1.6 hours. Mean gemifloxacin Cmax increased 8%.