ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling:Disabling and Potentially Irreversible Serious Adverse Reactions [see Warnings and Precautions (5.1)] Tendinitis and Tendon Rupture [see Warnings and Precautions (5.2)] Peripheral Neuropathy [see Warnings and Precautions (5.3)] Central Nervous System Effects [see Warnings and Precautions (5.4)] Hypersensitivity Reactions [see Warnings and Precautions (5.6)] Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.7)]Blood Glucose Disturbances [see Warnings and Precautions (5.10)] Disabling and Potentially Irreversible Serious Adverse Reactions [see Warnings and Precautions (5.1)] Tendinitis and Tendon Rupture [see Warnings and Precautions (5.2)] Peripheral Neuropathy [see Warnings and Precautions (5.3)] Central Nervous System Effects [see Warnings and Precautions (5.4)] Hypersensitivity Reactions [see Warnings and Precautions (5.6)] Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.7)]. Blood Glucose Disturbances [see Warnings and Precautions (5.10)] Most common adverse reactions (incidence >= 2%) are nausea, diarrhea, headache, transaminase elevations, and vomiting. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Melinta Therapeutics at 1-844-633-6568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of BAXDELA cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.. Overview of the Safety Evaluation of BAXDELABAXDELA was evaluated in three Phase multicenter, multinational, randomized, double-blind clinical trials. These trials included two trials in ABSSSI patients (Trial and Trial 2) and one trial in CABP (Trial 3). total of 1170 patients were treated with BAXDELA across all Phase trials (741 patients in the two ABSSSI trials and 429 patients in the CABP trial).. Acute Bacterial Skin and Skin Structure Infections (ABSSSI)BAXDELA was evaluated in two multicenter, multinational, randomized, double-blind, double-dummy, non-inferiority trials (Trial and Trial 2) in adults with ABSSSI. In Trial patients received BAXDELA 300 mg by intravenous infusion every 12 hours and in Trial the patients received BAXDELA 300 mg by intravenous infusion every 12 hours for doses then were switched to BAXDELA 450 mg tablets every 12 hours. The total treatment duration was to 14 days. Adverse reactions were evaluated for 741 patients treated with BAXDELA and 751 patients treated with comparator antibacterial drugs. The median age of patients treated with BAXDELA was 49 years, ranging between 18 and 94 years old; 15% were age 65 years and older. Patients treated with BAXDELA were predominantly male (62%) and Caucasian (86%). The BAXDELA treated population included 44% obese patients (BMI >= 30 kg/m2), 11% with diabetes, and 16% with baseline renal impairment (calculated creatinine clearance less than 90 mL/min).. Serious Adverse Reactions and Adverse Reactions Leading to DiscontinuationSerious adverse reactions occurred in 3/741 (0.4%) of patients treated with BAXDELA and in 6/751 (0.8%) of patients treated with the comparator.BAXDELA was discontinued due to an adverse reaction in 7/741 (0.9%) patients and the comparator was discontinued due to an adverse reaction in 21/751 (2.8%) patients. The most commonly reported adverse reactions leading to study discontinuation in the BAXDELA arm included urticaria (2/741; 0.3%) and hypersensitivity (2/741; 0.3%); whereas, the most commonly reported adverse reactions leading to study discontinuation in the comparator arm included urticaria (5/751; 0.7%), rash (4/751; 0.5%), hypersensitivity and infusion site extravasation (2/751; 0.3%).. Most Common Adverse ReactionsThe most common adverse reactions in patients treated with BAXDELA were nausea (8%), diarrhea (8%), headache (3%), transaminase elevations (3%), and vomiting (2%). Table lists selected adverse reactions occurring in >= 2% of patients receiving BAXDELA in the pooled adult Phase clinical trials.Table Selected Adverse Reactions Occurring in >= 2% of Patients Receiving BAXDELA in the Pooled Adult Phase ABSSSI Clinical TrialsAdverse ReactionsBAXDELA = 741 (%)Vancomycin/aztreonam = 751 (%)Nausea8%6%Diarrhea8%3%HeadacheThe data are not an adequate basis for comparison of rates between the study drug and the active control. 3%6%Transaminase ElevationsPooled reports include hypertransaminasaemia, increased transaminases, and increased ALT and AST. 3%4%Vomiting2%2%. Community-Acquired Bacterial PneumoniaBAXDELA was evaluated in one multicenter, multinational, randomized, double-blind trial in adults with CABP (Trial 3). Patients received BAXDELA 300 mg over 60 minutes every 12 hours for minimum of doses with an option to switch to oral BAXDELA tablet 450 mg every 12 hours for the remaining doses (total of 10 to 20 doses of intravenous infusion and oral combined). Adverse reactions were evaluated for 429 patients treated with BAXDELA and 427 patients treated with moxifloxacin. The median age of patients treated with BAXDELA was 63 years, ranging between 18 and 89 years; 47.1% were 65 years of age and older and 19.6% were 75 years of age and older. Patients treated with BAXDELA were predominantly male (58.3%) and white (92.3%). The BAXDELA-treated population included patients with obesity (BMI greater than or equal to 30) (24.0%), COPD/asthma (14.2%), cardiac disease (24.2%), diabetes (16.3%), and baseline renal impairment including 36.4% with moderate renal impairment (CrCl less than 30-59 mL/min), and 4.0% with severe renal impairment (CrCl less than 29 mL/min). Overall, approximately 12.4% of patients were in PORT Risk Class II, 60.1% were in PORT Risk Class III, 26.6% were in PORT Risk Class IV, and 0.9% were in PORT Risk Class V.. Serious Adverse Reactions and Adverse Reactions Leading to DiscontinuationSerious adverse reactions occurred in 2/429 (0.5%) of patients treated with BAXDELA and in 1/427 (0.2%) of patients treated with moxifloxacin. Discontinuation due to an adverse reaction occurred in 9/429 (2.1%) patients treated with BAXDELA and in 4/427 (0.9%) treated with moxifloxacin. The most commonly reported adverse reactions leading to study drug discontinuation in the BAXDELA arm were transaminase elevations (2/429; 0.5%). The most commonly reported adverse reactions leading to study drug discontinuation in the comparator arm were infusion site reactions (1/427; 0.2%).. Most Common Adverse ReactionsThe most common adverse reactions in patients treated with BAXDELA were diarrhea (5%) and transaminase elevations (5%). Table lists selected adverse reactions occurring in >= 2% of patients receiving BAXDELA in the adult Phase CABP clinical trial.Table Selected Adverse Reactions Occurring in >= 2% of Patients Receiving BAXDELA in the Adult Phase CABP Clinical TrialAdverse ReactionsBAXDELA = 429Moxifloxacin = 427Diarrhea5%3%Transaminase elevationsIncludes hepatic enzyme increased, transaminases increased and alanine aminotransferase (ALT) increased. 5%3%. Adverse Reactions Occurring in Less Than 2% of Patients Receiving BAXDELA in the ABSSSI (Trials and 2) and CABP (Trial 3) Clinical TrialsThe following selected adverse reactions were reported in BAXDELA-treated patients at rate of less than 2% in the ABSSSI (Trials and 2) and CABP (Trial 3) clinical trials:Blood and Lymphatic System Disorders: agranulocytosis, anemia, leukopenia, neutropenia, pancytopeniaCardiac Disorders: sinus tachycardia, palpitations, bradycardia, ventricular extrasystolesEar and Labyrinth Disorders: tinnitus, vertigo, vestibular disorderEye Disorders: vision blurredGeneral disorders and administration site conditions: infusion related reactionsGastrointestinal Disorders: abdominal pain, dyspepsiaImmune System Disorders: hypersensitivityInfections and Infestations: Clostridium difficile infection, fungal infection, oral candidiasis, vulvovaginal candidiasisLaboratory Investigations: blood alkaline phosphatase increased, blood creatinine increased, blood creatine phosphokinase increasedMetabolism and Nutrition Disorders: hyperglycemia, hypoglycemiaMusculoskeletal and Connective Tissue Disorders: myalgiaNervous System Disorders: dizziness, hypoesthesia, paraesthesia, dysgeusia, presyncope, syncopePsychiatric Disorders: agitation, anxiety, confusional state, insomnia, abnormal dreamsRenal and Urinary: renal impairment, renal failureSkin and Subcutaneous Tissue Disorders: pruritus, urticaria, dermatitis, rashVascular Disorders: flushing, hypotension, hypertension.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. BAXDELA is an antibacterial drug [see Microbiology (12.4)].. 12.2 Pharmacodynamics. The antibacterial activity of delafloxacin appears to best correlate with the ratio of area under the concentration-time curve of free delafloxacin to minimal inhibitory concentration (fAUC/MIC) for Gram-positive organisms such as Staphylococcus aureus and Gram-negative organisms such as Escherichia coli based on animal models of infection.. Cardiac ElectrophysiologyIn randomized, positive- and placebo-controlled, thorough QT/QTc study, 51 healthy subjects received BAXDELA 300 mg IV, BAXDELA 900 mg IV, oral moxifloxacin 400 mg, or placebo. Neither BAXDELA 300 mg nor BAXDELA 900 mg (three times the intravenous therapeutic dose) had any clinically relevant adverse effect on cardiac repolarization.. Photosensitivity PotentialA study of photosensitizing potential to ultraviolet (UVA and UVB) and visible radiation was conducted in 52 healthy volunteers (originally 13 subjects per treatment group). BAXDELA, at 200 mg/day and 400 mg/day (0.22 and 0.44 times the approved recommended daily oral dosage, respectively) for days, and placebo did not demonstrate clinically significant phototoxic potential at any wavelengths tested (295 nm to 430 nm), including solar simulation. The active comparator (lomefloxacin) demonstrated moderate degree of phototoxicity at UVA 335 nm and 365 nm and solar simulation wavelengths.. 12.3 Pharmacokinetics. The pharmacokinetic parameters of delafloxacin following single- and multiple-dose (every 12 hours) oral (450 mg) and intravenous (300 mg) administration are shown in Table 6. Steady-state was achieved within approximately three days with accumulation of approximately 10% and 36% following IV and oral administration, respectively.Table Mean (SD) Delafloxacin Pharmacokinetic Parameters Following Single and Multiple Oral and Intravenous AdministrationParametersTabletIntravenous InjectionSingle Dose 450 mgSteady State 450 mg Q12hQ12h is every 12 hours Single Dose 300 mgSteady State 300 mg Q12h Cmax maximum concentration; Tmax time to reach Cmax; AUC area under the concentration-time curve; CL systemic clearance; CL/F apparent oral clearance; Rac accumulation ratioTmax (h)Median (range) 0.75 (0.5, 4.0)1.00 (0.50, 6.00)1.0 (1.0, 1.2)1.0 (1.0, 1.0)Cmax (ug/mL)7.17 (2.01)7.45 (3.16)8.94 (2.54)9.29 (1.83)AUC (ugh/mL)AUC is AUC (AUC from time to 12 hours) for single dose and multiple-dose administration 22.7 (6.21)30.8 (11.4)21.8 (4.54)23.4 (6.90)CL or CL/F(L/h)CL is reported for intravenous injection. CL/F is reported for tablet 20.6 (6.07)16.8 (6.54)14.1 (2.81)13.8 (3.96)CLr (L/h)--5.89 (1.53)6.69 (2.19)Rac -1.36-1.1. AbsorptionThe absolute bioavailability for BAXDELA 450 mg oral tablet administered as single dose was 58.8%. The AUC of delafloxacin following administration of single 450 mg oral (tablet) dose was comparable to that following single 300 mg intravenous dose. The Cmax of delafloxacin was achieved within about hour after oral administration under fasting condition. Food (kcal: 917, Fat: 58.5%, Protein: 15.4%, Carbohydrate: 26.2%). did not affect the bioavailability of delafloxacin [see Dosage and Administration (2.1)].. DistributionThe steady state volume of distribution of delafloxacin is 30-48 which approximates total body water. The plasma protein binding of delafloxacin is approximately 84%; delafloxacin primarily binds to albumin. Plasma protein binding of delafloxacin is not significantly affected by renal impairment.Following IV administration of doses of 300 mg of BAXDELA to 30 healthy volunteers, the mean BAXDELA AUC0-12 (3.6 hrmcg/mL) in alveolar macrophages was 80% of the free-plasma AUC0-12, and the mean BAXDELA AUC0-12 (2.8 hrmcg/mL) in epithelial lining fluid was 70% of the free-plasma AUC0-12. EliminationIn mass balance study, the mean half-life for delafloxacin was 3.7 hours (SD 0.7 hour) after single dose intravenous administration. The mean half-life values for delafloxacin ranged from 4.2 to 8.5 hours following multiple oral administrations. Following administration of single 300 mg intravenous dose of BAXDELA, the mean clearance (CL) of delafloxacin was 16.3 L/h (SD 3.7 L/h), and the renal clearance (CLr) of delafloxacin accounts for 35-45% of the total clearance.. MetabolismGlucuronidation of delafloxacin is the primary metabolic pathway with oxidative metabolism representing about 1% of an administered dose. The glucuronidation of delafloxacin is mediated mainly by UGT1A1, UGT1A3, and UGT2B15. Unchanged parent drug is the predominant component in plasma. There are no significant circulating metabolites in humans.. ExcretionAfter single intravenous dose of 14C-labeled delafloxacin, 65% of the radioactivity was excreted in urine as unchanged delafloxacin and glucuronide metabolites and 28% was excreted in feces as unchanged delafloxacin. Following single oral dose of 14C-labeled delafloxacin, 50% of the radioactivity was excreted in urine as unchanged delafloxacin and glucuronide metabolites and 48% was excreted in feces as unchanged delafloxacin.. Specific PopulationsNo clinical significance in the pharmacokinetics of delafloxacin was observed based on age, sex, race, weight, body mass index, and disease state (ABSSSI and CABP).. Patients with Hepatic ImpairmentNo clinically meaningful changes in delafloxacin Cmax and AUC were observed, following administration of single 300 mg intravenous dose of BAXDELA to patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B, and C) compared to matched healthy control subjects.. Patients with Renal ImpairmentFollowing single intravenous (300 mg) administration of delafloxacin to subjects with mild (eGFR 51-80 mL/min/1.73 m2), moderate (eGFR 31-50 mL/min/1.73 m2), severe (eGFR 15-29 mL/min/1.73 m2) renal impairment, and ESRD on hemodialysis receiving intravenous delafloxacin within hour before and hour after hemodialysis, mean total exposure (AUCt) of delafloxacin was 1.3, 1.6, 1.8, 2.1, and 2.6-fold higher, respectively than that for matched normal control subjects. The mean dialysate clearance (CLd) of delafloxacin was 4.21 L/h (SD 1.56 L/h). After about hours of hemodialysis, the mean fraction of administered delafloxacin recovered in the dialysate was about 19% [see Use in Specific Populations (8.7)].Following single oral (400 mg) administration of delafloxacin to subjects with mild (eGFR 51-80 mL/min/1.73 m2), moderate (eGFR 31-50 mL/min/1.73 m2), or severe (eGFR 15-29 mL/min/1.73 m2) renal impairment, the mean total exposure (AUCt) of delafloxacin was about 1.5-fold higher for subjects with moderate and severe renal impairment compared with healthy subjects, whereas total systemic exposures of delafloxacin in subjects with mild renal impairment were comparable with healthy subjects.In patients with moderate (eGFR 31-50 mL/min/1.73 m2), or severe (eGFR 15-29 mL/min/1.73 m2) renal impairment or ESRD on hemodialysis, accumulation of the intravenous vehicle SBECD occurs. The mean systemic exposure (AUC) increased 2-fold, 5-fold, 7.5-fold, and 27-fold for patients with moderate impairment, severe impairment, ESRD on hemodialysis receiving intravenous delafloxacin within hour before, and hour after hemodialysis respectively, compared to the healthy control group. In subjects with ESRD undergoing hemodialysis, SBECD is dialyzed with clearance of 4.74 L/h. When hemodialysis occurred hour after the BAXDELA infusion in subjects with ESRD, the mean fraction of SBECD recovered in the dialysate was 56.1% over approximately hours.. Geriatric PatientsFollowing single oral administration of 250 mg delafloxacin (approximately 0.6 times the approved recommended oral dose), the mean delafloxacin Cmax and AUC values in elderly subjects (>= 65 years) were about 35% higher compared to values obtained in young adults (18 to 40 years). This difference is not considered clinically relevant. population pharmacokinetic analysis of patients with ABSSSI or CABP indicated that patients over the age of 65 years have slower clearance than younger patients. However, the overall impact on delafloxacin pharmacokinetics is not considered clinically significant and dose adjustment in elderly patients is not warranted.. Male and Female PatientsFollowing single oral administration of 250 mg delafloxacin (approximately 0.6 times the approved recommended oral dose), the mean delafloxacin Cmax and AUC values in male subjects were comparable to female subjects. Results from population pharmacokinetic analysis showed that females have 24% lower AUC than males. This difference is not considered clinically relevant.. Drug Interaction Studies. Drug Metabolizing EnzymesDelafloxacin at clinically relevant concentrations does not inhibit the cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in vitro in human liver microsomes. At delafloxacin concentration (500 uM) well above clinically relevant exposures, the activity of CYP2E1was increased.In human hepatocytes, delafloxacin showed no potential for in vitro induction of CYP1A2, 2B6, 2C19, or 2C8 but was mild inducer of CYP2C9 at concentration of 100 uM and CYP3A4 at clinically relevant concentration. Administration of BAXDELA 450 mg every 12 hours for days to healthy male and female subjects (n 22) prior to and on Day with single oral mg dose of midazolam (a sensitive CYP3A substrate), did not affect the Cmax and AUC values for midazolam or 1-hydroxy midazolam compared to administration of midazolam alone.. TransportersDelafloxacin was not an inhibitor of the following hepatic and renal transporters in vitro at clinically relevant concentrations: MDR1, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, OCT1 and OCT2. Delafloxacin was not substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1 or OATP. Delafloxacin was shown to be substrate of P-gp and BCRP in vitro. The clinical relevance of co-administration of delafloxacin and P-gp and/or BCRP inhibitors is unknown.. 12.4 Microbiology. Mechanism of ActionDelafloxacin belongs to the fluoroquinolone class of antibacterial drugs and is anionic in nature. The antibacterial activity of delafloxacin is due to the inhibition of both bacterial topoisomerase IV and DNA gyrase (topoisomerase II) enzymes which are required for bacterial DNA replication, transcription, repair, and recombination. Delafloxacin exhibits concentration-dependent bactericidal activity against gram-positive and gram-negative bacteria in vitro.. ResistanceResistance to fluoroquinolones, including delafloxacin, can occur due to mutations in defined regions of the target bacterial enzymes topoisomerase IV and DNA gyrase referred to as Quinolone-Resistance Determining Regions (QRDRs), or through altered efflux.Fluoroquinolones, including delafloxacin, have different chemical structure and mechanism of action relative to other classes of antibacterial compounds (e.g., aminoglycosides, macrolides, -lactams, glycopeptides, tetracyclines and oxazolidinones).In vitro resistance to delafloxacin develops by multiple step mutations in the QRDRs of gram-positive and gram-negative bacteria. Delafloxacin-resistant mutants were selected in vitro at frequency of 10-9.Although cross-resistance between delafloxacin and other fluoroquinolone-class antibacterial agents has been observed, some isolates resistant to other fluoroquinolone-class antibacterial agents may be susceptible to BAXDELA including some S. aureus isolates carrying mutations in the quinolone resistance determining region (gyrA, parC and parE).Additionally, delafloxacin has activity against some isolates of beta-lactamase positive H. influenzae and H. parainfluenzae.. Interaction With Other AntimicrobialsIn vitro drug combination studies with delafloxacin and amoxicillin/clavulanate, azithromycin, aztreonam, ceftaroline, ceftazidime, ceftriaxone, colistin, daptomycin, doxycycline, linezolid, meropenem, penicillin, rifampin, tigecycline, trimethoprim/sulfamethoxazole and vancomycin demonstrated neither synergy nor antagonism.. Antimicrobial ActivityBAXDELA has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections, [see Indications and Usage (1.1, 1.2)].. Acute Bacterial Skin and Skin Structure Infections (ABSSSI)Aerobic bacteria Gram-positive bacteria Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates) Staphylococcus haemolyticus Staphylococcus lugdunensis Streptococcus pyogenes Streptococcus agalactiae Streptococcus anginosus Group (including S. anginosus, S. intermedius, and S. constellatus) Enterococcus faecalis Gram-negative bacteria Escherichia coli Klebsiella pneumoniae Enterobacter cloacae Pseudomonas aeruginosa. Gram-positive bacteria. Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates). Staphylococcus haemolyticus. Staphylococcus lugdunensis. Streptococcus pyogenes. Streptococcus agalactiae. Streptococcus anginosus Group (including S. anginosus, S. intermedius, and S. constellatus). Enterococcus faecalis. Gram-negative bacteria. Escherichia coli. Klebsiella pneumoniae. Enterobacter cloacae. Pseudomonas aeruginosa. Community-Acquired Bacterial Pneumonia (CABP)Aerobic bacteria Gram-positive bacteria Streptococcus pneumoniae Staphylococcus aureus (methicillin-susceptible isolates only) Gram-negative bacteria Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Pseudomonas aeruginosa Other microorganisms Chlamydia pneumoniae Legionella pneumophila Mycoplasma pneumoniaeThe following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint of delafloxacin against isolates of similar genus or organism group. However, the efficacy of BAXDELA in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.Aerobic bacteria Gram-positive bacteria Streptococcus dysgalactiae Gram-negative bacteria Enterobacter aerogenes Klebsiella oxytoca Proteus mirabilis Moraxella catarrhalis. Gram-positive bacteria. Streptococcus pneumoniae. Staphylococcus aureus (methicillin-susceptible isolates only). Gram-negative bacteria. Escherichia coli. Haemophilus influenzae. Haemophilus parainfluenzae. Klebsiella pneumoniae. Pseudomonas aeruginosa. Other microorganisms. Chlamydia pneumoniae. Legionella pneumophila. Mycoplasma pneumoniae. Gram-positive bacteria. Streptococcus dysgalactiae. Gram-negative bacteria. Enterobacter aerogenes. Klebsiella oxytoca. Proteus mirabilis. Moraxella catarrhalis. Susceptibility Test MethodsFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Acute Bacterial Skin and Skin Structure Infections. total of 1510 adults with acute bacterial skin and skin structure infections (ABSSSI) were randomized in multicenter, multinational, double-blind, double-dummy, non-inferiority trials. Trial compared BAXDELA 300 mg via intravenous infusion every 12 hours to comparator. In Trial 2, patients received BAXDELA 300 mg via intravenous infusion every 12 hours for doses then made mandatory switch to oral BAXDELA 450 mg every 12 hours. In both studies, the comparator was the intravenous combination of vancomycin 15 mg/kg actual body weight and aztreonam. Aztreonam therapy was discontinued if no gram-negative pathogens were identified in the baseline cultures.In Trial 1, 331 patients with ABSSSI were randomized to BAXDELA and 329 patients were randomized to vancomycin plus aztreonam. Patients in this trial had the following infections: cellulitis (39%), wound infection (35%), major cutaneous abscess (25%), and burn infection (1%). The overall mean surface area of the infected lesion as measured by digital planimetry was 307 cm2. The average age of patients was 46 years (range 18 to 94 years). Patients were predominately male (63%) and white (91%); 32% had BMI >= 30 kg/m2. The population studied in Trial included distribution of patients with associated comorbidities such as hypertension (21%), diabetes (9%), and renal impairment (16%; 0.2% with severe renal impairment or ESRD). Current or recent history of drug abuse, including IV drug abuse, was reported by 55% of patients. Bacteremia was documented at baseline in 2% of patients.In Trial 2, 423 patients were randomized to BAXDELA and 427 patients were randomized to vancomycin plus aztreonam. Patients in this trial had the following infections: cellulitis (48%), wound infection (26%), major cutaneous abscess (25%), and burn infection (1%). The overall mean surface area of the infected lesion, as measured by digital planimetry, was 353 cm2. The average age of patients was 51 years (range 18 to 93 years). Patients were predominately male (63%) and white (83%); 50 had BMI >= 30 kg/m2. The population studied in Trial included distribution of patients with associated comorbidities such as hypertension (31%), diabetes (13%) and renal impairment (16%; 0.2% with severe renal impairment or ESRD). Current or recent history of drug abuse, including IV drug abuse, was reported by 30% of patients. Bacteremia was documented at baseline in 2% of patients.In both trials, objective clinical response at 48 to 72 hours post initiation of treatment was defined as 20% or greater decrease in lesion size as determined by digital planimetry of the leading edge of erythema. Table summarizes the objective clinical response rates in both of these trials.Table Clinical Response at 48-72 hoursObjective clinical response was defined as 20% or greater decrease in lesion size as determined by digital planimetry of the leading edge of erythema at 48 to 72 hours after initiation of treatment without any reasons for failure (less than 20% reduction in lesion size, administration of rescue antibacterial therapy, use of another antibacterial or surgical procedure to treat for lack of efficacy, or death). Missing patients were treated as failures. in the ITT Population with ABSSSI in Trial and Trial 2CI Confidence Interval; ITT Intent To Treat and includes all randomized patientsTrialBAXDELA(300 mg IV)Vancomycin 15 mg/kg AztreonamTreatment DifferenceTreatment difference, expressed as percentage, and CI based on Miettinen and Nurminen method without stratification.(2-sided 95% CI)Trial 1Total N331329Responder, (%)259 (78.2%)266 (80.9%)-2.6 (-8.8, 3.6)BAXDELA (300 mg IV and 450 mg oral)Vancomycin 15 mg/kg AztreonamTrial 2Total N423427Responder, (%)354 (83.7%)344 (80.6%)3.1 (-2.0, 8.3)In both trials, an investigator assessment of response was made at Follow-up (Day 14 +- 1) in the ITT and CE populations. Success was defined as cure improved, where patients had complete or near resolution of signs and symptoms, with no further antibacterial needed. The success rates in the ITT and CE populations are shown in Table 8.Table Investigator-Assessed Success at the Follow-up Visit in ABSSSI --ITT Population and CE Population in Trial and 2CI Confidence Interval; ITT Intent To Treat and includes all randomized patients; CE Clinically Evaluable consisted of all ITT patients who had diagnosis of ABSSSI, received at least 80% of expected doses of study drug, did not have any protocol deviations that would affect the assessment of efficacy and had investigator assessment at the Follow-Up Visit.TrialBAXDELA (300 mg IV)Vancomycin 15 mg/kg AztreonamTreatment DifferenceTreatment difference, expressed as percentage, and CI based on Miettinen and Nurminen method without stratification. (2-sided 95% CI)Trial 1SuccessSuccess was cure improved where patients had complete or near resolution of signs and symptoms with no further antibacterial needed., n/N (%) ITT270/331 (81.6%)274/329 (83.3%)-1.7 (-7.6, 4.1)Success, n/N (%) CE232/240 (96.7%)238/244 (97.5%)-0.9 (-4.3, 2.4)BAXDELA (300 mg IV and 450 mg Oral)Vancomycin 15 mg/kg AztreonamTrial 2Success, n/N (%) ITT369/423 (87.2%)362/427 (84.8%)2.5 (-2.2, 7.2)Success, n/N (%) CE339/353 (96.0%)319/329 (97.0%)-0.9 (-3.9, 2.0)Six delafloxacin patients had baseline S. aureus bacteremia with ABSSSI. Five of these patients (83.3%) were clinical responders at 48 to 72 hours and 5/6 (83.3%) were considered clinical success for ABSSSI at Day 14 +- 1. Two delafloxacin patients had baseline Gram-negative bacteremia (K. pneumoniae and P. aeruginosa), and both were clinical responders and successes.The investigator assessments of clinical success rates were also similar between treatment groups at Late Follow-up (LFU, day 21-28).Objective clinical response and investigator-assessed success by baseline pathogens from the primary infection site or blood cultures for the microbiological ITT (MITT) patient population pooled across Trial and Trial are presented in Table 9.Table Outcomes by Baseline Pathogen (Pooled across Trial and Trial 2; MITTMicrobiological ITT (MITT) consists of all randomized patients who had baseline pathogen identified that is known to cause ABSSSI. Population)Clinical ResponseObjective clinical response was defined as 20% or greater decrease in lesion size as determined by digital planimetry of the leading edge of erythema at 48 to 72 hours after initiation of treatment. at 48-72 hoursInvestigator-Assessed SuccessInvestigator-assessed success was defined as complete or near resolution of signs and symptoms, with no further antibacterial needed at Follow-up Visit (Day14 +- 1).at Follow-upBAXDELAComparatorBAXDELAComparatorPathogenn/N (%)n/N (%)n/N (%)n/N (%)Staphylococcus aureus271/319 (85.0)269/324 (83.0)275/319 (86.2)269/324 (83.0) Methicillin-susceptibleDiscrepancy in the total numbers is due to the multiple subjects having both MRSA and MSSA isolates. 149/177 (84.2)148/183 (80.9)154/177 (87.0)153/183 (83.6) Methicillin-resistant 125/144 (86.8)121/141 (85.8)122/144 (84.7)116/141 (82.3)Streptococcus pyogenes17/23 (73.9)9/18 (50.0)21/23 (91.3)16/18 (88.9)Staphylococcus haemolyticus11/15 (73.3)7/8 (87.5)13/15 (86.7)7/8 (87.5)Streptococcus agalactiae10/14 (71.4)9/12 (75.0)12/14 (85.7)11/12 (91.7)Streptococcus anginosus Group59/64 (92.2)55/61 (90.2)54/64 (84.4)47/61 (77.0)Staphylococcus lugdunensis8/11 (72.7)6/9 (66.7)10/11 (90.9)8/9 (88.9)Enterococcus faecalis11/11 (100.0)12/16 (75.0)9/11 (81.8)14/16 (87.5)Escherichia coli12/14 (85.7)16/20 (80.0)12/14 (85.7)18/20 (90.0)Enterobacter cloacae10/14 (71.4)8/11 (72.7)12/14 (85.7)10/11 (90.9)Klebsiella pneumoniae19/22 (86.4)22/23 (95.7)20/22 (90.9)21/23 (91.3)Pseudomonas aeruginosa9/11 (81.8)11/12 (91.7)11/11 (100.0)12/12 (100.0). 14.2 Community-Acquired Bacterial Pneumonia. total of 859 adults with CABP were randomized in multicenter, multinational, double-blind, double-dummy, noninferiority trial comparing BAXDELA to moxifloxacin (Trial 3, NCT 02679573). In this trial, BAXDELA for injection 300 mg was administered intravenously (IV) every 12 hours with an option to switch to BAXDELA tablet 450 mg orally every 12 hours. Moxifloxacin 400 mg was administered IV every 24 hours with an option to switch to moxifloxacin tablet 400 mg orally every 24 hours. Switch to oral treatment was allowed after minimum of days of IV dosing. Total treatment duration was to 10 days. In the moxifloxacin arm, the investigator could switch patients to linezolid 600 mg every 12 hours if methicillin-resistant Staphylococcus aureus (MRSA) was confirmed.A total of 431 patients were randomized to BAXDELA and 428 to moxifloxacin. Patient demographic and baseline characteristics were balanced between the treatment arms. In this trial, 12.9% of patients were in PORT Risk Class II, 60.3% were in PORT Risk Class III, 25.4% were in PORT Risk Class IV, and 1.4% were in PORT Risk Class V. The average age of patients was 60 years (range 18 to 93 years). Patients were predominantly male (58.7%) and white (91.5%); average BMI was 26.9 kg/m2. Associated comorbidities included pre-existing pulmonary disease (13.6%), cardiac disease (23.9%), diabetes (15.3%), and mild to severe renal impairment (76.9%). Bacteremia was documented at baseline in 1.5% of patients. The majority of sites were in Eastern Europe, which accounted for 82.8% of enrollment. One subject (0.2%) was enrolled in the BAXDELA arm and (1.2%) in the moxifloxacin arm from the United States.Early clinical response (ECR) at 72-120 hours after the first dose was defined as survival with improvement in at least two of four symptoms (cough, sputum production, chest pain, dyspnea) from baseline without deterioration in any of these symptoms, and without use of additional antimicrobial therapy for treatment of the current CABP infection due to lack of efficacy.Table 10 Early Clinical ResponseEarly Clinical Response (ECR) at 72-120 hours after the first dose, was defined as survival with improvement in at least two of four symptoms (cough, sputum production, chest pain, dyspnea) from baseline without deterioration in any of these symptoms, and without use of additional antimicrobial therapy for treatment of the current CABP infection due to lack of efficacy. at 72 to 120 hours in the ITT Population with CABP (Trial 3)Trial 3BAXDELA (300 mg IV and 450 mg oral)Moxifloxacin (400 mg IV and 400 mg oral)Treatment DifferenceTreatment difference, expressed as percentage, and CI based on Miettinen and Nurminen method without stratification. (2-sided 95% CI)CI Confidence Interval; ITT Intent To Treat includes all randomized patientsTotal N431428Responder (%)383 (88.9)381 (89.0)-0.2 (-4.4, 4.1)Clinical response was also assessed by the investigator at the test of cure (TOC) visit and defined as survival with resolution or near resolution of the symptoms of CABP present at study entry, and no use of additional antimicrobial therapy for the current CABP infection, and no new symptoms associated with the current CABP infection.Clinical response rates at the TOC visit for the ITT and Clinically Evaluable (CE) populations are presented in Table 11.Table 11 Investigator-Assessed Success at the TOC Visit in CABP --ITT Population and CE Population in Trial 3Trial 3BAXDELA (300 mg IV and 450 mg oral)Moxifloxacin (400 mg IV and 400 mg oral)Treatment DifferenceTreatment difference, expressed as percentage, and CI based on Miettinen and Nurminen method without stratification. (2-sided 95% CI)CI Confidence Interval; ITT Intent To Treat and includes all randomized patients; CE Clinically EvaluableClinically Evaluable consisted of all ITT patients who had evidence of acute CABP, received at least 80% of expected doses of the correct study drug, did not receive any concomitant, systemic antibacterial therapy except for lack of efficacy, and did not have any protocol deviations that would affect the assessment of efficacy.SuccessSuccess was survival with resolution or near resolution of the symptoms of CABP present at study entry, and no use of additional antimicrobial therapy for the current infection, and no new symptoms associated with the current CABP infection., n/N (%) ITT390/431 (90.5)384/428 (89.7)0.8 (-3.3, 4.8)Success, n/N (%) CE376/397 (94.7)373/394 (94.7)0.0 (-3.2, 3.3)Early clinical response and investigator-assessed clinical response at the TOC visit is presented in Table 12 by baseline pathogen for the Microbiological ITT (MITT) population which comprised all randomized patients who had baseline pathogen identified that is known to cause CABP.Table 12 Outcome by Baseline Pathogen (CABP, Trial 3, MITT Population)Excludes patients with baseline pathogens resistant or non-susceptible to moxifloxacin. Early Clinical ResponseEarly Clinical Response (ECR) at 72-120 hours after the first dose, was defined as survival with improvement in at least two of four symptoms (cough, sputum production, chest pain, dyspnea) from baseline without deterioration in any of these symptoms, and without use of additional antimicrobial therapy for treatment of the current CABP infection due to lack of efficacy.at 96 hours +- 24 hoursInvestigator-Assessed SuccessInvestigator-assessed success was defined as survival with resolution or near resolution of the symptoms of CABP present at study entry, and no use of additional antimicrobial therapy for the current infection, and no new symptoms associated with the current CABP infection at Test of Cure (TOC) visit at (5 to 10 days after last dose of study drug).at Test-of Cure (TOC)BAXDELAMoxifloxacinBAXDELAMoxifloxacinPathogenn/N (%)n/N (%)n/N (%)n/N (%)Staphylococcus aureus24/26 (92.3)25/28 (89.3)24/26 (92.3)26/28 (92.9) Methicillin-susceptible22/24 (91.7)25/28 (89.3)22/24 (91.7)26/28 (92.9)Streptococcus pneumoniae66/71 (93.0)51/62 (82.3)64/71 (90.1)54/62 (87.1)Haemophilus influenzae25/26 (96.2)31/35 (88.6)24/26 (92.3)31/35 (88.6)Haemophilus parainfluenzae30/32 (93.8)27/33 (81.8)30/32 (93.8)26/33 (78.8)Escherichia coli15/16 (93.8)8/11 (72.7)15/16 (93.8)10/11 (90.9)Klebsiella pneumoniae13/17 (76.5)15/16 (93.8)14/17 (82.4)16/16 (100.0)Pseudomonas aeruginosa12/13 (92.3)10/11 (90.9)11/13 (84.6)11/11 (100.0)Chlamydia pneumoniae24/25 (96.0)14/16 (87.5)25/25 (100.0)16/16 (100.0)Legionella pneumophilia27/29 (93.1)28/33 (84.8)27/29 (93.1)32/33 (97.0)Mycoplasma pneumoniae30/35 (85.7)29/30 (96.7)34/35 (97.1)30/30 (100.0).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of BAXDELA cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.. Overview of the Safety Evaluation of BAXDELABAXDELA was evaluated in three Phase multicenter, multinational, randomized, double-blind clinical trials. These trials included two trials in ABSSSI patients (Trial and Trial 2) and one trial in CABP (Trial 3). total of 1170 patients were treated with BAXDELA across all Phase trials (741 patients in the two ABSSSI trials and 429 patients in the CABP trial).. Acute Bacterial Skin and Skin Structure Infections (ABSSSI)BAXDELA was evaluated in two multicenter, multinational, randomized, double-blind, double-dummy, non-inferiority trials (Trial and Trial 2) in adults with ABSSSI. In Trial patients received BAXDELA 300 mg by intravenous infusion every 12 hours and in Trial the patients received BAXDELA 300 mg by intravenous infusion every 12 hours for doses then were switched to BAXDELA 450 mg tablets every 12 hours. The total treatment duration was to 14 days. Adverse reactions were evaluated for 741 patients treated with BAXDELA and 751 patients treated with comparator antibacterial drugs. The median age of patients treated with BAXDELA was 49 years, ranging between 18 and 94 years old; 15% were age 65 years and older. Patients treated with BAXDELA were predominantly male (62%) and Caucasian (86%). The BAXDELA treated population included 44% obese patients (BMI >= 30 kg/m2), 11% with diabetes, and 16% with baseline renal impairment (calculated creatinine clearance less than 90 mL/min).. Serious Adverse Reactions and Adverse Reactions Leading to DiscontinuationSerious adverse reactions occurred in 3/741 (0.4%) of patients treated with BAXDELA and in 6/751 (0.8%) of patients treated with the comparator.BAXDELA was discontinued due to an adverse reaction in 7/741 (0.9%) patients and the comparator was discontinued due to an adverse reaction in 21/751 (2.8%) patients. The most commonly reported adverse reactions leading to study discontinuation in the BAXDELA arm included urticaria (2/741; 0.3%) and hypersensitivity (2/741; 0.3%); whereas, the most commonly reported adverse reactions leading to study discontinuation in the comparator arm included urticaria (5/751; 0.7%), rash (4/751; 0.5%), hypersensitivity and infusion site extravasation (2/751; 0.3%).. Most Common Adverse ReactionsThe most common adverse reactions in patients treated with BAXDELA were nausea (8%), diarrhea (8%), headache (3%), transaminase elevations (3%), and vomiting (2%). Table lists selected adverse reactions occurring in >= 2% of patients receiving BAXDELA in the pooled adult Phase clinical trials.Table Selected Adverse Reactions Occurring in >= 2% of Patients Receiving BAXDELA in the Pooled Adult Phase ABSSSI Clinical TrialsAdverse ReactionsBAXDELA = 741 (%)Vancomycin/aztreonam = 751 (%)Nausea8%6%Diarrhea8%3%HeadacheThe data are not an adequate basis for comparison of rates between the study drug and the active control. 3%6%Transaminase ElevationsPooled reports include hypertransaminasaemia, increased transaminases, and increased ALT and AST. 3%4%Vomiting2%2%. Community-Acquired Bacterial PneumoniaBAXDELA was evaluated in one multicenter, multinational, randomized, double-blind trial in adults with CABP (Trial 3). Patients received BAXDELA 300 mg over 60 minutes every 12 hours for minimum of doses with an option to switch to oral BAXDELA tablet 450 mg every 12 hours for the remaining doses (total of 10 to 20 doses of intravenous infusion and oral combined). Adverse reactions were evaluated for 429 patients treated with BAXDELA and 427 patients treated with moxifloxacin. The median age of patients treated with BAXDELA was 63 years, ranging between 18 and 89 years; 47.1% were 65 years of age and older and 19.6% were 75 years of age and older. Patients treated with BAXDELA were predominantly male (58.3%) and white (92.3%). The BAXDELA-treated population included patients with obesity (BMI greater than or equal to 30) (24.0%), COPD/asthma (14.2%), cardiac disease (24.2%), diabetes (16.3%), and baseline renal impairment including 36.4% with moderate renal impairment (CrCl less than 30-59 mL/min), and 4.0% with severe renal impairment (CrCl less than 29 mL/min). Overall, approximately 12.4% of patients were in PORT Risk Class II, 60.1% were in PORT Risk Class III, 26.6% were in PORT Risk Class IV, and 0.9% were in PORT Risk Class V.. Serious Adverse Reactions and Adverse Reactions Leading to DiscontinuationSerious adverse reactions occurred in 2/429 (0.5%) of patients treated with BAXDELA and in 1/427 (0.2%) of patients treated with moxifloxacin. Discontinuation due to an adverse reaction occurred in 9/429 (2.1%) patients treated with BAXDELA and in 4/427 (0.9%) treated with moxifloxacin. The most commonly reported adverse reactions leading to study drug discontinuation in the BAXDELA arm were transaminase elevations (2/429; 0.5%). The most commonly reported adverse reactions leading to study drug discontinuation in the comparator arm were infusion site reactions (1/427; 0.2%).. Most Common Adverse ReactionsThe most common adverse reactions in patients treated with BAXDELA were diarrhea (5%) and transaminase elevations (5%). Table lists selected adverse reactions occurring in >= 2% of patients receiving BAXDELA in the adult Phase CABP clinical trial.Table Selected Adverse Reactions Occurring in >= 2% of Patients Receiving BAXDELA in the Adult Phase CABP Clinical TrialAdverse ReactionsBAXDELA = 429Moxifloxacin = 427Diarrhea5%3%Transaminase elevationsIncludes hepatic enzyme increased, transaminases increased and alanine aminotransferase (ALT) increased. 5%3%. Adverse Reactions Occurring in Less Than 2% of Patients Receiving BAXDELA in the ABSSSI (Trials and 2) and CABP (Trial 3) Clinical TrialsThe following selected adverse reactions were reported in BAXDELA-treated patients at rate of less than 2% in the ABSSSI (Trials and 2) and CABP (Trial 3) clinical trials:Blood and Lymphatic System Disorders: agranulocytosis, anemia, leukopenia, neutropenia, pancytopeniaCardiac Disorders: sinus tachycardia, palpitations, bradycardia, ventricular extrasystolesEar and Labyrinth Disorders: tinnitus, vertigo, vestibular disorderEye Disorders: vision blurredGeneral disorders and administration site conditions: infusion related reactionsGastrointestinal Disorders: abdominal pain, dyspepsiaImmune System Disorders: hypersensitivityInfections and Infestations: Clostridium difficile infection, fungal infection, oral candidiasis, vulvovaginal candidiasisLaboratory Investigations: blood alkaline phosphatase increased, blood creatinine increased, blood creatine phosphokinase increasedMetabolism and Nutrition Disorders: hyperglycemia, hypoglycemiaMusculoskeletal and Connective Tissue Disorders: myalgiaNervous System Disorders: dizziness, hypoesthesia, paraesthesia, dysgeusia, presyncope, syncopePsychiatric Disorders: agitation, anxiety, confusional state, insomnia, abnormal dreamsRenal and Urinary: renal impairment, renal failureSkin and Subcutaneous Tissue Disorders: pruritus, urticaria, dermatitis, rashVascular Disorders: flushing, hypotension, hypertension.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For ABSSSI and CABP: Administer BAXDELA for injection 300 mg by intravenous infusion over 60 minutes, every 12 hours, or 450 mg BAXDELA tablet orally every 12 hours. (2.1, 2.2)Recommended duration of treatment: (2.2) ABSSSI: to 14 daysCABP: to 10 days Dosage for patients with renal impairment is based on the estimated glomerular filtration rate (eGFR) (2.3)Estimated Glomerular Filtration Rate (eGFR)(mL/min/1.73m2)Estimate of GFR based on Modification of Diet in Renal Disease (MDRD) equation. Recommended Dosage Regimen for BAXDELAFor total treatment duration of to 14 days for the treatment of ABSSSI and to 10 days for the treatment of CABP. OralIntravenousAll intravenous doses of BAXDELA are administered over 60 minutes. 30-89No dosage adjustmentNo dosage adjustment15-29No dosage adjustment200 mg every 12 hoursEnd Stage Renal Disease (ESRD) (< 15 including hemodialysis)Not RecommendedNot recommended due to insufficient information to provide dosing recommendations. For ABSSSI and CABP: Administer BAXDELA for injection 300 mg by intravenous infusion over 60 minutes, every 12 hours, or 450 mg BAXDELA tablet orally every 12 hours. (2.1, 2.2). Recommended duration of treatment: (2.2) ABSSSI: to 14 daysCABP: to 10 days ABSSSI: to 14 days. CABP: to 10 days. Dosage for patients with renal impairment is based on the estimated glomerular filtration rate (eGFR) (2.3). 2.1 Important Administration Instructions. BAXDELA TabletsAdminister BAXDELA at least hours before or hours after antacids containing magnesium, or aluminum, with sucralfate, with metal cations such as iron, or with multivitamin preparations containing zinc or iron, or with didanosine buffered tablets for oral suspension or the pediatric powder for oral solution [see Drug Interactions (7.1)].BAXDELA Tablets can be taken with or without food [see Clinical Pharmacology (12.3)].If patients miss dose, they should take it as soon as possible anytime up to hours prior to their next scheduled dose. If less than hours remain before the next dose, wait until their next scheduled dose.. BAXDELA for InjectionDo NOT administer BAXDELA for Injection with any solution containing multivalent cations, e.g., calcium and magnesium, through the same intravenous line [see Drug Interactions (7.1)]. Do NOT co-infuse BAXDELA for Injection with other medications [see Dosage and Administration (2.4)].. 2.2 Recommended Dosage Regimen. For treatment of adults with ABSSSI or CABP, the recommended dosage regimen of BAXDELA is described in Table below.Table Dosage of BAXDELA in Adult ABSSSI or CABP PatientsInfectionDosage and Route of AdministrationTotal Duration (days)ABSSSI300 mg of BAXDELA for Injection every 12 hours over 60 minutes by intravenous infusion Or 300 mg of BAXDELA for Injection every 12 hours over 60 minutes by intravenous infusion, then switch to 450 mg BAXDELA tablet orally every 12 hours at the discretion of the physician Or 450 mg BAXDELA tablet orally every 12 hours.5 to 14CABP5 to 10. 300 mg of BAXDELA for Injection every 12 hours over 60 minutes by intravenous infusion Or 300 mg of BAXDELA for Injection every 12 hours over 60 minutes by intravenous infusion, then switch to 450 mg BAXDELA tablet orally every 12 hours at the discretion of the physician Or 450 mg BAXDELA tablet orally every 12 hours.. 2.3 Dosage in Patients with Renal Impairment. Table below describes the dosage modification based on the estimated glomerular filtration rate (eGFR) that is recommended in patients with renal impairment. Dosage adjustment is required for patients with severe renal impairment (eGFR 15-29 mL/min/1.73m2).In patients with severe renal impairment receiving BAXDELA intravenously, closely monitor serum creatinine levels and eGFR [see Use in Specific Populations (8.7)]. If serum creatinine level increases, consider switching to BAXDELA Tablets. Discontinue BAXDELA if eGFR decreases to 15 mL/min/1.73 m2.Table Dosage Adjustment of BAXDELA in Patients with Renal ImpairmentEstimated Glomerular Filtration Rate (eGFR) (mL/min/1.73 m2)As calculated using the MDRD eGFR equation as follows: eGFR (mL/min/1.73m2) 175 (serum creatinine)-1.154 (age)-0.203 (0.742 if female) (1.212 if African American). Recommended Dosage RegimenFor total treatment duration of to 14 days for the treatment of ABSSSI and to 10 days for the treatment of CABP in adult patients. BAXDELA TabletsBAXDELA for InjectionAll doses of BAXDELA are administered by intravenous infusion over 60 minutes. 30-89No dosage adjustmentNo dosage adjustment15-29No dosage adjustment200 mg every 12 hours Or 200 mg every 12 hours, then switch to 450 mg BAXDELA tablet orally every 12 hours at the discretion of the physicianEnd Stage Renal Disease (ESRD) (< 15), including patients on hemodialysis (HD)Not RecommendedNot recommended due to insufficient information to provide dosing recommendations. 2.4 Preparation and Administration of BAXDELA for Injection Intravenous Solution. Reconstitution and DilutionBAXDELA must be reconstituted and then further diluted under aseptic conditions. Reconstitute the powder in the BAXDELA vial using 10.5 mL of 5% Dextrose Injection (D5W) or 0.9% Sodium Chloride Injection for each 300 mg vial. Shake the vial vigorously until contents are completely dissolved. The reconstituted vial contains 300 mg per 12 mL (25 mg/mL) of BAXDELA as clear yellow to amber colored solution.The reconstituted solution must then be diluted to total volume of 250 mL using either 0.9% Sodium Chloride or D5W to achieve concentration of 1.2 mg/mL, prior to administration. Prepare the required dose for intravenous infusion by withdrawing the appropriate volume from the reconstituted vial per Table below: Table Preparation of BAXDELA DosesBAXDELA for Injection DoseVolume of Reconstituted Solution to Withdraw300 mg12 mL200 mg8 mL Aseptically transfer the required volume of BAXDELA reconstituted solution from the vial to an intravenous bag to achieve 250 mL volume of infusion solution. Discard any unused portion of the reconstituted solution.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.. BAXDELA must be reconstituted and then further diluted under aseptic conditions. Reconstitute the powder in the BAXDELA vial using 10.5 mL of 5% Dextrose Injection (D5W) or 0.9% Sodium Chloride Injection for each 300 mg vial. Shake the vial vigorously until contents are completely dissolved. The reconstituted vial contains 300 mg per 12 mL (25 mg/mL) of BAXDELA as clear yellow to amber colored solution.. The reconstituted solution must then be diluted to total volume of 250 mL using either 0.9% Sodium Chloride or D5W to achieve concentration of 1.2 mg/mL, prior to administration. Prepare the required dose for intravenous infusion by withdrawing the appropriate volume from the reconstituted vial per Table below: Table Preparation of BAXDELA DosesBAXDELA for Injection DoseVolume of Reconstituted Solution to Withdraw300 mg12 mL200 mg8 mL Aseptically transfer the required volume of BAXDELA reconstituted solution from the vial to an intravenous bag to achieve 250 mL volume of infusion solution. Discard any unused portion of the reconstituted solution.. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.. Storage of the Reconstituted and Diluted SolutionsReconstituted vials, as described above, may be stored either refrigerated at 2C to 8C (36F to 46F), or at controlled room temperature 20C to 25C (68F to 77F) for up to 24 hours. Do not freeze.Once diluted into the intravenous bag, as described above, BAXDELA may be stored either refrigerated at 2C to 8C (36F to 46F) or at controlled room temperature of 20C to 25C (68F to 77F) for up to 24 hours. Do not freeze.. AdministrationAfter reconstitution and dilution, administer BAXDELA by intravenous infusion, using total infusion time of 60 minutes [see Dosage and Administration (2.1)].The compatibility of reconstituted BAXDELA with intravenous medications, additives, or substances other than D5W or 0.9% Sodium Chloride Injection has not been established. If common intravenous line is being used to administer other drugs in addition to BAXDELA the line should be flushed before and after each BAXDELA infusion with 0.9% Sodium Chloride Injection or D5W.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. Serious Adverse ReactionsAdvise patients to stop taking BAXDELA 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 BAXDELA or other fluoroquinolone use:Disabling and Potentially Irreversible Serious Adverse Reactions that may occur together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of fluoroquinolones and may occur together in the same patient. Inform patients to stop taking BAXDELA 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 tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue BAXDELA treatment. Symptoms may be irreversible. The risk of severe tendon disorder 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 Neuropathy: Inform patients that peripheral neuropathies have been associated with BAXDELA use, 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, immediately discontinue BAXDELA and tell them to 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. Instruct patients to notify their physician before taking this drug if they have history of convulsions. Inform patients that they should know how they react to BAXDELA before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.Hypersensitivity Reactions: Inform patients that BAXDELA can cause hypersensitivity reactions, even following single dose, and to discontinue BAXDELA at the first sign of skin rash, hives or other skin reactions, rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.Diarrhea: Diarrhea is 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, instruct patients to contact their physician as soon as possible.Aortic Aneurysm and Dissection: Inform patients to seek emergency medical care if they experience sudden chest, stomach, or back pain.Antibacterial Resistance: Patients should be counseled that antibacterial drugs including BAXDELA Tablets and Injection should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When BAXDELA Tablets and BAXDELA Injection are prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by BAXDELA Tablets and BAXDELA Injection or other antibacterial drugs in the future.. Disabling and Potentially Irreversible Serious Adverse Reactions that may occur together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of fluoroquinolones and may occur together in the same patient. Inform patients to stop taking BAXDELA 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 tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue BAXDELA treatment. Symptoms may be irreversible. The risk of severe tendon disorder 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 Neuropathy: Inform patients that peripheral neuropathies have been associated with BAXDELA use, 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, immediately discontinue BAXDELA and tell them to 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. Instruct patients to notify their physician before taking this drug if they have history of convulsions. Inform patients that they should know how they react to BAXDELA before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.. Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.. Hypersensitivity Reactions: Inform patients that BAXDELA can cause hypersensitivity reactions, even following single dose, and to discontinue BAXDELA at the first sign of skin rash, hives or other skin reactions, rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.. Diarrhea: Diarrhea is 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, instruct patients to contact their physician as soon as possible.. Aortic Aneurysm and Dissection: Inform patients to seek emergency medical care if they experience sudden chest, stomach, or back pain.. Antibacterial Resistance: Patients should be counseled that antibacterial drugs including BAXDELA Tablets and Injection should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When BAXDELA Tablets and BAXDELA Injection are prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by BAXDELA Tablets and BAXDELA Injection or other antibacterial drugs in the future.. Administration with Food and Concomitant MedicationsInform patients that BAXDELA Tablets may be taken with or without food and without any dietary restrictions [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].Inform patients that BAXDELA Tablets should be taken at least hours before or hours after antacids containing magnesium, or aluminum, with sucralfate, with metal cations such as iron, or with multivitamin preparations containing zinc or iron, or with didanosine buffered tablets for oral suspension or the pediatric powder for oral solution.. Inform patients that BAXDELA Tablets may be taken with or without food and without any dietary restrictions [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].. Inform patients that BAXDELA Tablets should be taken at least hours before or hours after antacids containing magnesium, or aluminum, with sucralfate, with metal cations such as iron, or with multivitamin preparations containing zinc or iron, or with didanosine buffered tablets for oral suspension or the pediatric powder for oral solution.

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionDelafloxacin belongs to the fluoroquinolone class of antibacterial drugs and is anionic in nature. The antibacterial activity of delafloxacin is due to the inhibition of both bacterial topoisomerase IV and DNA gyrase (topoisomerase II) enzymes which are required for bacterial DNA replication, transcription, repair, and recombination. Delafloxacin exhibits concentration-dependent bactericidal activity against gram-positive and gram-negative bacteria in vitro.. ResistanceResistance to fluoroquinolones, including delafloxacin, can occur due to mutations in defined regions of the target bacterial enzymes topoisomerase IV and DNA gyrase referred to as Quinolone-Resistance Determining Regions (QRDRs), or through altered efflux.Fluoroquinolones, including delafloxacin, have different chemical structure and mechanism of action relative to other classes of antibacterial compounds (e.g., aminoglycosides, macrolides, -lactams, glycopeptides, tetracyclines and oxazolidinones).In vitro resistance to delafloxacin develops by multiple step mutations in the QRDRs of gram-positive and gram-negative bacteria. Delafloxacin-resistant mutants were selected in vitro at frequency of 10-9.Although cross-resistance between delafloxacin and other fluoroquinolone-class antibacterial agents has been observed, some isolates resistant to other fluoroquinolone-class antibacterial agents may be susceptible to BAXDELA including some S. aureus isolates carrying mutations in the quinolone resistance determining region (gyrA, parC and parE).Additionally, delafloxacin has activity against some isolates of beta-lactamase positive H. influenzae and H. parainfluenzae.. Interaction With Other AntimicrobialsIn vitro drug combination studies with delafloxacin and amoxicillin/clavulanate, azithromycin, aztreonam, ceftaroline, ceftazidime, ceftriaxone, colistin, daptomycin, doxycycline, linezolid, meropenem, penicillin, rifampin, tigecycline, trimethoprim/sulfamethoxazole and vancomycin demonstrated neither synergy nor antagonism.. Antimicrobial ActivityBAXDELA has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections, [see Indications and Usage (1.1, 1.2)].. Acute Bacterial Skin and Skin Structure Infections (ABSSSI)Aerobic bacteria Gram-positive bacteria Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates) Staphylococcus haemolyticus Staphylococcus lugdunensis Streptococcus pyogenes Streptococcus agalactiae Streptococcus anginosus Group (including S. anginosus, S. intermedius, and S. constellatus) Enterococcus faecalis Gram-negative bacteria Escherichia coli Klebsiella pneumoniae Enterobacter cloacae Pseudomonas aeruginosa. Gram-positive bacteria. Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates). Staphylococcus haemolyticus. Staphylococcus lugdunensis. Streptococcus pyogenes. Streptococcus agalactiae. Streptococcus anginosus Group (including S. anginosus, S. intermedius, and S. constellatus). Enterococcus faecalis. Gram-negative bacteria. Escherichia coli. Klebsiella pneumoniae. Enterobacter cloacae. Pseudomonas aeruginosa. Community-Acquired Bacterial Pneumonia (CABP)Aerobic bacteria Gram-positive bacteria Streptococcus pneumoniae Staphylococcus aureus (methicillin-susceptible isolates only) Gram-negative bacteria Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Pseudomonas aeruginosa Other microorganisms Chlamydia pneumoniae Legionella pneumophila Mycoplasma pneumoniaeThe following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint of delafloxacin against isolates of similar genus or organism group. However, the efficacy of BAXDELA in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.Aerobic bacteria Gram-positive bacteria Streptococcus dysgalactiae Gram-negative bacteria Enterobacter aerogenes Klebsiella oxytoca Proteus mirabilis Moraxella catarrhalis. Gram-positive bacteria. Streptococcus pneumoniae. Staphylococcus aureus (methicillin-susceptible isolates only). Gram-negative bacteria. Escherichia coli. Haemophilus influenzae. Haemophilus parainfluenzae. Klebsiella pneumoniae. Pseudomonas aeruginosa. Other microorganisms. Chlamydia pneumoniae. Legionella pneumophila. Mycoplasma pneumoniae. Gram-positive bacteria. Streptococcus dysgalactiae. Gram-negative bacteria. Enterobacter aerogenes. Klebsiella oxytoca. Proteus mirabilis. Moraxella catarrhalis. Susceptibility Test MethodsFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetic parameters of delafloxacin following single- and multiple-dose (every 12 hours) oral (450 mg) and intravenous (300 mg) administration are shown in Table 6. Steady-state was achieved within approximately three days with accumulation of approximately 10% and 36% following IV and oral administration, respectively.Table Mean (SD) Delafloxacin Pharmacokinetic Parameters Following Single and Multiple Oral and Intravenous AdministrationParametersTabletIntravenous InjectionSingle Dose 450 mgSteady State 450 mg Q12hQ12h is every 12 hours Single Dose 300 mgSteady State 300 mg Q12h Cmax maximum concentration; Tmax time to reach Cmax; AUC area under the concentration-time curve; CL systemic clearance; CL/F apparent oral clearance; Rac accumulation ratioTmax (h)Median (range) 0.75 (0.5, 4.0)1.00 (0.50, 6.00)1.0 (1.0, 1.2)1.0 (1.0, 1.0)Cmax (ug/mL)7.17 (2.01)7.45 (3.16)8.94 (2.54)9.29 (1.83)AUC (ugh/mL)AUC is AUC (AUC from time to 12 hours) for single dose and multiple-dose administration 22.7 (6.21)30.8 (11.4)21.8 (4.54)23.4 (6.90)CL or CL/F(L/h)CL is reported for intravenous injection. CL/F is reported for tablet 20.6 (6.07)16.8 (6.54)14.1 (2.81)13.8 (3.96)CLr (L/h)--5.89 (1.53)6.69 (2.19)Rac -1.36-1.1. AbsorptionThe absolute bioavailability for BAXDELA 450 mg oral tablet administered as single dose was 58.8%. The AUC of delafloxacin following administration of single 450 mg oral (tablet) dose was comparable to that following single 300 mg intravenous dose. The Cmax of delafloxacin was achieved within about hour after oral administration under fasting condition. Food (kcal: 917, Fat: 58.5%, Protein: 15.4%, Carbohydrate: 26.2%). did not affect the bioavailability of delafloxacin [see Dosage and Administration (2.1)].. DistributionThe steady state volume of distribution of delafloxacin is 30-48 which approximates total body water. The plasma protein binding of delafloxacin is approximately 84%; delafloxacin primarily binds to albumin. Plasma protein binding of delafloxacin is not significantly affected by renal impairment.Following IV administration of doses of 300 mg of BAXDELA to 30 healthy volunteers, the mean BAXDELA AUC0-12 (3.6 hrmcg/mL) in alveolar macrophages was 80% of the free-plasma AUC0-12, and the mean BAXDELA AUC0-12 (2.8 hrmcg/mL) in epithelial lining fluid was 70% of the free-plasma AUC0-12. EliminationIn mass balance study, the mean half-life for delafloxacin was 3.7 hours (SD 0.7 hour) after single dose intravenous administration. The mean half-life values for delafloxacin ranged from 4.2 to 8.5 hours following multiple oral administrations. Following administration of single 300 mg intravenous dose of BAXDELA, the mean clearance (CL) of delafloxacin was 16.3 L/h (SD 3.7 L/h), and the renal clearance (CLr) of delafloxacin accounts for 35-45% of the total clearance.. MetabolismGlucuronidation of delafloxacin is the primary metabolic pathway with oxidative metabolism representing about 1% of an administered dose. The glucuronidation of delafloxacin is mediated mainly by UGT1A1, UGT1A3, and UGT2B15. Unchanged parent drug is the predominant component in plasma. There are no significant circulating metabolites in humans.. ExcretionAfter single intravenous dose of 14C-labeled delafloxacin, 65% of the radioactivity was excreted in urine as unchanged delafloxacin and glucuronide metabolites and 28% was excreted in feces as unchanged delafloxacin. Following single oral dose of 14C-labeled delafloxacin, 50% of the radioactivity was excreted in urine as unchanged delafloxacin and glucuronide metabolites and 48% was excreted in feces as unchanged delafloxacin.. Specific PopulationsNo clinical significance in the pharmacokinetics of delafloxacin was observed based on age, sex, race, weight, body mass index, and disease state (ABSSSI and CABP).. Patients with Hepatic ImpairmentNo clinically meaningful changes in delafloxacin Cmax and AUC were observed, following administration of single 300 mg intravenous dose of BAXDELA to patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B, and C) compared to matched healthy control subjects.. Patients with Renal ImpairmentFollowing single intravenous (300 mg) administration of delafloxacin to subjects with mild (eGFR 51-80 mL/min/1.73 m2), moderate (eGFR 31-50 mL/min/1.73 m2), severe (eGFR 15-29 mL/min/1.73 m2) renal impairment, and ESRD on hemodialysis receiving intravenous delafloxacin within hour before and hour after hemodialysis, mean total exposure (AUCt) of delafloxacin was 1.3, 1.6, 1.8, 2.1, and 2.6-fold higher, respectively than that for matched normal control subjects. The mean dialysate clearance (CLd) of delafloxacin was 4.21 L/h (SD 1.56 L/h). After about hours of hemodialysis, the mean fraction of administered delafloxacin recovered in the dialysate was about 19% [see Use in Specific Populations (8.7)].Following single oral (400 mg) administration of delafloxacin to subjects with mild (eGFR 51-80 mL/min/1.73 m2), moderate (eGFR 31-50 mL/min/1.73 m2), or severe (eGFR 15-29 mL/min/1.73 m2) renal impairment, the mean total exposure (AUCt) of delafloxacin was about 1.5-fold higher for subjects with moderate and severe renal impairment compared with healthy subjects, whereas total systemic exposures of delafloxacin in subjects with mild renal impairment were comparable with healthy subjects.In patients with moderate (eGFR 31-50 mL/min/1.73 m2), or severe (eGFR 15-29 mL/min/1.73 m2) renal impairment or ESRD on hemodialysis, accumulation of the intravenous vehicle SBECD occurs. The mean systemic exposure (AUC) increased 2-fold, 5-fold, 7.5-fold, and 27-fold for patients with moderate impairment, severe impairment, ESRD on hemodialysis receiving intravenous delafloxacin within hour before, and hour after hemodialysis respectively, compared to the healthy control group. In subjects with ESRD undergoing hemodialysis, SBECD is dialyzed with clearance of 4.74 L/h. When hemodialysis occurred hour after the BAXDELA infusion in subjects with ESRD, the mean fraction of SBECD recovered in the dialysate was 56.1% over approximately hours.. Geriatric PatientsFollowing single oral administration of 250 mg delafloxacin (approximately 0.6 times the approved recommended oral dose), the mean delafloxacin Cmax and AUC values in elderly subjects (>= 65 years) were about 35% higher compared to values obtained in young adults (18 to 40 years). This difference is not considered clinically relevant. population pharmacokinetic analysis of patients with ABSSSI or CABP indicated that patients over the age of 65 years have slower clearance than younger patients. However, the overall impact on delafloxacin pharmacokinetics is not considered clinically significant and dose adjustment in elderly patients is not warranted.. Male and Female PatientsFollowing single oral administration of 250 mg delafloxacin (approximately 0.6 times the approved recommended oral dose), the mean delafloxacin Cmax and AUC values in male subjects were comparable to female subjects. Results from population pharmacokinetic analysis showed that females have 24% lower AUC than males. This difference is not considered clinically relevant.. Drug Interaction Studies. Drug Metabolizing EnzymesDelafloxacin at clinically relevant concentrations does not inhibit the cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in vitro in human liver microsomes. At delafloxacin concentration (500 uM) well above clinically relevant exposures, the activity of CYP2E1was increased.In human hepatocytes, delafloxacin showed no potential for in vitro induction of CYP1A2, 2B6, 2C19, or 2C8 but was mild inducer of CYP2C9 at concentration of 100 uM and CYP3A4 at clinically relevant concentration. Administration of BAXDELA 450 mg every 12 hours for days to healthy male and female subjects (n 22) prior to and on Day with single oral mg dose of midazolam (a sensitive CYP3A substrate), did not affect the Cmax and AUC values for midazolam or 1-hydroxy midazolam compared to administration of midazolam alone.. TransportersDelafloxacin was not an inhibitor of the following hepatic and renal transporters in vitro at clinically relevant concentrations: MDR1, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, OCT1 and OCT2. Delafloxacin was not substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1 or OATP. Delafloxacin was shown to be substrate of P-gp and BCRP in vitro. The clinical relevance of co-administration of delafloxacin and P-gp and/or BCRP inhibitors is unknown.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration MEL011-R007Revised: 6/2021 MEDICATION GUIDE BAXDELA(R) (Bax-de-lah) (delafloxacin) for injectionBAXDELA(R) (Bax-de-lah) (delafloxacin) tablets for oral useWhat is the most important information should know about BAXDELABAXDELA, fluoroquinolone antibacterial medicine, can cause serious side effects. Some of these serious side effects can happen at the same time and could result in death. If you get any of the following serious side effects while you take BAXDELA, you should stop taking BAXDELA immediately and get medical help right away.1.Tendon rupture or swelling of the tendon (tendinitis).Tendon problems can happen in people of all ages who take BAXDELA. Tendons are tough cords of tissue that connect muscles to bones. Symptoms of tendon problems may include: Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites.The risk of getting tendon problems while you take BAXDELA is higher if you:are over 60 years of ageare taking steroids (corticosteroids)have had kidney, heart or lung transplantTendon problems can happen in people who do not have the above risk factors when they take BAXDELA. Other reasons that can increase your risk of tendon problems can include:physical activity or exercisekidney failuretendon problems in the past, such as in people with rheumatoid arthritis (RA)Stop taking BAXDELA immediately and call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking BAXDELA until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. The most common area of pain and swelling is in the Achilles tendon at the back of your ankle. This can also happen with other tendons.Talk to your healthcare provider about the risk of tendon rupture with continued use of BAXDELA. You may need different antibacterial that is not fluoroquinolone to treat your infection.Tendon rupture can happen while you are taking or after you have finished taking fluoroquinolone antibacterial medicines like BAXDELA. Tendon ruptures can happen within hours or days of taking fluoroquinolone and have happened up to several months after patients have finished taking their fluoroquinolone.Stop taking BAXDELA immediately and get medical help right away if you get any of the following signs or symptoms of tendon rupture:hear or feel snap or pop in tendon areabruising right after an injury in tendon areaunable to move the affected area or bear weight2.Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including BAXDELA. Stop taking BAXDELA immediately and talk to your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:painburningtinglingnumbnessweakness BAXDELA may need to be stopped to prevent permanent nerve damage.3.Central Nervous System (CNS) effects. Seizures have been reported in people who take fluoroquinolone antibacterial medicines. Tell your healthcare provider if you have history of seizures before you start taking BAXDELA. CNS side effects may happen as soon as after taking the first dose of BAXDELA. Stop taking BAXDELA immediately and talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior:seizureshear voices, see things, or sense things that are not there (hallucinations)feel restlesstremorsfeel anxious or nervousconfusiondepressiontrouble sleepingnightmaresfeel lightheaded or dizzyfeel more suspicious (paranoia)suicidal thoughts or actsheadaches that will not go away, with or without blurred visionmemory problemsfalse or strange thoughts or beliefs (delusions)difficulty paying attentionreduced awareness of surroundings4.Worsening of Myasthenia Gravis (a problem that causes muscle weakness). Fluoroquinolones like BAXDELA may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Tell your healthcare provider if you have history of myasthenia gravis before you start taking BAXDELA. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems.What is BAXDELABAXDELA is fluoroquinolone antibacterial medicine used to treat certain types of infections caused by certain germs called bacteria in adults 18 years or older. These bacterial infections include: skin infectionscommunity-acquired bacterial pneumonia It is not known if BAXDELA is safe and effective in people under 18 years of age, and use in people under 18 years of age is not recommended. Children younger than 18 years of age may have higher chance of getting bone, joint, and tendon (musculoskeletal) problems while taking fluoroquinolone antibacterial medicines.Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in the sinuses and lungs, such as the common cold or flu. Antibacterial medicines, including BAXDELA, do not kill viruses. Call your healthcare provider if you think your condition is not getting better while you are taking BAXDELA.Do not take BAXDELA if:you have ever had severe allergic reaction to an antibacterial known as fluoroquinolone, or if you are allergic to any of the ingredients in BAXDELA. Ask your healthcare provider if you are not sure. See the list of ingredients in BAXDELA at the end of this Medication Guide.What should tell my healthcare provider before taking BAXDELASee What is the most important information should know about BAXDELA Before you take BAXDELA, tell your healthcare provider about all your medical conditions, including if you:have tendon problems. BAXDELA should not be used in patients who have history of tendon problems.have disease that causes muscle weakness (myasthenia gravis). BAXDELA should not be used in patients who have history of myasthenia gravis.have central nervous system problems (such as epilepsy).have nerve problems. BAXDELA should not be used in patients who have history of nerve problem called peripheral neuropathy.have history of seizures.have kidney problems.have rheumatoid arthritis (RA) or other history of joint problems.have diabetes and take anti-diabetes medicines or insulin.are pregnant or planning to become pregnant. It is not known if BAXDELA will harm your unborn child.are breast-feeding or planning to breastfeed. It is not known if BAXDELA passes into human breast milk. You and your healthcare provider should decide whether you will take BAXDELA or breast-feed.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal and dietary supplements.BAXDELA and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take: steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of tendon injury. See What is the most important information should know about BAXDELACertain medicines may keep BAXDELA from working correctly. BAXDELA Tablets should be taken at least hours before or hours after: an antacid, multivitamin, or other product that has magnesium, aluminum, iron, or zincsucralfatedidanosine buffered tablets for oral suspension or the pediatric powder for oral solution Ask your healthcare provider if you are not sure if any of your medicines are listed above. Know the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.How should take BAXDELATake BAXDELA tablets times day exactly as your healthcare provider tells you to take it.If you have kidney problems, talk with your doctor about how you should take BAXDELA.BAXDELA can be taken with or without food.BAXDELA IV is given to you by intravenous (IV) infusion into your vein slowly, over 60 minutes, as prescribed by your healthcare provider.Do not skip any doses, or stop taking BAXDELA even if you begin to feel better, until you finish your prescribed treatment, unless you have: tendon problems, nerve problems, or central nervous system problems (see What is the most important information should know about BAXDELA).a serious allergic reaction. See What are the possible side effects of BAXDELA), or your healthcare provider tells you to stop.Unless you are experiencing any of the harmful side effects listed in this medication guide, take your BAXDELA, as your healthcare provider tells you to take it, to help lower the chance that bacteria will become resistant to BAXDELA. If this happens, BAXDELA and other antibacterial medicines may not work in the future.If you miss dose of BAXDELA, take it as soon as you remember up to hours before your next dose. If you have less than hours before your next dose, wait to take your next dose at your regular time. Do not take more BAXDELA to make up for the missed dose.If you take too much BAXDELA, call your healthcare provider or get medical help immediately.What should avoid while taking BAXDELABAXDELA 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 BAXDELA affects you.What are the possible side effects of BAXDELABAXDELA may cause serious side effects, including: See What is the most important information should know about BAXDELA Serious allergic reactions. Serious allergic reactions, including death, can happen in people taking fluoroquinolones, including BAXDELA, even after only dose. Stop taking BAXDELA and get emergency medical help right away if you get any of the following symptoms of severe allergic reaction: hivesswelling of the lips, tongue, facerapid heartbeatskin rashtrouble breathing or swallowingthroat tightness, hoarsenessfaintSkin rash may happen in people taking fluoroquinolones even after only dose. Stop taking BAXDELA at the first sign of skin rash and call your healthcare provider. Skin rash may be sign of more serious reaction to BAXDELA.Clostridium difficile-associated diarrhea (CDAD). CDAD is an infection of your intestines (bowels) that can happen with many antibacterial medicines, including BAXDELA, and may cause mild diarrhea to life-threatening swelling of your intestines (colitis). Call your healthcare provider right away if you get stomach cramps, fever, watery diarrhea, diarrhea that does not go away, or bloody stools. CDAD can happen or more months after you have finished your antibacterial medicine.Aortic aneurysm and dissection. Tell your healthcare provider if you have ever been told that you have an aortic aneurysm, swelling of the large artery that carries blood from the heart to the body. Get emergency medical help right away if you have sudden chest, stomach or back pain.Changes in blood sugar. People who take fluoroquinolone medicines with oral anti-diabetes medicines or with insulin can get low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia). Follow your healthcare providers instructions for how often to check your blood sugar. If you have diabetes and you get low blood sugar while taking BAXDELA, stop taking BAXDELA and call your healthcare provider right away. Your antibiotic medicine may need to be changed.The most common side effects of BAXDELA include:nauseadiarrheaheadachechanges in liver testsvomitingThese are not all the possible side effects of BAXDELA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store BAXDELABAXDELA Tablets:Store BAXDELA Tablets at room temperature between 68F to 77F (20C to 25C).Keep BAXDELA away from moisture (humidity).Keep BAXDELA and all medicines out of the reach of children.General information about the safe and effective use of BAXDELA.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use BAXDELA for condition for which it was not prescribed. Do not give BAXDELA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about BAXDELA that is written for health professionals.What are the ingredients in BAXDELABAXDELA Tablets: 450 mgActive ingredient: 450 mg delafloxacin (equivalent to 649 mg delafloxacin meglumine) Inactive ingredients: Citric acid, Crospovidone, Magnesium stearate, Microcrystalline Cellulose, Povidone, Sodium bicarbonate, and Sodium phosphate monobasic, monohydrate.BAXDELA for Injection: 300 mgActive ingredient: delafloxacin Inactive ingredients: Meglumine, beta-cyclodextrin sulfobutyl ether, and EDTA. Sodium hydroxide and/or hydrochloric acid may have been used to adjust the pH.Distributed by: Melinta Therapeutics, LLC 300 Tri-State International, Lincolnshire, Illinois, 60069 USA Trademarks depicted herein are the property of their respective owners. (C)2021 Melinta Therapeutics, LLC All rights reserved For more information go to BAXDELA.com or call 1-844-633-6568.. 1.Tendon rupture or swelling of the tendon (tendinitis).Tendon problems can happen in people of all ages who take BAXDELA. Tendons are tough cords of tissue that connect muscles to bones. Symptoms of tendon problems may include: Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites.The risk of getting tendon problems while you take BAXDELA is higher if you:are over 60 years of ageare taking steroids (corticosteroids)have had kidney, heart or lung transplantTendon problems can happen in people who do not have the above risk factors when they take BAXDELA. Other reasons that can increase your risk of tendon problems can include:physical activity or exercisekidney failuretendon problems in the past, such as in people with rheumatoid arthritis (RA)Stop taking BAXDELA immediately and call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking BAXDELA until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. The most common area of pain and swelling is in the Achilles tendon at the back of your ankle. This can also happen with other tendons.Talk to your healthcare provider about the risk of tendon rupture with continued use of BAXDELA. You may need different antibacterial that is not fluoroquinolone to treat your infection.Tendon rupture can happen while you are taking or after you have finished taking fluoroquinolone antibacterial medicines like BAXDELA. Tendon ruptures can happen within hours or days of taking fluoroquinolone and have happened up to several months after patients have finished taking their fluoroquinolone.Stop taking BAXDELA immediately and get medical help right away if you get any of the following signs or symptoms of tendon rupture:hear or feel snap or pop in tendon areabruising right after an injury in tendon areaunable to move the affected area or bear weight. Tendon problems can happen in people of all ages who take BAXDELA. Tendons are tough cords of tissue that connect muscles to bones. Symptoms of tendon problems may include: Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites.. Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites.. The risk of getting tendon problems while you take BAXDELA is higher if you:are over 60 years of ageare taking steroids (corticosteroids)have had kidney, heart or lung transplant. are over 60 years of age. are taking steroids (corticosteroids). have had kidney, heart or lung transplant. Tendon problems can happen in people who do not have the above risk factors when they take BAXDELA. Other reasons that can increase your risk of tendon problems can include:physical activity or exercisekidney failuretendon problems in the past, such as in people with rheumatoid arthritis (RA). physical activity or exercise. kidney failure. tendon problems in the past, such as in people with rheumatoid arthritis (RA). Stop taking BAXDELA immediately and call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking BAXDELA until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. The most common area of pain and swelling is in the Achilles tendon at the back of your ankle. This can also happen with other tendons.. Talk to your healthcare provider about the risk of tendon rupture with continued use of BAXDELA. You may need different antibacterial that is not fluoroquinolone to treat your infection.. Tendon rupture can happen while you are taking or after you have finished taking fluoroquinolone antibacterial medicines like BAXDELA. Tendon ruptures can happen within hours or days of taking fluoroquinolone and have happened up to several months after patients have finished taking their fluoroquinolone.. Stop taking BAXDELA immediately and get medical help right away if you get any of the following signs or symptoms of tendon rupture:hear or feel snap or pop in tendon areabruising right after an injury in tendon areaunable to move the affected area or bear weight. hear or feel snap or pop in tendon area. bruising right after an injury in tendon area. unable to move the affected area or bear weight. 2.Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including BAXDELA. Stop taking BAXDELA immediately and talk to your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:. pain. burning. tingling. numbness. weakness. BAXDELA may need to be stopped to prevent permanent nerve damage.. 3.Central Nervous System (CNS) effects. Seizures have been reported in people who take fluoroquinolone antibacterial medicines. Tell your healthcare provider if you have history of seizures before you start taking BAXDELA. CNS side effects may happen as soon as after taking the first dose of BAXDELA. Stop taking BAXDELA immediately and talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior:. seizures. hear voices, see things, or sense things that are not there (hallucinations). feel restless. tremors. feel anxious or nervous. confusion. depression. trouble sleeping. nightmares. feel lightheaded or dizzy. feel more suspicious (paranoia). suicidal thoughts or acts. headaches that will not go away, with or without blurred vision. memory problems. false or strange thoughts or beliefs (delusions). difficulty paying attention. reduced awareness of surroundings. 4.Worsening of Myasthenia Gravis (a problem that causes muscle weakness). Fluoroquinolones like BAXDELA may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Tell your healthcare provider if you have history of myasthenia gravis before you start taking BAXDELA. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems.. skin infections. community-acquired bacterial pneumonia. have tendon problems. BAXDELA should not be used in patients who have history of tendon problems.. have disease that causes muscle weakness (myasthenia gravis). BAXDELA should not be used in patients who have history of myasthenia gravis.. have central nervous system problems (such as epilepsy).. have nerve problems. BAXDELA should not be used in patients who have history of nerve problem called peripheral neuropathy.. have history of seizures.. have kidney problems.. have rheumatoid arthritis (RA) or other history of joint problems.. have diabetes and take anti-diabetes medicines or insulin.. are pregnant or planning to become pregnant. It is not known if BAXDELA will harm your unborn child.. are breast-feeding or planning to breastfeed. It is not known if BAXDELA passes into human breast milk. You and your healthcare provider should decide whether you will take BAXDELA or breast-feed.. steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of tendon injury. See What is the most important information should know about BAXDELA. Certain medicines may keep BAXDELA from working correctly. BAXDELA Tablets should be taken at least hours before or hours after: an antacid, multivitamin, or other product that has magnesium, aluminum, iron, or zincsucralfatedidanosine buffered tablets for oral suspension or the pediatric powder for oral solution an antacid, multivitamin, or other product that has magnesium, aluminum, iron, or zinc. sucralfate. didanosine buffered tablets for oral suspension or the pediatric powder for oral solution. Take BAXDELA tablets times day exactly as your healthcare provider tells you to take it.. If you have kidney problems, talk with your doctor about how you should take BAXDELA.. BAXDELA can be taken with or without food.. BAXDELA IV is given to you by intravenous (IV) infusion into your vein slowly, over 60 minutes, as prescribed by your healthcare provider.. Do not skip any doses, or stop taking BAXDELA even if you begin to feel better, until you finish your prescribed treatment, unless you have: tendon problems, nerve problems, or central nervous system problems (see What is the most important information should know about BAXDELA).a serious allergic reaction. See What are the possible side effects of BAXDELA), or your healthcare provider tells you to stop.Unless you are experiencing any of the harmful side effects listed in this medication guide, take your BAXDELA, as your healthcare provider tells you to take it, to help lower the chance that bacteria will become resistant to BAXDELA. If this happens, BAXDELA and other antibacterial medicines may not work in the future.. tendon problems, nerve problems, or central nervous system problems (see What is the most important information should know about BAXDELA).. serious allergic reaction. See What are the possible side effects of BAXDELA), or your healthcare provider tells you to stop.. If you miss dose of BAXDELA, take it as soon as you remember up to hours before your next dose. If you have less than hours before your next dose, wait to take your next dose at your regular time. Do not take more BAXDELA to make up for the missed dose.. If you take too much BAXDELA, call your healthcare provider or get medical help immediately.. See What is the most important information should know about BAXDELA Serious allergic reactions. Serious allergic reactions, including death, can happen in people taking fluoroquinolones, including BAXDELA, even after only dose. Stop taking BAXDELA and get emergency medical help right away if you get any of the following symptoms of severe allergic reaction:. hives. swelling of the lips, tongue, face. rapid heartbeat. skin rash. trouble breathing or swallowing. throat tightness, hoarseness. faint. Clostridium difficile-associated diarrhea (CDAD). CDAD is an infection of your intestines (bowels) that can happen with many antibacterial medicines, including BAXDELA, and may cause mild diarrhea to life-threatening swelling of your intestines (colitis). Call your healthcare provider right away if you get stomach cramps, fever, watery diarrhea, diarrhea that does not go away, or bloody stools. CDAD can happen or more months after you have finished your antibacterial medicine.. Aortic aneurysm and dissection. Tell your healthcare provider if you have ever been told that you have an aortic aneurysm, swelling of the large artery that carries blood from the heart to the body. Get emergency medical help right away if you have sudden chest, stomach or back pain.. Changes in blood sugar. People who take fluoroquinolone medicines with oral anti-diabetes medicines or with insulin can get low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia). Follow your healthcare providers instructions for how often to check your blood sugar. If you have diabetes and you get low blood sugar while taking BAXDELA, stop taking BAXDELA and call your healthcare provider right away. Your antibiotic medicine may need to be changed.. nausea. diarrhea. headache. changes in liver tests. vomiting. Store BAXDELA Tablets at room temperature between 68F to 77F (20C to 25C).. Keep BAXDELA away from moisture (humidity).. BAXDELA Tablets: 450 mgActive ingredient: 450 mg delafloxacin (equivalent to 649 mg delafloxacin meglumine) Inactive ingredients: Citric acid, Crospovidone, Magnesium stearate, Microcrystalline Cellulose, Povidone, Sodium bicarbonate, and Sodium phosphate monobasic, monohydrate.. BAXDELA for Injection: 300 mgActive ingredient: delafloxacin Inactive ingredients: Meglumine, beta-cyclodextrin sulfobutyl ether, and EDTA. Sodium hydroxide and/or hydrochloric acid may have been used to adjust the pH.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Renal Impairment: Closely monitor serum creatinine levels in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) receiving intravenous delafloxacin. If serum creatinine level increases occur, consider changing to oral delafloxacin. Discontinue BAXDELA if eGFR decreases to 15 mL/min/1.73 m2 (8.6).. 8.1 Pregnancy. Risk SummaryThe limited available data with BAXDELA use in pregnant women are insufficient to inform drug-associated risk of major birth defects and miscarriages. When delafloxacin (as the N-methyl glucamine salt) was administered orally to rats during the period of organogenesis, no malformations or fetal death were observed at up to times the estimated clinical exposure based on AUC. When rats were dosed intravenously in late pregnancy and through lactation, there were no adverse effects on offspring at exposures approximating the clinical intravenous (IV) exposure based on AUC [see Data]. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal DataIn embryo-fetal studies, oral administration of delafloxacin to pregnant rats during the period of major organogenesis resulted in maternal toxicity and reduced fetal body weights at the highest dose (1600 mg/kg/day) and fetal ossification delays at all doses. No malformations were reported up to the highest dose tested (approximately times the estimated human plasma exposure based on AUC). The lowest dose, 200 mg/kg/day (approximately 2.5 times the estimated human plasma exposure based on AUC), was still toxic to the fetus, based on ossification delays. In rabbits, species known to be extremely sensitive to maternal toxicity of antibacterial drugs, no embryo-fetal developmental toxicity was observed up to the highest dose which induced maternal toxicity (1.6 mg/kg/day, or approximately 0.01 times the estimated human plasma exposure based on AUC). In pre-postnatal study in rats of IV administered delafloxacin, dams at the highest dose tested (120 mg/kg/day) exhibited slightly lower body weights and slightly longer gestation length than control animals. Exposure at that dose was estimated to be approximately times human plasma exposure based on AUC, as determined in separate shorter term study at an earlier stage of pregnancy. Effects on pups at that dose included increased mortality during lactation, small stature, and lower body weights, but no changes in learning and memory, sensory function, locomotor activity, developmental landmarks, or reproductive performance were reported. The No Adverse Effect Level (NOAEL) for maternal toxicity pup development in that study was 60 mg/kg/day (approximately 580 mg/day IV for 60 kg patient, or just below the clinical IV dose).. 8.2 Lactation. Risk SummaryThere are no data available on the presence of delafloxacin in human milk, the effects on the breast-fed infant, or the effects on milk production. Delafloxacin is excreted in the breast milk of rats [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for BAXDELA and any potential adverse effects on the breast-fed child from BAXDELA or from the underlying maternal condition.. DataAfter single oral dose of 20 mg/kg (approximately 194 mg for 60 kg patient) 14C-labeled delafloxacin on post-natal day 11, the radioactivity was transferred into the milk of lactating rats. The mean milk/plasma radioactivity concentration ratios in dams at and hours after dosing were 8.5 and 4.0, respectively, and essentially background by 24 hours. The rate of elimination of radioactivity was similar in milk and plasma. Absorption of radioactive drug by rat pups following nursing was observed.. 8.4 Pediatric Use. Use in patients under 18 years of age is not recommended. Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Pediatric studies were not conducted because risk-benefit considerations do not support the use of BAXDELA for ABSSSI in this population. Fluoroquinolones cause arthropathy in juvenile animals.. 8.5 Geriatric Use. Of the 754 adult ABSSSI patients treated with BAXDELA, in Trials and 2, 111/754 (15%) were 65 years of age and older. The clinical response rates at 48-72 hours for the BAXDELA-treated and comparator-treated patients were 84/111 (75.7%) and 72/101 (71.3%), respectively in ABSSSI patients aged 65 years and older compared to patients aged less than 65 years of age 529/643 (82.3%) and 538/655 (82.1%), respectively. In the safety population, of the 741 adult patients treated with BAXDELA, 18/110 (16.4%) patients aged 65 years and older and 146/631 (23.1%) patients aged less than 65 years had at least one adverse drug reaction.Of the 431 adult CABP patients treated with BAXDELA, in Trial 3, 203/431 (47.1%) were 65 years of age and older, while 85/431 (19.7%) were 75 and over. The clinical response rates at 72-120 hours for the BAXDELA-treated and moxifloxacin-treated patients were 177/203 (87.2%) and 161/179 (89.9%), respectively in the CABP patients aged 65 years and older compared to patients aged less than 65 years old (206/228 (90.4%) and 220/249 (88.4%), respectively). In the safety population, of the 429 adult patients treated with BAXDELA, 10/84 (11.9%) patients aged 75 and older, 27/202 (13.4%) patients aged 65 years and older and 38/227 (16.7%) patients aged less than 65 years old had at least one adverse drug reaction.Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with fluoroquinolone. 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 BAXDELA to elderly patients especially those on corticosteroids. Patients should be informed of this potential adverse reaction and advised to discontinue BAXDELA and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see Warnings and Precautions (5.1)].Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients [see Warnings and Precautions (5.8)].In elderly subjects (>= 65 years), the mean Cmax and AUC of delafloxacin were about 35% higher compared with young adults, which is not considered clinically significant [see Clinical Pharmacology (12.3)].. 8.6 Hepatic Impairment. No dosage adjustment is necessary for BAXDELA in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment. No dosage adjustment of BAXDELA is necessary in patients with mild (eGFR 60-89 mL/min/1.73 m2) or moderate (eGFR 30-59 mL/min/1.73 m2) renal impairment. The dose of BAXDELA intravenous IV infusion in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) should be decreased to 200 mg intravenously every 12 hours; the dose of oral BAXDELA in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) is 450 mg orally every 12 hours. BAXDELA is not recommended in patients with End Stage Renal Disease [ESRD] (eGFR of 15 mL/min/1.73 m2) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].In patients with severe renal impairment or ESRD (eGFR of 15 mL/min/1.73 m2), accumulation of the intravenous vehicle, sulfobutylether--cyclodextrin (SBECD) occurs. Serum creatinine levels should be closely monitored in patients with severe renal impairment receiving intravenous BAXDELA. If serum creatinine level increases occur, consideration should be given to changing to oral BAXDELA. If eGFR decreases to 15 mL/min/1.73 m2, BAXDELA should be discontinued.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity Reactions: May occur after first or subsequent doses of BAXDELA. Discontinue BAXDELA at the first sign of skin rash or any other sign of hypersensitivity. (5.6)Clostridium difficile-associated diarrhea: Evaluate if diarrhea occurs. (5.7). Hypersensitivity Reactions: May occur after first or subsequent doses of BAXDELA. Discontinue BAXDELA at the first sign of skin rash or any other sign of hypersensitivity. (5.6). Clostridium difficile-associated diarrhea: Evaluate if diarrhea occurs. (5.7). 5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy and Central Nervous System Effects. Fluoroquinolones 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 could occur within hours to weeks after starting fluoroquinolone. Patients of any age or without pre-existing risk factors have experienced these adverse reactions [see Warnings and Precautions (5.2, 5.3 and 5.4)].Discontinue BAXDELA immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including BAXDELA, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.. 5.2 Tendinitis and Tendon Rupture. Fluoroquinolones 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 of starting fluoroquinolone, or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally.This risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over age 60 years of age, in patients taking corticosteroid drugs, and, in patients with kidney, heart, and lung transplant. Other factors 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 BAXDELA immediately if the patient experiences pain, swelling, inflammation or rupture of tendon. Advise patients, at the first sign of tendon pain, swelling, or inflammation, to stop taking BAXDELA, to avoid exercise and use of the affected area, and to promptly contact their healthcare provider about changing to non-quinolone antimicrobial drug. Avoid BAXDELA in patients who have history of tendon disorders or have experienced tendinitis or tendon rupture. 5.3 Peripheral Neuropathy. Fluoroquinolones 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 BAXDELA. Symptoms may occur soon after initiation of fluoroquinolones and may be irreversible in some patients [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Discontinue BAXDELA immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including BAXDELA in patients who have previously experienced peripheral neuropathy [see Adverse Reactions (6.1)].. 5.4 Central Nervous System Effects. Psychiatric Adverse ReactionsFluoroquinolones, including BAXDELA, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychosis; hallucinations, or paranoia; depression, or suicidal thoughts or acts; delirium, disorientation, confusion, or disturbances in attention; anxiety, agitation, or nervousness; insomnia or nightmares; memory impairment. These adverse reactions may occur following the first dose. If these reactions occur in patients receiving BAXDELA, discontinue BAXDELA immediately and institute appropriate measures.. Central Nervous System Adverse ReactionsFluoroquinolones have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri), dizziness, and tremors. As with all fluoroquinolones, use BAXDELA when the benefits of treatment exceed the risks in patients with known or suspected CNS disorders (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold. If these reactions occur in patients receiving BAXDELA, discontinue BAXDELA immediately and institute appropriate measures.. 5.5 Exacerbation of Myasthenia Gravis. Fluoroquinolones have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post-marketing serious adverse reactions, including death and requirement for ventilator support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid BAXDELA in patients with known history of myasthenia gravis [see Patient Counseling Information (17)].. 5.6 Hypersensitivity Reactions. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Hypersensitivity reactions have been reported in patients receiving BAXDELA. These reactions may occur after first or subsequent doses of BAXDELA [see Adverse Reactions (6.1)]. Discontinue BAXDELA at the first appearance of skin rash or any other sign of hypersensitivity.. 5.7 Clostridium difficile-Associated Diarrhea. Clostridium difficile-associated diarrhea (CDAD) has been reported in users of nearly all systemic antibacterial drugs, including BAXDELA, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon and may permit overgrowth of C. difficile.C. difficile produces toxins 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 antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than months after the administration of antibacterial agents.If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.. 5.8 Risk of Aortic Aneurysm and Dissection. Epidemiologic studies report an increased risk of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients. The cause for the increased risk has not been identified. In patients with known aortic aneurysm or patients who are at greater risk for aortic aneurysms, reserve BAXDELA for use only when there are no alternative antibacterial treatments available.. 5.9 Development of Drug-Resistant Bacteria. Prescribing BAXDELA in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.. 5.10 Blood Glucose Disturbances. Fluoroquinolones have been associated with disturbances of blood glucose, including symptomatic hyperglycemia and hypoglycemia, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. Severe cases of hypoglycemia resulting in coma or death have been reported with other fluoroquinolones. If hypoglycemic reaction occurs in patient being treated with BAXDELA, discontinue BAXDELA and initiate appropriate therapy immediately [see Adverse Reactions (6.1)].