ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are described, or described in greater detail, in other sections: Anaphylaxis/hypersensitivity reactions [see Warnings and Precautions (5.1)]Myopathy and rhabdomyolysis [see Warnings and Precautions (5.2)]Eosinophilic pneumonia [see Warnings and Precautions (5.3)]Drug reaction with eosinophilia and systemic symptoms [see Warnings and Precautions (5.4)] Tubulointerstitial nephritis [see Warnings and Precautions (5.5)]Peripheral neuropathy [see Warnings and Precautions (5.6)]Increased International Normalized Ratio (INR)/prolonged prothrombin time [see Warnings and Precautions (5.11) and Drug Interactions (7.2)] Adult cSSSI Patients: The most common adverse reactions that occurred in >= 2% of adult cSSSI patients receiving daptomycin mg/kg were diarrhea, headache, dizziness, rash, abnormal liver function tests, elevated creatine phosphokinase (CPK),urinary tract infections hypotension, and dyspnea. (6.1)Pediatric cSSSI Patients: The most common adverse reactions that occurred in >=2% of pediatric patients receiving daptomycin were diarrhea, vomiting, abdominal pain, pruritus, pyrexia, elevated CPK, and headache. (6.1) Adult S. aureus bacteremia/endocarditis Patients: The most common adverse reactions that occurred in >=5% of S. aureus bacteremia/endocarditis patients receiving daptomycin mg/kg were sepsis, bacteremia, abdominal pain, chest pain, edema, pharyngolaryngeal pain, pruritus, increased sweating, insomnia, elevated CPK and hypertension.(6.1)Pediatric S. aureus bacteremia Patients: The most common adverse reactions that occurred in >=5% of pediatric patients receiving daptomycin were vomiting and elevated CPK. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact NorthStar RxLLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Adult cSSSI Patients: The most common adverse reactions that occurred in >= 2% of adult cSSSI patients receiving daptomycin mg/kg were diarrhea, headache, dizziness, rash, abnormal liver function tests, elevated creatine phosphokinase (CPK),urinary tract infections hypotension, and dyspnea. (6.1). Pediatric cSSSI Patients: The most common adverse reactions that occurred in >=2% of pediatric patients receiving daptomycin were diarrhea, vomiting, abdominal pain, pruritus, pyrexia, elevated CPK, and headache. (6.1) Adult S. aureus bacteremia/endocarditis Patients: The most common adverse reactions that occurred in >=5% of S. aureus bacteremia/endocarditis patients receiving daptomycin mg/kg were sepsis, bacteremia, abdominal pain, chest pain, edema, pharyngolaryngeal pain, pruritus, increased sweating, insomnia, elevated CPK and hypertension.(6.1). Pediatric S. aureus bacteremia Patients: The most common adverse reactions that occurred in >=5% of pediatric patients receiving daptomycin were vomiting and elevated CPK. (6.1) 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trial Experience in Adult PatientsClinical trials enrolled 1,864 adult patients treated with daptomycin for injection and 1,416 treated with comparatorComplicated Skin and Skin Structure Infection Trials in AdultsIn Phase complicated skin and skin structure infection (cSSSI) trials in adult patients, daptomycin for injection was discontinued in 15/534 (2.8%) patients due to an adverse reaction, while comparator was discontinued in 17/558 (3%) patients. The rates of the most common adverse reactions, organized by body system, observed in adult patients with, cSSSI (receiving mg/kg daptomycin for injection) are displayed in Table 6.Table 6. Incidence of Adverse Reactions that Occurred in >=2% of Adult Patients in the Daptomycin for Injection Treatment Group and >= the Comparator Treatment Group in Phase cSSSI TrialsAdverse ReactionAdult Patients (%)Daptomycin for Injection mg/kg (N=534)Comparator(N=558)Gastrointestinal disordersDiarrhea5.24.3Nervous system disordersHeadache5.45.4Dizziness2.22.0Skin/subcutaneous disordersRash4.33.8Diagnostic investigationsAbnormal liver function tests3.01.6Elevated CPK2.81.8InfectionsUrinary tract infections2.40.5Vascular disordersHypotension2.41.4Respiratory disordersDyspnea2.11.6 Comparator: vancomycin (1 IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; to 12 g/day IV in divided doses). Drug-related adverse reactions (possibly or probably drug-related) that occurred in <1% of adult patients receiving daptomycin for injection in the cSSSI trials are as follows: Body as Whole: fatigue, weakness, rigors, flushing, hypersensitivityBlood/Lymphatic System: leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased International Normalized Ratio (INR)Cardiovascular System: supraventricular arrhythmiaDermatologic System: eczemaDigestive System: abdominal distension, stomatitis, jaundice, increased serum lactate dehydrogenaseMetabolic/Nutritional System: hypomagnesemia, increased serum bicarbonate, electrolyte disturbanceMusculoskeletal System: myalgia, muscle cramps, muscle weakness, arthralgiaNervous System: vertigo, mental status change, paresthesiaSpecial Senses: taste disturbance, eye irritation S. aureus Bacteremia/Endocarditis Trial in AdultsIn the S. aureus bacteremia/endocarditis trial involving adult patients, daptomycin for injection was discontinued in 20/120 (16.7%) patients due to an adverse reaction, while comparator was discontinued in 21/116 (18.1%) patients.Serious Gram-negative infections (including bloodstream infections) were reported in 10/120 (8.3%) daptomycin for injection-treated patients and 0/115 comparator-treated patients. Comparator-treated patients received dual therapy that included initial gentamicin for days. Infections were reported during treatment and during early and late follow-up. Gram-negative infections included cholangitis, alcoholic pancreatitis, sternal osteomyelitis/mediastinitis, bowel infarction, recurrent Crohns disease, recurrent line sepsis, and recurrent urosepsis caused by number of different Gram-negative bacteria. The rates of the most common adverse reactions, organized by System Organ Class (SOC), observed in adult patients with S. aureus bacteremia/endocarditis (receiving mg/kg daptomycin for injection) are displayed in Table 7. Table 7. Incidence of Adverse Reactions that Occurred in >=5% of Adult Patients in the Daptomycin For Injection Treatment Group and >= the Comparator Treatment Group in the S. aureus Bacteremia/Endocarditis TrialAdverse ReactionAdult Patients (%)Daptomycin for Injection mg/kg (N=120)Comparator+ (N=116)Infections and infestationsSepsis NOS6 (5%)3 (3%)Bacteremia6 (5%)0 (0%)Gastrointestinal disordersAbdominal pain NOS7 (6%)4 (3%)General disorders and administration site conditionsChest pain8 (7%)7 (6%)Edema NOS8 (7%)5 (4%)Respiratory, thoracic and mediastinal disordersPharyngolaryngeal pain10 (8%)2 (2%)Skin and subcutaneous tissue disordersPruritus7 (6%)6 (5%)Sweating increased6 (5%)0 (0%)Psychiatric disordersInsomnia11 (9%)8 (7%)InvestigationsBlood creatine phosphokinase increased8 (7%)1 (1%)Vascular disordersHypertension NOS (6%)3 (3%) NOS, not otherwise specified.+ Comparator: vancomycin (1 IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; g IV q4h), each with initial low-dose gentamicin.The following reactions, not included above, were reported as possibly or probably drug-related in the daptomycin for injection-treated group:Blood and Lymphatic System Disorders: eosinophilia, lymphadenopathy, thrombocythemia, thrombocytopeniaCardiac Disorders: atrial fibrillation, atrial flutter, cardiac arrestEar and Labyrinth Disorders: tinnitusEye Disorders: vision blurredGastrointestinal Disorders: dry mouth, epigastric discomfort, gingival pain, hypoesthesia oralInfections and Infestations: candidal infection NOS, vaginal candidiasis, fungemia, oral candidiasis, urinary tract infection fungalInvestigations: blood phosphorous increased, blood alkaline phosphatase increased, INR increased, liver function test abnormal, alanine aminotransferase increased, aspartate aminotransferase increased, prothrombin time prolongedMetabolism and Nutrition Disorders: appetite decreased NOS Musculoskeletal and Connective Tissue Disorders: myalgia Nervous System Disorders: dyskinesia, paresthesia Psychiatric Disorders: hallucination NOSRenal and Urinary Disorders: proteinuria, renal impairment NOSSkin and Subcutaneous Tissue Disorders: pruritus generalized, rash vesicularOther Trials in AdultsIn Phase trials of community-acquired pneumonia (CAP) in adult patients, the death rate and rates of serious cardiorespiratory adverse events were higher in daptomycin for injection-treated patients than in comparator- treated patients. These differences were due to lack of therapeutic effectiveness of daptomycin for injection in the treatment of CAP in patients experiencing these adverse events [see Indications and Usage (1.4)]. Laboratory Changes in AdultsComplicated Skin and Skin Structure Infection Trials in AdultsIn Phase cSSSI trials of adult patients receiving daptomycin for injection at dose of mg/kg, elevations in CPK were reported as clinical adverse events in 15/534 (2.8%) daptomycin for injection-treated patients, compared with 10/558 (1.8%) comparator-treated patients. Of the 534 patients treated with daptomycin for injection, (0.2%) had symptoms of muscle pain or weakness associated with CPK elevations to greater than times the upper limit of normal (ULN). The symptoms resolved within days and CPK returned to normal within to 10 days after treatment was discontinued [see Warnings and Precautions (5.2)]. Table summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI adult trials.Table 8. Incidence of CPK Elevations from Baseline during Therapy in Either the Daptomycin for Injection Treatment Group or the Comparator Treatment Group in Phase cSSSI Adult TrialsChange in CPKAll Adult PatientsAdult Patients with Normal CPK at BaselineDaptomycin for Injection4 mg/kg (N=430)Comparator (N=459)Daptomycin for Injection4 mg/kg(N=374)Comparator (N=392)%n%n%n%nNo Increase90.739091.141891.234191.1357Maximum Value >1x ULN+ 9.3408.9418.8338.935>2x ULN4.9214.8223.7143.112>4x ULN1.461.571.1414>5x ULN1.460.421.1400>10x ULN0.520.210.2100Note: Elevations in CPK observed in adult patients treated with daptomycin for injection or comparator were not clinically or statistically significantly different. Comparator: vancomycin (1 IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; to 12 g/day IV in divided doses).+ ULN (Upper Limit of Normal) is defined as 200 U/L. S. aureus Bacteremia/Endocarditis Trial in AdultsIn the S. aureus bacteremia/endocarditis trial in adult patients, at dose of mg/kg, 11/120 (9.2%) daptomycin for injection- treated patients, including two patients with baseline CPK levels >500 U/L, had CPK elevations to levels >500 U/L, compared with 1/116 (0.9%) comparator-treated patients. Of the 11 daptomycin for injection-treated patients, had prior or concomitant treatment with an HMG-CoA reductase inhibitor. Three of these 11 daptomycin for injection-treated patients discontinued therapy due to CPK elevation, while the one comparator-treated patient did not discontinue therapy [see Warnings and Precautions (5.2)].Clinical Trial Experience in Pediatric Patients Complicated Skin and Skin Structure Infection Trial in Pediatric Patients The safety of daptomycin was evaluated in one clinical trial (in cSSSI), which included 256 pediatric patients (1 to 17 years of age) treated with intravenous daptomycin and 133 patients treated with comparator agents. Patients were given age-dependent doses once daily for treatment period of up to 14 days (median treatment period was days). The doses given by age group were as follows: 10mg/kg for to 2 years, mg/kg for to years, 7mg/kg for to 11 years and mg/kg for 12 to 17 years of age [see Clinical Studies (14)]. Patients treated with daptomycin were (51%) male, (49%) female and (46%) Caucasian and (32%) Asian. Adverse Reactions Leading to Discontinuation In the cSSSI study, daptomycin was discontinued in 7/256 (2.7%) patients due to an adverse reaction, while comparator was discontinued in 7/133 (5.3%) patients. Most Common Adverse Reactions The rates of the most common adverse reactions, organized by body system, observed in these pediatric patients with cSSSI are displayed in Table 9.Table 9: Adverse Reactions that Occurred in >=2% of Pediatric Patients in the Daptomycin Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the cSSSI Pediatric TrialAdverse Reaction Daptomycin(N 256)Comparator(N 133)n (%)n (%)Gastrointestinal disordersDiarrhea 18 (7.0) (5.3) Vomiting (2.7) (0.8) Abdominal Pain (2.0) Skin and subcutaneous tissue disordersPruritus (3.1) (1.5) General disorders and administration site conditionsPyrexia 10 (3.9) (3.0) InvestigationsBlood CPK increased 14 (5.5) (5.3) Nervous system disordersHeadache (2.7) (2.3) Comparators included intravenous therapy with either vancomycin, clindamycin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin) The safety profile in the clinical trial of cSSSI pediatric patients was similar to that observed in the cSSSI adult patients. S. aureus Bacteremia Trial in Pediatric Patients The safety of daptomycin was evaluated in one clinical trial (in S. aureus bacteremia), which treated 55 pediatric patients with intravenous daptomycin and 26 patients with comparator agents. Patients were given age-dependent doses once daily for treatment period of up to 42 days (mean duration of IV treatment was 12 days). The doses by age group were as follows: 12 mg/kg for to <6 years, mg/kg for to 11 years and mg/kg for 12 to 17 years of age [see Clinical Studies (14)]. Patients treated with daptomycin were (69%) male and (31%) female. No patients to <2 years of age were enrolled. Adverse Reactions Leading to Discontinuation In the bacteremia study, daptomycin was discontinued in 3/55 (5.5%) patients due to an adverse reaction, while comparator was discontinued in 2/26 (7.7%) patients. Most Common Adverse Reactions The rates of the most common adverse reactions, organized by body system, observed in these pediatric patients with bacteremia are displayed in Table 10.Table 10: Incidence of Adverse Reactions that Occurred in >=5% of Pediatric Patients in the Daptomycin Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the Pediatric Bacteremia TrialAdverse Reaction Daptomycin(N 55)Comparator(N 26)n (%)n (%)Gastrointestinal disordersVomiting (10.9) (7.7) InvestigationsBlood CPK increased (7.3) Comparators included intravenous therapy with either vancomycin, cefazolin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin). 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of daptomycin for injection. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and lymphatic system disorders: anemia, thrombocytopenia General and administration site conditions: pyrexiaImmune System Disorders: anaphylaxis; hypersensitivity reactions, including angioedema, pruritus, hives, shortness of breath, difficulty swallowing, truncal, erythema, and pulmonary eosinophilia [see Contraindications (4), Warnings and Precautions (5.1)] Infections and Infestations: Clostridioides difficile-associated diarrhea [see Warnings and Precautions (5.8)] Laboratory Investigations: platelet count decreasedMusculoskeletal Disorders: myoglobin increased; rhabdomyolysis (some reports involved patients treated concurrently with daptomycin for injection and HMG-CoA reductase inhibitors) [see Warnings and Precautions (5.2), Drug Interactions (7.1), and Clinical Pharmacology (12.3)] Respiratory, Thoracic, and Mediastinal Disorders: cough, eosinophilic pneumonia, organizing pneumonia. [see Warnings and Precautions (5.3)] Nervous System Disorders: peripheral neuropathy [see Warnings and Precautions (5.6)] Skin and Subcutaneous Tissue Disorders: serious skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome and vesiculobullous rash (with or without mucous membrane involvement), acute generalized exanthematous pustulosis [see Warnings and Precautions (5.4)] Gastrointestinal Disorders: nausea, vomiting Renal and urinary disorders: acute kidney injury, renal insufficiency, renal failure and tubulointerstitial nephritis (TIN) [see Warnings and Precautions (5.5)] Special Senses: visual disturbances.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Adult AnimalsIn animals, daptomycin administration has been associated with effects on skeletal muscle. However, there were no changes in cardiac or smooth muscle. Skeletal muscle effects were characterized by microscopic degenerative/regenerative changes and variable elevations in creatine phosphokinase (CPK). No fibrosis or rhabdomyolysis was evident in repeat-dose studies up to the highest doses tested in rats (150 mg/kg/day) and dogs (100 mg/kg/day). The degree of skeletal myopathy showed no increase when treatment was extended from month to up to months. Severity was dose-dependent. All muscle effects, including microscopic changes, were fully reversible within 30 days following the cessation of dosing.In adult animals, effects on peripheral nerve (characterized by axonal degeneration and frequently accompanied by significant losses of patellar reflex, gag reflex, and pain perception) were observed at daptomycin doses higher than those associated with skeletal myopathy. Deficits in the dogs patellar reflexes were seen within weeks after the start of treatment at 40 mg/kg/day (9 times the human Cmax at the mg/kg/day dose), with some clinical improvement noted within weeks after the cessation of dosing. However, at 75 mg/kg/day for month, of dogs failed to regain full patellar reflex responses within 3-month recovery period. In separate study in dogs receiving doses of 75 and 100 mg/kg/day for weeks, minimal residual histological changes were noted at months after the cessation of dosing. However, recovery of peripheral nerve function was evident. Tissue distribution studies in rats showed that daptomycin is retained in the kidney but appears to penetrate the blood-brain barrier only minimally following single and multiple doses.Juvenile Animals Target organs of daptomycin-related effects in 7-week-old juvenile dogs were skeletal muscle and nerve, the same target organs as in adult dogs. In juvenile dogs, nerve effects were noted at lower daptomycin blood concentrations than in adult dogs following 28 days of dosing. In contrast to adult dogs, juvenile dogs also showed evidence of effects in nerves of the spinal cord as well as peripheral nerves after 28 days of dosing. No nerve effects were noted in juvenile dogs following 14 days of dosing at doses up to 75 mg/kg/day. Administration of daptomycin to 7-week-old juvenile dogs for 28 days at doses of 50 mg/kg/day produced minimal degenerative effects on the peripheral nerve and spinal cord in several animals, with no corresponding clinical signs. dose of 150 mg/kg/day for 28 days produced minimal degeneration in the peripheral nerve and spinal cord as well as minimal to mild degeneration of the skeletal muscle in majority of animals, accompanied by slight to severe muscle weakness evident in most dogs. Following 28-day recovery phase, microscopic examination revealed recovery of the skeletal muscle and the ulnar nerve effects, but nerve degeneration in the sciatic nerve and spinal cord was still observed in all 150 mg/kg/day dogs. Following once-daily administration of daptomycin to juvenile dogs for 28 days, microscopic effects in nerve tissue were noted at Cmax value of 417 mcg/mL, which is approximately 3-fold less than the Cmax value associated with nerve effects in adult dogs treated once daily with daptomycin for 28 days (1308 mcg/mL). Neonatal AnimalsNeonatal dogs (4 to 31 days old) were more sensitive to daptomycin-related adverse nervous system and/or muscular system effects than either juvenile or adult dogs. In neonatal dogs, adverse nervous system and/or muscular system effects were associated with Cmax value approximately 3-fold less than the Cmax in juvenile dogs, and 9-fold less than the Cmax in adult dogs following 28 days of dosing. At dose of 25 mg/kg/day with associated Cmax and AUCinf values of 147 mcg/mL and 717 mcgoh/mL, respectively (1.6 and 1-fold the adult human Cmax and AUC, respectively, at the mg/kg/day dose), mild clinical signs of twitching and one incidence of muscle rigidity were observed with no corresponding effect on body weight. These effects were found to be reversible within 28 days after treatment had stopped.At higher dose levels of 50 and 75 mg/kg/day with associated Cmax and AUCinf values of >=321 mcg/mL and >=1470 mcgoh/mL, respectively, marked clinical signs of twitching, muscle rigidity in the limbs, and impaired use of limbs were observed. Resulting decreases in body weights and overall body condition at doses >=50 mg/kg/day necessitated early discontinuation by postnatal day (PND) 19.Histopathological assessment did not reveal any daptomycin-related changes in the peripheral and central nervous system tissue, as well as in the skeletal muscle or other tissues assessed, at any dose level.No adverse effects were observed in the dogs that received daptomycin at 10 mg/kg/day, the NOAEL, with associated Cmax and AUCinf values of 62 mcg/mL and 247 mcgoh/mL, respectively (or 0.6 and 0.4-fold the adult human Cmax and AUC, respectively at the mg/kg dose).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Daptomycin is an antibacterial drug [see Clinical Pharmacology (12.4)].. 12.2 Pharmacodynamics. Based on animal models of infection, the antimicrobial activity of daptomycin appears to correlate with the AUC/MIC (area under the concentration-time curve/minimum inhibitory concentration) ratio for certain pathogens, including S. aureus. The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with daptomycin for injection.. 12.3 Pharmacokinetics. Daptomycin for Injection Administered over 30-Minute Period in AdultsThe mean and standard deviation (SD) pharmacokinetic parameters of daptomycin at steady- state following intravenous (IV) administration of daptomycin for injection over 30-minute period at to 12 mg/kg q24h to healthy young adults are summarized in Table 11.Table 11. Mean (SD) Daptomycin Pharmacokinetic Parameters in Healthy Adult Volunteers at Steady-StateDose+ (mg/kg)Pharmacokinetic ParametersAUC0-24 (mcgoh/mL) t1/2 (h) Vss (L/kg) CLT (mL/h/kg) Cmax (mcg/mL) (N=6) 494 (75) 8.1 (1.0) 0.096 (0.009) 8.3 (1.3) 57.8 (3.0) (N=6) 632 (78) 7.9 (1.0) 0.101 (0.007) 9.1 (1.5) 93.9 (6.0) (N=6) 858 (213) 8.3 (2.2) 0.101 (0.013) (3.0) 123.3 (16.0)10 (N=9) 1039 (178) 7.9 (0.6) 0.098 (0.017) 8.8 (2.2) 141.1 (24.0)12 (N=9) 1277 (253) 7.7 (1.1) 0.097 (0.018) (2.8) 183.7 (25.0) Daptomycin for injection was administered by IV infusion over 30-minute period.+ Doses of daptomycin for injection in excess of mg/kg have not been approved. AUC0-24, area under the concentration-time curve from to 24 hours; t1/2, elimination half-life; Vss, volume of distribution at steady-state; CLT, total plasma clearance; Cmax, maximum plasma concentration.Daptomycin pharmacokinetics were generally linear and time-independent at daptomycin for injection doses of to 12 mg/kg q24h administered by IV infusion over 30-minute period for up to 14 days. Steady-state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following the administration of 4, 6, 8, 10, and 12 mg/kg q24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9), and 13.7 (5.2) mcg/mL, respectively.Daptomycin for Injection Administered over 2-Minute Period in AdultsFollowing IV administration of daptomycin for injection over 2-minute period to healthy adult volunteers at doses of mg/kg (N=8) and mg/kg (N=12), the mean (SD) steady-state systemic exposure (AUC) values were 475 (71) and 701 (82) mcgoh/mL, respectively. Values for maximum plasma concentration (Cmax) at the end of the 2-minute period could not be determined adequately in this study. However, using pharmacokinetic parameters from 14 healthy adult volunteers who received single dose of daptomycin for injection mg/kg IV administered over 30-minute period in separate study, steady-state Cmax values were simulated for daptomycin for injection and mg/kg IV administered over 2-minute period. The simulated mean (SD) steady-state Cmax values were 77.7 (8.1) and 116.6 (12.2) mcg/mL, respectively.DistributionDaptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in concentration-independent manner. The overall mean binding ranges from 90 to 93%.In clinical studies, mean serum protein binding in adult subjects with creatinine clearance (CLCR) >=30 mL/min was comparable to that observed in healthy adult subjects with normal renal function. However, there was trend toward decreasing serum protein binding among subjects with CLCR <30 mL/min (88%), including those receiving hemodialysis (86%) and continuous ambulatory peritoneal dialysis (CAPD) (84%). The protein binding of daptomycin in adult subjects with moderate hepatic impairment (Child-Pugh Class B) was similar to that in healthy adult subjects.The volume of distribution at steady-state (Vss) of daptomycin in healthy adult subjects was approximately 0.1 L/kg and was independent of dose.MetabolismIn in vitro studies, daptomycin was not metabolized by human liver microsomes.In healthy adults after infusion of radiolabeled 14C-daptomycin, the plasma total radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference between total radioactive concentrations and microbiologically active concentrations. In separate study, no metabolites were observed in plasma on Day following the administration of daptomycin for injection at mg/kg to adult subjects. Minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.ExcretionDaptomycin is excreted primarily by the kidneys. In mass balance study of healthy adult subjects using radiolabeled daptomycin, approximately 78% of the administered dose was recovered from urine based on total radioactivity (approximately 52% of the dose based on microbiologically active concentrations), and 5.7% of the administered dose was recovered from feces (collected for up to days) based on total radioactivity.Specific PopulationsRenal ImpairmentPopulation-derived pharmacokinetic parameters were determined for infected adult patients (complicated skin and skin structure infections [cSSSI] and S. aureus bacteremia) and noninfected adult subjects with various degrees of renal function (Table 12). Total plasma clearance (CLT), elimination half-life (t1/2), and volume of distribution at steady-state (Vss) in patients with cSSSI were similar to those in patients with S. aureus bacteremia. Following administration of daptomycin for injection mg/kg q24h by IV infusion over 30-minute period, the mean CLT was 9%, 22%, and 46% lower among subjects and patients with mild (CLCR 50 to 80 mL/min), moderate (CLCR 30-<50 mL/min), and severe (CLCR <30 mL/min) renal impairment, respectively, than in those with normal renal function (CLCR >80 mL/min). The mean steady-state systemic exposure (AUC), t1/2, and Vss increased with decreasing renal function, although the mean AUC for patients with CLCR 30 to 80 mL/min was not markedly different from the mean AUC for patients with normal renal function. The mean AUC for patients with CLCR <30 mL/min and for patients on dialysis (CAPD and hemodialysis dosed post-dialysis) was approximately and times higher, respectively, than for patients with normal renal function. The mean Cmax ranged from 60 to 70 mcg/mL in patients with CLCR >=30 mL/min, while the mean Cmax for patients with CLCR <30 mL/min ranged from 41 to 58 mcg/mL. After administration of daptomycin for injection mg/kg q24h by IV infusion over 30-minute period, the mean Cmax ranged from 80 to 114 mcg/mL in patients with mild to moderate renal impairment and was similar to that of patients with normal renal function.Table 12. Mean (SD) Daptomycin Population Pharmacokinetic Parameters Following Infusion of Daptomycin for Injection mg/kg or mg/kg to Infected Adult Patients and Noninfected Adult Subjects with Various Degrees of Renal FunctionRenal FunctionPharmacokinetic Parameterst1/2+(h)4 mg/kgVss+(L/kg)4 mg/kgCLT+(mL/h/kg)4 mg/kgAUC0-+(mcgoh/mL)4 mg/kgAUCss (mcgoh/mL)6 mg/kgCmin, ss (mcg/mL)6 mg/kg Normal (CLCR >80 mL/min) 9.39 (4.74) N=165 0.13 (0.05) N=165 10.9 (4.0) N=165 417 (155) N=165 545 (296) N=62 6.9 (3.5) N=61 Mild Renal Impairment (CLCR 50 to 80 mL/min) 10.75 (8.36) N=64 0.12 (0.05) N=64 9.9 (4.0) N=64 466 (177) N=64 637 (215) N=29 12.4 (5.6) N=29 Moderate Renal Impairment (CLCR 30 <50 mL/min) 14.70 (10.50) N=24 0.15 (0.06) N=24 8.5 (3.4) N=24 560 (258) N=24 868 (349) N=15 19 (9) N=14 Severe Renal Impairment (CLCR <30 mL/min) 27.83 (14.85) N=8 0.20 (0.15) N=8 5.9 (3.9) N=8 925 (467) N=8 1050 (892) N=2 24.4 (21.4) N=2 Hemodialysis 30.51 (6.51) N=16 0.16 (0.04) N=16 3.9 (2.1) N=16 1193 (399) N=16 NA NA CAPD 27.56 (4.53) N=5 0.11 (0.02) N=5 2.9 (0.4) N=5 1409 (238) N=5 NA NA Note: Daptomycin for injection was administered over 30-minute period. CLCR, creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; CAPD, continuous ambulatory peritoneal dialysis; AUC0-, area under the concentration-time curve extrapolated to infinity; AUCss, area under the concentration-time curve calculated over the 24-hour dosing interval at steady-state; Cmin,ss, trough concentration at steady-state; NULL, not applicable. Parameters obtained following single dose from patients with complicated skin and skin structure infections and healthy subjects. Parameters obtained at steady-state from patients with S.aureus bacteremia. Because renal excretion is the primary route of elimination, adjustment of daptomycin for injection dosage interval is necessary in adult patients with severe renal impairment (CLCR <30 mL/min) [see Dosage and Administration (2.4)].Hepatic ImpairmentThe pharmacokinetics of daptomycin were evaluated in 10 adult subjects with moderate hepatic impairment (Child-Pugh Class B) and compared with those in healthy adult volunteers (N=9) matched for gender, age, and weight. The pharmacokinetics of daptomycin were not altered in subjects with moderate hepatic impairment. No dosage adjustment is warranted when daptomycin for injection is administered to patients with mild to moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh Class C) have not been evaluated.GenderNo clinically significant gender-related differences in daptomycin pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when daptomycin for injection is administered. GeriatricThe pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects (>=75 years of age) and 11 healthy young adult controls (18 to 30 years of age). Following administration of single mg/kg dose of daptomycin for injection by IV infusion over 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0-was approximately 58% higher in elderly subjects than in healthy young adult subjects. There were no differences in Cmax [see Use in Specific Populations (8.5)].ObesityThe pharmacokinetics of daptomycin were evaluated in moderately obese (Body Mass Index [BMI] 25 to 39.9 kg/m2) and extremely obese (BMI >=40 kg/m2) adult subjects and controls matched for age, gender, and renal function. Following administration of daptomycin for injection by IV infusion over 30-minute period as single mg/kg dose based on total body weight, the total plasma clearance of daptomycin normalized to total body weight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects than in nonobese controls. The AUC0- of daptomycin was approximately 30% higher in moderately obese subjects and 31% higher in extremely obese subjects than in nonobese controls. The differences were most likely due to differences in the renal clearance of daptomycin. No adjustment of daptomycin for injection dosage is warranted in obese patients. Pediatric The pharmacokinetics of daptomycin in pediatric subjects was evaluated in single-dose pharmacokinetic studies. In general, body weight-normalized total body clearance in pediatric patients was higher than in adults and increased with decrease of age, whereas elimination half-life tends to decrease with decrease of age. Body weight-normalized total body clearance and elimination half-life of daptomycin in children to years of age were similar at different doses. study was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in pediatric patients (1 to 17 years old, inclusive) with cSSSI caused by Gram-positive pathogens. Patients were enrolled into age groups [see Clinical Studies (14.1)], and intravenous daptomycin doses of to 10 mg/kg once daily were administered. Following administration of multiple doses, daptomycin exposure (AUCss and Cmax,ss) was similar across different age groups after dose adjustment based on body weight and age (Table 13). Table 13: Mean (SD) Daptomycin Population Pharmacokinetic Parameters in cSSSI Pediatric PatientsAgePharmacokinetic ParametersDose (mg/kg) Infusion Duration (min) AUCss (mcgoh/mL) t1/2 (h) Vss (mL) CLT (mL/h/kg) Cmax,ss (mcg/mL) 12 to 17 years (N=6) 30 434 (67.9) 7.1 (0.9) 8200 (3250) 11.8 (2.15) 76.4 (6.75) to 11 years (N=2) 30 543 6.8 4470 13.2 92.4 to years (N=7) 60 452 (93.1) 4.6 (0.8) 2750 (832) 20.8 (4.29) 90.3 (14.0) to less than years (N=27) 10 60 462 (138) 4.8 (0.6) 1670 (446) 23.1 (5.43) 81.6 (20.7) AUCss, area under the concentration-time curve at steady state; CLT, clearance normalized to body weight; Vss, volume of distribution at steady state; 1/2 terminal half-life Mean is calculated from N=2 study was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in pediatric patients with S. aureus bacteremia. Patients were enrolled into age groups [see Clinical Studies (14.2)], and intravenous doses of to 12 mg/kg once daily were administered. Following administration of multiple doses, daptomycin exposure (AUCss and Cmax,ss) was similar across different age groups after dose adjustment based on body weight and age (Table 14). Table 14: Mean (SD) of Daptomycin Pharmacokinetics in Bacteremia Pediatric PatientsAge Pharmacokinetic Parameters Dose (mg/kg) Infusion Duration (min) AUCss (mcgoh/mL) t1/2 (h) Vss (mL) CLT (mL/h/kg) Cmax,ss (mcg/mL) 12 to 17 years(N=13)7 30 656 (334) 7.5 (2.3) 6420 (1980)12.4 (3.9) 104 (35.5) to 11 years(N=19)9 30 579 (116) 6.0 (0.8) 4510 (1470)15.9 (2.8) 104 (14.5) to years(N=19)12 60 620 (109) 5.1 (0.6) 2200 (570) 19.9 (3.4) 106 (12.8) AUCss, area under the concentration-time curve at steady state; CLT, clearance normalized to body weight; Vss, volume of distribution at steady state; 1/2 terminal half-life No patients to <2 years of age were enrolled in the study. Simulation using population pharmacokinetic model demonstrated that the AUCss of daptomycin in pediatric patients to <2 years of age receiving 12 mg/kg once daily would be comparable to that in adult patients receiving mg/kg once daily.Drug-Drug InteractionsIn Vitro Studies In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the P450 system. AztreonamIn study in which 15 healthy adult subjects received single dose of daptomycin for injection mg/kg IV and combination dose of daptomycin for injection mg/kg IV and aztreonam g IV, administered over 30-minute period, the Cmax and AUC0- of daptomycin were not significantly altered by aztreonam. TobramycinIn study in which healthy adult males received single dose of daptomycin for injection mg/kg IV, tobramycin mg/kg IV, and both in combination, administered over 30-minute period, the mean Cmax and AUC0- of daptomycin were 12.7% and 8.7% higher, respectively, when daptomycin for injection was coadministered with tobramycin. The mean Cmax and AUC0- of tobramycin were 10.7% and 6.6% lower, respectively, when tobramycin was coadministered with daptomycin for injection. These differences were not statistically significant. The interaction between daptomycin and tobramycin with clinical dose of daptomycin for injection is unknown.WarfarinIn 16 healthy adult subjects, administration of daptomycin for injection mg/kg q24h by IV infusion over 30-minute period for days, with coadministration of single oral dose of warfarin (25 mg) on the 5th day, had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR (International Normalized Ratio). SimvastatinIn 20 healthy adult subjects on stable daily dose of simvastatin 40 mg, administration of daptomycin for injection mg/kg q24h by IV infusion over 30-minute period for 14 days (N=10) had no effect on plasma trough concentrations of simvastatin and was not associated with higher incidence of adverse events, including skeletal myopathy, than in subjects receiving placebo once daily (N=10) [see Warnings and Precautions (5.2) and Drug Interactions (7.1)]. ProbenecidConcomitant administration of probenecid (500 mg times daily) and single dose of daptomycin for injection mg/kg by IV infusion over 30-minute period in adults did not significantly alter the Cmax or AUC0- of daptomycin.. 12.4 Microbiology. Daptomycin belongs to the cyclic lipopeptide class of antibacterials. Daptomycin has clinical utility in the treatment of infections caused by aerobic, Gram-positive bacteria. The in vitro spectrum of activity of daptomycin encompasses most clinically relevant Gram-positive pathogenic bacteria. Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive bacteria in vitro. This has been demonstrated both by time-kill curves and by MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. Daptomycin maintained bactericidal activity in vitro against stationary phase S. aureus in simulated endocardial vegetations. The clinical significance of this is not known.Mechanism of Action Daptomycin binds to bacterial cell membranes and causes rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of DNA, RNA, and protein synthesis, which results in bacterial cell death. ResistanceThe mechanism(s) of daptomycin resistance is not fully understood. Currently, there are no known transferable elements that confer resistance to daptomycin. Interactions with Other Antibacterials In vitro studies have investigated daptomycin interactions with other antibacterials. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, -lactam antibacterials, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates). Complicated Skin and Skin Structure Infection (cSSSI) Trials in AdultsThe emergence of daptomycin non-susceptible isolates occurred in infected patients across the set of Phase and pivotal Phase clinical trials of cSSSI in adult patients. In one case, non-susceptible S. aureus was isolated from patient in Phase trial who received daptomycin for injection at less than the protocol-specified dose for the initial days of therapy. In the second case, non-susceptible Enterococcus faecalis was isolated from patient with an infected chronic decubitus ulcer who was enrolled in salvage trial.S. aureus Bacteremia/Endocarditis and Other Post-Approval Trials in AdultsIn subsequent clinical trials in adult patients, non-susceptible isolates were recovered. S. aureus was isolated from patient in compassionate-use trial and from patients in the S. aureus bacteremia/endocarditis trial [see Clinical Studies (14.2)]. An E. faecium was isolated from patient in vancomycin-resistant enterococci trial.Antimicrobial Activity Daptomycin 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)].Gram-Positive BacteriaEnterococcus faecalis (vancomycin-susceptible isolates only) Staphylococcus aureus (including methicillin-resistant isolates) StreptococcusagalactiaeStreptococcus dysgalactiae subsp. equisimilisStreptococcuspyogenes.The 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 for daptomycin against isolates of genus or organism group. However, the efficacy of daptomycin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.Gram-Positive BacteriaCorynebacterium jeikeiumEnterococcus faecalis (vancomycin-resistant isolates) Enterococcus faecium (including vancomycin-resistant isolates) Staphylococcus epidermidis (including methicillin-resistant isolates) Staphylococcus haemolyticusSusceptibility TestingFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for daptomycin, please see:https://www.fda.gov/STIC.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Complicated Skin and Skin Structure Infections Adults with cSSSIAdult patients with clinically documented complicated skin and skin structure infections (cSSSI) (Table 15) were enrolled in two randomized, multinational, multicenter, investigator-blinded trials comparing daptomycin for injection (4 mg/kg IV q24h) with either vancomycin (1 IV q12h) or an anti- staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; to 12 IV per day). Patients could switch to oral therapy after minimum of days of IV treatment if clinical improvement was demonstrated. Patients known to have bacteremia at baseline were excluded. Patients with creatinine clearance (CLCR) between 30 and 70 mL/min were to receive lower dose of daptomycin for injection as specified in the protocol; however, the majority of patients in this subpopulation did not have the dose of daptomycin for injection adjusted.Table 15. Investigators Primary Diagnosis in the cSSSI Trials in Adult Patients (Population: ITT)Primary DiagnosisAdult Patients (Daptomycin For Injection/Comparator)Study 9801N=264 N=266Study 9901N=270 N=292PooledN=534 N=558Wound Infection99 (38%) 116 (44%)102 (38%) 108 (37%)201 (38%) 224 (40%)Major Abscess55 (21%) 43 (16%)59 (22%) 65 (22%)114 (21%) 108 (19%)Ulcer Infection71 (27%) 75 (28%)53 (20%) 68 (23%)124 (23%) 143 (26%)Other Infection+ 39 (15%) 32 (12%)56 (21%) 51 (18%)95 (18%) 83 (15%) Comparator: vancomycin (1 IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; to 12 g/day IV in divided doses).+ The majority of cases were subsequently categorized as complicated cellulitis, major abscesses, or traumatic wound infections.One trial was conducted primarily in the United States and South Africa (study 9,801), and the second was conducted at non-US sites only (study 9,901). The two trials were similar in design but differed in patient characteristics, including history of diabetes and peripheral vascular disease. There were total of 534 adult patients treated with daptomycin for injection and 558 treated with comparator in the two trials. The majority (89.7%) of patients received IV medication exclusively.The efficacy endpoints in both trials were the clinical success rates in the intent-to-treat (ITT) population and in the clinically evaluable (CE) population. In study 9801, clinical success rates in the ITT population were 62.5% (165/264) in patients treated with daptomycin for injection and 60.9% (162/266) in patients treated with comparator drugs. Clinical success rates in the CE population were 76% (158/208) in patients treated with daptomycin for injection and 76.7% (158/206) in patients treated with comparator drugs. In study 9901, clinical success rates in the ITT population were 80.4% (217/270) in patients treated with daptomycin for injection and 80.5% (235/292) in patients treated with comparator drugs. Clinical success rates in the CE population were 89.9% (214/238) in patients treated with daptomycin for injection and 90.4% (226/250) in patients treated with comparator drugs.The success rates by pathogen for microbiologically evaluable patients are presented in Table 16.Table 16. Clinical Success Rates by Infecting Pathogen in the cSSSI Trials in Adult Patients (Population: Microbiologically Evaluable)PathogenSuccess Rate n/N (%)Daptomycin For InjectionComparatorMethicillin-susceptible Staphylococcus aureus (MSSA)+ 170/198(86%)180/207 (87%)Methicillin-resistant Staphylococcus aureus (MRSA)+ 21/28 (75%)25/36 (69%)Streptococcus pyogenes79/84 (94%)80/88 (91%)Streptococcus agalactiae23/27 (85%)22/29 (76%)Streptococcus dysgalactiae subsp. equisimilis8/8 (100%)9/11 (82%)Enterococcus faecalis (vancomycin-susceptible only)27/37 (73%)40/53 (76%) Comparator: vancomycin (1 IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; to 12 g/day IV in divided doses). +As determined by the central laboratory. Pediatric Patients (1 to 17 Years of Age) with cSSSIThe cSSSI pediatric trial was single prospective multi-center, randomized, comparative trial. total of 396 pediatric patients aged to 17 years with cSSSI caused by Gram positive pathogens were enrolled into the study. Patients known to have bacteremia, osteomyelitis, endocarditis, and pneumonia at baseline were excluded. Patients were enrolled in stepwise approach into four age groups and given age-dependent doses of daptomycin once daily for up to 14 days. The different age groups and doses evaluated were as follows: Adolescents (12 to 17 years) treated with mg/kg of daptomycin (n=113), Children (7 to 11 years) treated with mg/kg of daptomycin (n=113), Children (2 to years) treated with mg/kg of daptomycin (n=125) and Infants (1 to <2 years) treated with 10 mg/kg (n= 45). Patients were randomized 2:1 to receive daptomycin or standard of care (SOC) comparator, which included intravenous therapy with either vancomycin, clindamycin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin, or cloxacillin). Patients could switch to oral therapy after clinical improvement was demonstrated (no minimum IV dosing was required). The primary objective of this study was to evaluate the safety of daptomycin. The clinical outcome was determined by resolution or improvement of symptoms at the End-of-Treatment (EOT), days after the last dose, and Test-of-Cure (TOC), to 14 days after the last dose. Investigator observed outcomes were verified in blinded fashion. Of the 396 subjects randomized in the study, 389 subjects were treated with daptomycin or comparator and included in the ITT population. Of these, 257 subjects were randomized to the daptomycin group and 132 subjects were randomized to the comparator group. Approximately 95% of subjects switched to oral therapy. The mean day of switch was day 4, and ranged from day to day 14. The clinical success rates determined at to 14 days after last dose of therapy (IV and oral) (TOC visit) were 88% (227/257) for daptomycin and 86% (114/132) for comparator.. 14.2 S. aureus Bacteremia/Endocarditis Adults with S.aureus Bacteremia/EndocarditisThe efficacy of daptomycin for injection in the treatment of adult patients with S. aureus bacteremia was demonstrated in randomized, controlled, multinational, multicenter, open-label trial. In this trial, adult patients with at least one positive blood culture for S. aureus obtained within calendar days prior to the first dose of study drug and irrespective of source were enrolled and randomized to either daptomycin for injection (6 mg/kg IV q24h) or standard of care [an anti-staphylococcal semi-synthetic penicillin g IV q4h (nafcillin, oxacillin, cloxacillin, or flucloxacillin) or vancomycin g IV q12h, each with initial gentamicin mg/kg IV every hours for first days]. Of the patients in the comparator group, 93% received initial gentamicin for median of days, compared with patient (<1%) in the daptomycin for injection group. Patients with prosthetic heart valves, intravascular foreign material that was not planned for removal within days after the first dose of study medication, severe neutropenia, known osteomyelitis, polymicrobial bloodstream infections, creatinine clearance <30 mL/min, and pneumonia were excluded.Upon entry, patients were classified for likelihood of endocarditis using the modified Duke criteria (Possible, Definite, or Not Endocarditis). Echocardiography, including transesophageal echocardiogram (TEE), was performed within days following study enrollment. The choice of comparator agent was based on the oxacillin susceptibility of the S. aureus isolate. The duration of study treatment was based on the investigators clinical diagnosis. Final diagnoses and outcome assessments at Test of Cure (6 weeks after the last treatment dose) were made by treatment-blinded Adjudication Committee, using protocol-specified clinical definitions and composite primary efficacy endpoint (clinical and microbiological success) at the Test of Cure visit.A total of 246 patients >=18 years of age (124 daptomycin for injection, 122 comparator) with S. aureus bacteremia were randomized from 48 centers in the US and Europe. In the ITT population, 120 patients received daptomycin for injection and 115 received comparator (62 received an anti-staphylococcal semi-synthetic penicillin and 53 received vancomycin). Thirty-five patients treated with an anti--staphylococcal semi-synthetic penicillin received vancomycin initially for to days, pending final susceptibility results for the S. aureus isolates. The median age among the 235 patients in the ITT population was 53 years (range: 21 to 91 years); 30/120 (25%) in the daptomycin for injection group and 37/115 (32%) in the comparator group were >=65 years of age. Of the 235 ITT patients, there were 141 (60%) males and 156 (66%) Caucasians across the two treatment groups. In addition, 176 (75%) of the ITT population had systemic inflammatory response syndrome (SIRS) at baseline and 85 (36%) had surgical procedures within 30 days prior to onset of the S. aureus bacteremia. Eighty-nine patients (38%) had bacteremia caused by methicillin-resistant S. aureus (MRSA). Entry diagnosis was based on the modified Duke criteria and comprised 37 (16%) Definite, 144 (61%) Possible, and 54 (23%) Not Endocarditis. Of the 37 patients with an entry diagnosis of Definite Endocarditis, all (100%) had final diagnosis of infective endocarditis, and of the 144 patients with an entry diagnosis of Possible Endocarditis, 15 (10%) had final diagnosis of infective endocarditis as assessed by the Adjudication Committee. Of the 54 patients with an entry diagnosis of Not Endocarditis, (2%) had final diagnosis of infective endocarditis as assessed by the Adjudication Committee.In the ITT population, there were 182 patients with bacteremia and 53 patients with infective endocarditis as assessed by the Adjudication Committee, including 35 with right-sided endocarditis and 18 with left-sided endocarditis. The 182 patients with bacteremia comprised 121 with complicated S. aureus bacteremia and 61 with uncomplicated S. aureus bacteremia.Complicated bacteremia was defined as S. aureus isolated from blood cultures obtained on at least different calendar days, and/or metastatic foci of infection (deep tissue involvement), and classification of the patient as not having endocarditis according to the modified Duke criteria. Uncomplicated bacteremia was defined as S. aureus isolated from blood culture(s) obtained on single calendar day, no metastatic foci of infection, no infection of prosthetic material, and classification of the patient as not having endocarditis according to the modified Duke criteria. The definition of right-sided infective endocarditis (RIE) used in the clinical trial was Definite or Possible Endocarditis according to the modified Duke criteria and no echocardiographic evidence of predisposing pathology or active involvement of either the mitral or aortic valve. Complicated RIE comprised patients who were not intravenous drug users, had positive blood culture for MRSA, serum creatinine >=2.5 mg/dL, or evidence of extrapulmonary sites of infection. Patients who were intravenous drug users, had positive blood culture for methicillin--susceptible S. aureus (MSSA), had serum creatinine <2.5 mg/dL, and were without evidence of extrapulmonary sites of infection were considered to have uncomplicated RIE.The coprimary efficacy endpoints in the trial were the Adjudication Committee success rates at the Test of Cure visit (6 weeks after the last treatment dose) in the ITT and Per Protocol (PP) populations. The overall Adjudication Committee success rates in the ITT population were 44.2% (53/120) in patients treated with daptomycin for injection and 41.7% (48/115) in patients treated with comparator (difference 2.4% [95% CI -10.2, 15.1]). The success rates in the PP population were 54.4% (43/79) in patients treated with daptomycin for injection and 53.3% (32/60) in patients treated with comparator (difference 1.1% [95% CI -15.6, 17.8]).Adjudication Committee success rates are shown in Table 17.Table 17. Adjudication Committee Success Rates at Test of Cure in the S. aureus Bacteremia/Endocarditis Trial in Adult Patients (Population: ITT)PopulationSuccess Rate n/N (%)Difference:Daptomycin for Injection -Comparator (Confidence Interval)Daptomycin for Injection6 mg/kgComparatorOverall53/120 (44%)48/115 (42%)2.4% (-10.2, 15.1)+ Baseline PathogenMethicillin-susceptible S. aureus 33/74 (45%)34/70 (49%)-4.0% (-22.6, 14.6) Methicillin-resistant S. aureus 20/45 (44%)14/44 (32%)12.6% (-10.2, 35.5) Entry Diagnosis Definite or Possible Infective Endocarditis41/90 (46%)37/91 (41%)4.9% (-11.6, 21.4) Not Infective Endocarditis12/30 (40%)11/24 (46%)-5.8% (-36.2, 24.5) Final DiagnosisUncomplicated Bacteremia18/32 (56%)16/29 (55%)1.1% (-31.7, 33.9) Complicated Bacteremia26/60 (43%)23/61 (38%)5.6% (-17.3, 28.6) Right-Sided Infective Endocarditis8/19 (42%)7/16 (44%)-1.6% (-44.9, 41.6) Uncomplicated Right-Sided Infective Endocarditis3/6 (50%)1/4 (25%)25.0% (-51.6, 100.0) Complicated Right-Sided Infective Endocarditis5/13 (39%)6/12 (50%)-11.5% (-62.4, 39.4) Left-Sided Infective Endocarditis1/9 (11%)2/9 (22%)-11.1% (-55.9, 33.6) Comparator: vancomycin (1 IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; g IV q4h), each with initial low-dose gentamicin.+ 95% Confidence Interval 97.5% Confidence Interval (adjusted for multiplicity) According to the modified Duke criteria5 99% Confidence Interval (adjusted for multiplicity)Eighteen (18/120) patients in the daptomycin for injection arm and 19/116 patients in the comparator arm died during the trial. These comprise 3/28 daptomycin for injection-treated patients and 8/26 comparator-treated patients with endocarditis, as well as 15/92 daptomycin for injection-treated patients and 11/90 comparator-treated patients with bacteremia. Among patients with persisting or relapsing S. aureus infections, 8/19 daptomycin for injection-treated patients and 7/11 comparator-treated patients died.Overall, there was no difference in time to clearance of S. aureus bacteremia between daptomycin for injection and comparator. The median time to clearance in patients with MSSA was days and in patients with MRSA was days.Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the Adjudication Committee in 19/120 (16%) daptomycin for injection-treated patients (12 with MRSA and with MSSA) and 11/115 (10%) comparator-treated patients (9 with MRSA treated with vancomycin and with MSSA treated with an anti-staphylococcal semi-synthetic penicillin). Among all failures, isolates from daptomycin for injection-treated patients and vancomycin-treated patient developed increasing MICs (reduced susceptibility) by central laboratory testing during or following therapy. Most patients who failed due to persisting or relapsing S. aureus infection had deep-seated infection and did not receive necessary surgical intervention [see Warnings and Precautions (5.9)].Pediatric Patients (1 to 17 Years of Age) with S. aureus Bacteremia The pediatric S. aureus bacteremia study was designed as prospective multi-center, randomized, comparative trial to treat pediatric patients aged to 17 years with bacteremia. Patients known to have endocarditis or pneumonia at baseline were excluded. Patients were enrolled in stepwise approach into three age groups and given age-dependent doses of daptomycin once daily for up to 42 days. The different age groups and doses evaluated were as follows: Adolescents (12 to 17 years, n=14 patients) treated with daptomycin dosed at mg/kg once daily, Children (7 to 11 years, n=19 patients) treated with daptomycin dosed at mg/kg once daily and Children (2 to years, n=22 patients) treated with daptomycin dosed at 12 mg/kg once daily. No patients to <2 years of age were enrolled. Patients were randomized 2:1 to receive daptomycin or standard of care comparator, which included intravenous therapy with vancomycin, semi-synthetic penicillin, first generation cephalosporin or clindamycin. Patients could switch to oral therapy after clinical improvement was demonstrated (no minimum IV dosing was required).The primary objective of this study was to assess the safety of daptomycin. The clinical outcome was determined by resolution or improvement of symptoms at test-of-cure (TOC) visit, to 14 days after the last dose, which was assessed by the site level Blinded Evaluator. Of the 82 subjects randomized in the study, 81 subjects were treated with daptomycin or comparator and included in the safety population, and 73 had proven S. aureus bacteremia at Baseline. Of these, 51 subjects were randomized to the daptomycin group and 22 subjects were randomized to the comparator group. The mean duration of IV therapy was 12 days, with range of to 44 days. Forty-eight subjects switched to oral therapy, and the mean duration of oral therapy was 21 days. The clinical success rates determined at to 14 days after last dose of therapy (IV and oral) (TOC visit) were 88% (45/51) for daptomycin and 77% (17/22) for comparator.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adult Patients Administer to adult patients intravenously in 0.9% sodium chloride, either by injection over 2-minute period or by infusion over 30-minute period. (2.1, 2.7) Recommended dosage regimen for adult patients (2.2, 2.4, 2.6):Creatinine Clearance (CLCR)Dosage RegimencSSSIFor to 14 daysS. aureus Bacteremia For to weeks>=30 mL/min4 mg/kg once every 24 hours6 mg/kg once every 24 hours<30 mL/min, including hemodialysis and CAPD4 mg/kg once every 48 hours mg/kg once every 48 hours Administered following hemodialysis on hemodialysis days.Pediatric PatientsUnlike in adults, do NOT administer by injection over two (2) minute period to pediatric patients. (2.1, 2.7) Administer to pediatric patients intravenously in 0.9% sodium chloride, by infusion over 30-or 60-minute period, based on age. (2.1, 2.7) Recommended dosage regimen for pediatric patients (1 to 17 years of age) with cSSSI, based on age (2.3): Age group Dosage Duration of therapy 12 to 17 years mg/kg once every 24 hours infused over 30 minutes Up to 14 days to 11 years mg/kg once every 24 hours infused over 30 minutes to years mg/kg once every 24 hours infused over 60 minutes to less than years 10 mg/kg once every 24 hours infused over 60 minutes Recommended dosage is for pediatric patients (1 to 17 years of age) with normal renal function. Dosage adjustment for pediatric patients with renal impairment has not been established. Recommended dosage regimen for pediatric patients (1 to 17 years of age) with S. aureus bacteremia, based on age (2.5): Age group Dosage Duration of therapy 12 to 17 years mg/kg once every 24 hours infused over 30 minutes Up to 42 days to 11 years mg/kg once every 24 hours infused over 30 minutes to years 12 mg/kg once every 24 hours infused over 60 minutes Recommended dosage is for pediatric patients (1 to 17 years of age) with normal renal function. Dosage adjustment for pediatric patients with renal impairment has not been established. There are two formulations of daptomycin that have differences concerning storage and reconstitution. Carefully follow the reconstitution and storage procedures in labeling. (2.7).Do not use in conjunction with ReadyMED(R) elastomeric infusion pumps in adult patients. (2.9).. Administer to adult patients intravenously in 0.9% sodium chloride, either by injection over 2-minute period or by infusion over 30-minute period. (2.1, 2.7) Recommended dosage regimen for adult patients (2.2, 2.4, 2.6):. Unlike in adults, do NOT administer by injection over two (2) minute period to pediatric patients. (2.1, 2.7) Administer to pediatric patients intravenously in 0.9% sodium chloride, by infusion over 30-or 60-minute period, based on age. (2.1, 2.7) Recommended dosage regimen for pediatric patients (1 to 17 years of age) with cSSSI, based on age (2.3):. Recommended dosage regimen for pediatric patients (1 to 17 years of age) with S. aureus bacteremia, based on age (2.5):. There are two formulations of daptomycin that have differences concerning storage and reconstitution. Carefully follow the reconstitution and storage procedures in labeling. (2.7).. Do not use in conjunction with ReadyMED(R) elastomeric infusion pumps in adult patients. (2.9).. 2.1 Important Administration Duration Instructions Adults: Administer the appropriate volume of the reconstituted daptomycin for injection (concentration of 50 mg/mL) to adult patients intravenously either by injection over two (2) minute period or by intravenous infusion over thirty (30) minute period. [see Dosage and Administration (2.2, 2.4, 2.7)]. Pediatric Patients (1 to 17 Years of Age) Unlike in adults, do NOT administer daptomycin by injection over two (2) minute period to pediatric patients. Pediatric Patients to 17 years of Age: Administer daptomycin for injection intravenously by infusion over 30-minute period [see Dosage and Administration (2.3, 2.5, 2.7)]. Pediatric Patients to years of Age: Administer daptomycin for injection intravenously by infusion over 60-minute period [see Dosage and Administration (2.3, 2.5, 2.7)]. Pediatric Patients to 17 years of Age: Administer daptomycin for injection intravenously by infusion over 30-minute period [see Dosage and Administration (2.3, 2.5, 2.7)]. Pediatric Patients to years of Age: Administer daptomycin for injection intravenously by infusion over 60-minute period [see Dosage and Administration (2.3, 2.5, 2.7)]. 2.2 Dosage in Adults for cSSSI Administer daptomycin for injection mg/kg to adult patients intravenously in 0.9% sodium chloride injection once every 24 hours for to 14 days. 2.3 Dosage in Pediatric Patients (1 to 17 Years of Age) for cSSSI. The recommended dosage regimens based on age for pediatric patients with cSSSI are shown in Table 1. Administer daptomycin intravenously in 0.9% sodium chloride injection once every 24 hours for up to 14 days. Table 1: Recommended Dosage of Daptomycin for Injection in Pediatric Patients (1 to 17 Years of Age) with cSSSI, Based on AgeAge Range Dosage Regimen Duration of therapy 12 to 17 years mg/kg once every 24 hours infused over 30 minutes Up to 14 days to 11 years mg/kg once every 24 hours infused over 30 minutes to years mg/kg once every 24 hours infused over 60 minutes to less than years 10 mg/kg once every 24 hours infused over 60 minutes Recommended dosage regimen is for pediatric patients (1 to 17 years of age) with normal renal function. Dosage adjustment for pediatric patients with renal impairment has not been established. 2.4 Dosage in Adult Patients with Staphylococcus aureus Bloodstream Infections (Bacteremia), Including Those with Right-Sided Infective Endocarditis, Caused by Methicillin-Susceptible and Methicillin-Resistant Isolates Administer daptomycin for injection mg/kg to adult patients intravenously in 0.9% sodium chloride injection once every 24 hours for to weeks.There are limited safety data for the use of daptomycin for injection for more than 28 days of therapy. In the Phase trial, there were total of 14 adult patients who were treated with daptomycin for injection for more than 28 days.. 2.5 Dosage in Pediatric Patients (1 to 17 Years of Age) with Staphylococcus aureus Bloodstream Infections (Bacteremia). The recommended dosage regimens based on age for pediatric patients with S. aureus bloodstream infections (bacteremia) are shown in Table 2. Administer daptomycin for injection intravenously in 0.9% sodium chloride injection once every 24 hours for up to 42 days. Table 2: Recommended Dosage of Daptomycin for Injection in Pediatric Patients (1 to 17 Years of Age) with S. aureus Bacteremia, Based on AgeAge group Dosage Duration of therapy 12 to 17 years mg/kg once every 24 hours infused over 30 minutes Up to 42 days to 11 years mg/kg once every 24 hours infused over 30 minutes to years 12 mg/kg once every 24 hours infused over 60 minutes Recommended dosage is for pediatric patients (1 to 17 years of age) with normal renal function. Dosage adjustment for pediatric patients with renal impairment has not been established. 2.6 Dosage in Patients with Renal Impairment Adult Patients: No dosage adjustment is required in adult patients with creatinine clearance (CLCR) greater than or equal to 30 mL/min. The recommended dosage regimen for daptomycin for injection in adult patients with CLCR less than 30 mL/min, including adult patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), is mg/kg (cSSSI) or mg/kg (S. aureus bloodstream infections) once every 48 hours (Table 3). When possible, daptomycin for injection should be administered following the completion of hemodialysis on hemodialysis days [see Warnings and Precautions (5.2, 5.10), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].Table 3: Recommended Dosage of Daptomycin for Injection in Adult Patients Creatinine Clearance(CLCR)Dosage Regimen in Adults cSSSIS. aureusBloodstream Infections Greater than or equal to 30 mL/min mg/kg once every 24 hours mg/kg once every 24 hours Less than 30 mL/min, including hemodialysis and CAPD mg/kg once every 48 hours mg/kg once every 48 hours When possible, administer daptomycin for injection following the completion of hemodialysis on hemodialysis days.Pediatric Patients: The dosage regimen for daptomycin for injection in pediatric patients with renal impairment has not been established.. 2.7 Preparation and Administration of Daptomycin for Injection Reconstitution of Daptomycin for Injection Vial Daptomycin for injection is supplied in single-dose vials, each containing 500 mg daptomycin as sterile, lyophilized cake or powder. The contents of daptomycin for injection vial should be reconstituted, using aseptic technique, to 50 mg/mL as follows: 1. To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution. 2. Remove the polypropylene flip-off cap from the daptomycin for injection vial to expose the central portion of the rubber stopper. 3. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. 4. Slowly transfer 10 mL of 0.9% sodium chloride injection through the center of the rubber stopper into the daptomycin for injection vial, pointing the transfer needle toward the wall of the vial. It is recommended that beveled sterile transfer needle that is 21 gauge or smaller in diameter, or needleless device is used, pointing the transfer needle toward the wall of the vial. 5. Ensure that all of the daptomycin for injection powder is wetted by gently rotating the vial. 1. Allow the wetted product to stand undisturbed for 10 minutes. 2. Gently rotate or swirl the vial contents for few minutes, as needed, to obtain completely reconstituted solution. Administration Instructions Parenteral drug products should be inspected visually for particulate matter prior to administration. Slowly remove reconstituted liquid (50 mg daptomycin/mL) from the vial using beveled sterile needle that is 21 gauge or smaller in diameter. Administer as an intravenous injection or infusion as described below: AdultsIntravenous Injection over period of minutesFor intravenous (IV) injection over period of minutes in adult patients only: Administer the appropriate volume of the reconstituted daptomycin for injection (concentration of 50 mg/mL).Intravenous Infusion over period of 30 minutesFor IV infusion over period of 30 minutes in adult patients: The appropriate volume of the reconstituted daptomycin for injection (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into 50 mL IV infusion bag containing 0.9% sodium chloride injection.Pediatric Patients (1 to 17 Years of Age) Intravenous Infusion over period of 30 or 60 minutes Unlike in Adults, do NOT administer daptomycin by injection over two (2) minute period to pediatric patients [see Dosage and Administration (2.1)].For Intravenous infusion over period of 60 minutes in pediatric patients to years of age: The appropriate volume of the reconstituted daptomycin for injection (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into an intravenous infusion bag containing 25 mL of 0.9% sodium chloride injection. The infusion rate should be maintained at 0.42 mL/minute over the 60-minute period. For Intravenous infusion over period of 30 minutes in pediatric patients to 17 years of age: The appropriate volume of the reconstituted daptomycin for injection (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into 50 mL IV infusion bag containing 0.9% sodium chloride injection. The infusion rate should be maintained at 1.67 mL/minute over the 30-minute period.No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the preparation of final IV solution. Do not exceed the In-Use storage conditions of the reconstituted and diluted solutions of daptomycin for injection described below. Discard unused portions of daptomycin for injection. In-Use Storage Conditions for Daptomycin for Injection Once Reconstituted in Acceptable Intravenous Diluents Stability studies have shown that the reconstituted solution is stable in the vial for 12 hours at room temperature and up to 48 hours if stored under refrigeration at to 8C (36 to 46F). The diluted solution is stable in the infusion bag for 12 hours at room temperature and 48 hours if stored under refrigeration. The combined storage time (reconstituted solution in vial and diluted solution in infusion bag) should not exceed 12 hours at room temperature or 48 hours under refrigeration.. For intravenous (IV) injection over period of minutes in adult patients only: Administer the appropriate volume of the reconstituted daptomycin for injection (concentration of 50 mg/mL).. For IV infusion over period of 30 minutes in adult patients: The appropriate volume of the reconstituted daptomycin for injection (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into 50 mL IV infusion bag containing 0.9% sodium chloride injection.. Unlike in Adults, do NOT administer daptomycin by injection over two (2) minute period to pediatric patients [see Dosage and Administration (2.1)].. For Intravenous infusion over period of 60 minutes in pediatric patients to years of age: The appropriate volume of the reconstituted daptomycin for injection (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into an intravenous infusion bag containing 25 mL of 0.9% sodium chloride injection. The infusion rate should be maintained at 0.42 mL/minute over the 60-minute period. For Intravenous infusion over period of 30 minutes in pediatric patients to 17 years of age: The appropriate volume of the reconstituted daptomycin for injection (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into 50 mL IV infusion bag containing 0.9% sodium chloride injection. The infusion rate should be maintained at 1.67 mL/minute over the 30-minute period.. 2.8 Compatible Intravenous Solutions. Daptomycin for injection is compatible with 0.9% sodium chloride injection and lactated Ringers injection.. 2.9 Incompatibilities. Daptomycin for injection is not compatible with dextrose-containing diluents. Daptomycin for injection should not be used in conjunction with ReadyMED(R) elastomeric infusion pumps. Stability studies of daptomycin for injection solutions stored in ReadyMED(R) elastomeric infusion pumps identified an impurity (2-mercaptobenzothiazole) leaching from this pump system into the daptomycin for injection solution. Because only limited data are available on the compatibility of daptomycin for injection with other IV substances, additives and other medications should not be added to daptomycin for injection single-dose vials or infusion bags, or infused simultaneously with daptomycin for injection through the same IV line. If the same IV line is used for sequential infusion of different drugs, the line should be flushed with compatible intravenous solution before and after infusion with daptomycin for injection.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Daptomycin for injection is lipopeptide antibacterial indicated for the treatment of: Complicated skin and skin structure infections (cSSSI) in adult and pediatric patients (1 to 17 years of age) (1.1) and,Staphylococcus aureus bloodstream infections (bacteremia), in adult patients including those with right-sided infective endocarditis (1.2) Staphylococcus aureus bloodstream infections (bacteremia) in pediatric patients (1 to 17 years of age). (1.3) Limitations of Use: Daptomycin for injection is not indicated for the treatment of pneumonia. (1.4) Daptomycin for injection is not indicated for the treatment of left-sided infective endocarditis due to S. aureus. (1.4) Daptomycin for injection is not recommended in pediatric patients younger than one year of age due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs. (1.4) To reduce the development of drug-resistant bacteria and maintain the effectiveness of daptomycin for injection and other antibacterial drugs, daptomycin for injection should be used to treat infections that are proven or strongly suspected to be caused by bacteria. (1.5) Complicated skin and skin structure infections (cSSSI) in adult and pediatric patients (1 to 17 years of age) (1.1) and,. Staphylococcus aureus bloodstream infections (bacteremia), in adult patients including those with right-sided infective endocarditis (1.2) Staphylococcus aureus bloodstream infections (bacteremia) in pediatric patients (1 to 17 years of age). (1.3) Daptomycin for injection is not indicated for the treatment of pneumonia. (1.4). Daptomycin for injection is not indicated for the treatment of left-sided infective endocarditis due to S. aureus. (1.4) Daptomycin for injection is not recommended in pediatric patients younger than one year of age due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs. (1.4) 1.1 Complicated Skin and Skin Structure Infections (cSSSI). Daptomycin for injection is indicated for the treatment of adult and pediatric patients (1 to 17 years of age) with complicated skin and skin structure infections (cSSSI) Daptomycin for injection is indicated for the treatment of adult patients with complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following Gram-positive bacteria: Staphylococcus aureus (including methicillin-resistant isolates),Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only). 1.2 Staphylococcus aureus Bloodstream Infections (Bacteremia) in Adult Patients, Including those with Right-Sided Infective Endocarditis, Caused by Methicillin-Susceptible and Methicillin-Resistant Isolates. Daptomycin for injection is indicated for the treatment of adult patients with Staphylococcus aureus bloodstream infections (bacteremia), including adult patients with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates. 1.3 Staphylococcus aureus Bloodstream Infections (Bacteremia) in Pediatric Patients (1 to 17 Years of Age) Daptomycin for injection is indicated for the treatment of pediatric patients (1 to 17 years of age) with Staphylococcus aureus bloodstream infections (bacteremia).. 1.4 Limitations of Use. Daptomycin for injection is not indicated for the treatment of pneumonia. Daptomycin for injection is not indicated for the treatment of left-sided infective endocarditis due to S. aureus. The clinical trial of daptomycin for injection in adult patients with S. aureus bloodstream infections included limited data from patients with left-sided infective endocarditis; outcomes in these patients were poor [see Clinical Trials (14.2)]. Daptomycin for injection has not been studied in patients with prosthetic valve endocarditis. Daptomycin for injection is not recommended in pediatric patients younger than year of age due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs [see Warnings and Precautions 5.7) and Nonclinical Toxicology (13.2)]. 1.5 Usage. Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to daptomycin. To reduce the development of drug-resistant bacteria and maintain the effectiveness of daptomycin for injection and other antibacterial drugs, daptomycin for injection should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information is available, it should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Empiric therapy may be initiated while awaiting test results.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies in animals have not been conducted to evaluate the carcinogenic potential of daptomycin for injection. However, neither mutagenic nor clastogenic potential was found in battery of genotoxicity tests, including the Ames assay, mammalian cell gene mutation assay, test for chromosomal aberrations in Chinese hamster ovary cells, an in vivo micronucleus assay, an in vitro DNA repair assay, and an in vivo sister chromatid exchange assay in Chinese hamsters.Daptomycin did not affect the fertility or reproductive performance of male and female rats when administered intravenously at doses of 25, 75, or 150 mg/kg/day, which is approximately up to times the estimated human exposure level based upon AUCs (or approximately up to times the recommended human dose of mg/kg based on body surface area comparison).. 13.2 Animal Toxicology and/or Pharmacology. Adult AnimalsIn animals, daptomycin administration has been associated with effects on skeletal muscle. However, there were no changes in cardiac or smooth muscle. Skeletal muscle effects were characterized by microscopic degenerative/regenerative changes and variable elevations in creatine phosphokinase (CPK). No fibrosis or rhabdomyolysis was evident in repeat-dose studies up to the highest doses tested in rats (150 mg/kg/day) and dogs (100 mg/kg/day). The degree of skeletal myopathy showed no increase when treatment was extended from month to up to months. Severity was dose-dependent. All muscle effects, including microscopic changes, were fully reversible within 30 days following the cessation of dosing.In adult animals, effects on peripheral nerve (characterized by axonal degeneration and frequently accompanied by significant losses of patellar reflex, gag reflex, and pain perception) were observed at daptomycin doses higher than those associated with skeletal myopathy. Deficits in the dogs patellar reflexes were seen within weeks after the start of treatment at 40 mg/kg/day (9 times the human Cmax at the mg/kg/day dose), with some clinical improvement noted within weeks after the cessation of dosing. However, at 75 mg/kg/day for month, of dogs failed to regain full patellar reflex responses within 3-month recovery period. In separate study in dogs receiving doses of 75 and 100 mg/kg/day for weeks, minimal residual histological changes were noted at months after the cessation of dosing. However, recovery of peripheral nerve function was evident. Tissue distribution studies in rats showed that daptomycin is retained in the kidney but appears to penetrate the blood-brain barrier only minimally following single and multiple doses.Juvenile Animals Target organs of daptomycin-related effects in 7-week-old juvenile dogs were skeletal muscle and nerve, the same target organs as in adult dogs. In juvenile dogs, nerve effects were noted at lower daptomycin blood concentrations than in adult dogs following 28 days of dosing. In contrast to adult dogs, juvenile dogs also showed evidence of effects in nerves of the spinal cord as well as peripheral nerves after 28 days of dosing. No nerve effects were noted in juvenile dogs following 14 days of dosing at doses up to 75 mg/kg/day. Administration of daptomycin to 7-week-old juvenile dogs for 28 days at doses of 50 mg/kg/day produced minimal degenerative effects on the peripheral nerve and spinal cord in several animals, with no corresponding clinical signs. dose of 150 mg/kg/day for 28 days produced minimal degeneration in the peripheral nerve and spinal cord as well as minimal to mild degeneration of the skeletal muscle in majority of animals, accompanied by slight to severe muscle weakness evident in most dogs. Following 28-day recovery phase, microscopic examination revealed recovery of the skeletal muscle and the ulnar nerve effects, but nerve degeneration in the sciatic nerve and spinal cord was still observed in all 150 mg/kg/day dogs. Following once-daily administration of daptomycin to juvenile dogs for 28 days, microscopic effects in nerve tissue were noted at Cmax value of 417 mcg/mL, which is approximately 3-fold less than the Cmax value associated with nerve effects in adult dogs treated once daily with daptomycin for 28 days (1308 mcg/mL). Neonatal AnimalsNeonatal dogs (4 to 31 days old) were more sensitive to daptomycin-related adverse nervous system and/or muscular system effects than either juvenile or adult dogs. In neonatal dogs, adverse nervous system and/or muscular system effects were associated with Cmax value approximately 3-fold less than the Cmax in juvenile dogs, and 9-fold less than the Cmax in adult dogs following 28 days of dosing. At dose of 25 mg/kg/day with associated Cmax and AUCinf values of 147 mcg/mL and 717 mcgoh/mL, respectively (1.6 and 1-fold the adult human Cmax and AUC, respectively, at the mg/kg/day dose), mild clinical signs of twitching and one incidence of muscle rigidity were observed with no corresponding effect on body weight. These effects were found to be reversible within 28 days after treatment had stopped.At higher dose levels of 50 and 75 mg/kg/day with associated Cmax and AUCinf values of >=321 mcg/mL and >=1470 mcgoh/mL, respectively, marked clinical signs of twitching, muscle rigidity in the limbs, and impaired use of limbs were observed. Resulting decreases in body weights and overall body condition at doses >=50 mg/kg/day necessitated early discontinuation by postnatal day (PND) 19.Histopathological assessment did not reveal any daptomycin-related changes in the peripheral and central nervous system tissue, as well as in the skeletal muscle or other tissues assessed, at any dose level.No adverse effects were observed in the dogs that received daptomycin at 10 mg/kg/day, the NOAEL, with associated Cmax and AUCinf values of 62 mcg/mL and 247 mcgoh/mL, respectively (or 0.6 and 0.4-fold the adult human Cmax and AUC, respectively at the mg/kg dose).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Daptomycin for Injection Administered over 30-Minute Period in AdultsThe mean and standard deviation (SD) pharmacokinetic parameters of daptomycin at steady- state following intravenous (IV) administration of daptomycin for injection over 30-minute period at to 12 mg/kg q24h to healthy young adults are summarized in Table 11.Table 11. Mean (SD) Daptomycin Pharmacokinetic Parameters in Healthy Adult Volunteers at Steady-StateDose+ (mg/kg)Pharmacokinetic ParametersAUC0-24 (mcgoh/mL) t1/2 (h) Vss (L/kg) CLT (mL/h/kg) Cmax (mcg/mL) (N=6) 494 (75) 8.1 (1.0) 0.096 (0.009) 8.3 (1.3) 57.8 (3.0) (N=6) 632 (78) 7.9 (1.0) 0.101 (0.007) 9.1 (1.5) 93.9 (6.0) (N=6) 858 (213) 8.3 (2.2) 0.101 (0.013) (3.0) 123.3 (16.0)10 (N=9) 1039 (178) 7.9 (0.6) 0.098 (0.017) 8.8 (2.2) 141.1 (24.0)12 (N=9) 1277 (253) 7.7 (1.1) 0.097 (0.018) (2.8) 183.7 (25.0) Daptomycin for injection was administered by IV infusion over 30-minute period.+ Doses of daptomycin for injection in excess of mg/kg have not been approved. AUC0-24, area under the concentration-time curve from to 24 hours; t1/2, elimination half-life; Vss, volume of distribution at steady-state; CLT, total plasma clearance; Cmax, maximum plasma concentration.Daptomycin pharmacokinetics were generally linear and time-independent at daptomycin for injection doses of to 12 mg/kg q24h administered by IV infusion over 30-minute period for up to 14 days. Steady-state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following the administration of 4, 6, 8, 10, and 12 mg/kg q24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9), and 13.7 (5.2) mcg/mL, respectively.Daptomycin for Injection Administered over 2-Minute Period in AdultsFollowing IV administration of daptomycin for injection over 2-minute period to healthy adult volunteers at doses of mg/kg (N=8) and mg/kg (N=12), the mean (SD) steady-state systemic exposure (AUC) values were 475 (71) and 701 (82) mcgoh/mL, respectively. Values for maximum plasma concentration (Cmax) at the end of the 2-minute period could not be determined adequately in this study. However, using pharmacokinetic parameters from 14 healthy adult volunteers who received single dose of daptomycin for injection mg/kg IV administered over 30-minute period in separate study, steady-state Cmax values were simulated for daptomycin for injection and mg/kg IV administered over 2-minute period. The simulated mean (SD) steady-state Cmax values were 77.7 (8.1) and 116.6 (12.2) mcg/mL, respectively.DistributionDaptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in concentration-independent manner. The overall mean binding ranges from 90 to 93%.In clinical studies, mean serum protein binding in adult subjects with creatinine clearance (CLCR) >=30 mL/min was comparable to that observed in healthy adult subjects with normal renal function. However, there was trend toward decreasing serum protein binding among subjects with CLCR <30 mL/min (88%), including those receiving hemodialysis (86%) and continuous ambulatory peritoneal dialysis (CAPD) (84%). The protein binding of daptomycin in adult subjects with moderate hepatic impairment (Child-Pugh Class B) was similar to that in healthy adult subjects.The volume of distribution at steady-state (Vss) of daptomycin in healthy adult subjects was approximately 0.1 L/kg and was independent of dose.MetabolismIn in vitro studies, daptomycin was not metabolized by human liver microsomes.In healthy adults after infusion of radiolabeled 14C-daptomycin, the plasma total radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference between total radioactive concentrations and microbiologically active concentrations. In separate study, no metabolites were observed in plasma on Day following the administration of daptomycin for injection at mg/kg to adult subjects. Minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.ExcretionDaptomycin is excreted primarily by the kidneys. In mass balance study of healthy adult subjects using radiolabeled daptomycin, approximately 78% of the administered dose was recovered from urine based on total radioactivity (approximately 52% of the dose based on microbiologically active concentrations), and 5.7% of the administered dose was recovered from feces (collected for up to days) based on total radioactivity.Specific PopulationsRenal ImpairmentPopulation-derived pharmacokinetic parameters were determined for infected adult patients (complicated skin and skin structure infections [cSSSI] and S. aureus bacteremia) and noninfected adult subjects with various degrees of renal function (Table 12). Total plasma clearance (CLT), elimination half-life (t1/2), and volume of distribution at steady-state (Vss) in patients with cSSSI were similar to those in patients with S. aureus bacteremia. Following administration of daptomycin for injection mg/kg q24h by IV infusion over 30-minute period, the mean CLT was 9%, 22%, and 46% lower among subjects and patients with mild (CLCR 50 to 80 mL/min), moderate (CLCR 30-<50 mL/min), and severe (CLCR <30 mL/min) renal impairment, respectively, than in those with normal renal function (CLCR >80 mL/min). The mean steady-state systemic exposure (AUC), t1/2, and Vss increased with decreasing renal function, although the mean AUC for patients with CLCR 30 to 80 mL/min was not markedly different from the mean AUC for patients with normal renal function. The mean AUC for patients with CLCR <30 mL/min and for patients on dialysis (CAPD and hemodialysis dosed post-dialysis) was approximately and times higher, respectively, than for patients with normal renal function. The mean Cmax ranged from 60 to 70 mcg/mL in patients with CLCR >=30 mL/min, while the mean Cmax for patients with CLCR <30 mL/min ranged from 41 to 58 mcg/mL. After administration of daptomycin for injection mg/kg q24h by IV infusion over 30-minute period, the mean Cmax ranged from 80 to 114 mcg/mL in patients with mild to moderate renal impairment and was similar to that of patients with normal renal function.Table 12. Mean (SD) Daptomycin Population Pharmacokinetic Parameters Following Infusion of Daptomycin for Injection mg/kg or mg/kg to Infected Adult Patients and Noninfected Adult Subjects with Various Degrees of Renal FunctionRenal FunctionPharmacokinetic Parameterst1/2+(h)4 mg/kgVss+(L/kg)4 mg/kgCLT+(mL/h/kg)4 mg/kgAUC0-+(mcgoh/mL)4 mg/kgAUCss (mcgoh/mL)6 mg/kgCmin, ss (mcg/mL)6 mg/kg Normal (CLCR >80 mL/min) 9.39 (4.74) N=165 0.13 (0.05) N=165 10.9 (4.0) N=165 417 (155) N=165 545 (296) N=62 6.9 (3.5) N=61 Mild Renal Impairment (CLCR 50 to 80 mL/min) 10.75 (8.36) N=64 0.12 (0.05) N=64 9.9 (4.0) N=64 466 (177) N=64 637 (215) N=29 12.4 (5.6) N=29 Moderate Renal Impairment (CLCR 30 <50 mL/min) 14.70 (10.50) N=24 0.15 (0.06) N=24 8.5 (3.4) N=24 560 (258) N=24 868 (349) N=15 19 (9) N=14 Severe Renal Impairment (CLCR <30 mL/min) 27.83 (14.85) N=8 0.20 (0.15) N=8 5.9 (3.9) N=8 925 (467) N=8 1050 (892) N=2 24.4 (21.4) N=2 Hemodialysis 30.51 (6.51) N=16 0.16 (0.04) N=16 3.9 (2.1) N=16 1193 (399) N=16 NA NA CAPD 27.56 (4.53) N=5 0.11 (0.02) N=5 2.9 (0.4) N=5 1409 (238) N=5 NA NA Note: Daptomycin for injection was administered over 30-minute period. CLCR, creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; CAPD, continuous ambulatory peritoneal dialysis; AUC0-, area under the concentration-time curve extrapolated to infinity; AUCss, area under the concentration-time curve calculated over the 24-hour dosing interval at steady-state; Cmin,ss, trough concentration at steady-state; NULL, not applicable. Parameters obtained following single dose from patients with complicated skin and skin structure infections and healthy subjects. Parameters obtained at steady-state from patients with S.aureus bacteremia. Because renal excretion is the primary route of elimination, adjustment of daptomycin for injection dosage interval is necessary in adult patients with severe renal impairment (CLCR <30 mL/min) [see Dosage and Administration (2.4)].Hepatic ImpairmentThe pharmacokinetics of daptomycin were evaluated in 10 adult subjects with moderate hepatic impairment (Child-Pugh Class B) and compared with those in healthy adult volunteers (N=9) matched for gender, age, and weight. The pharmacokinetics of daptomycin were not altered in subjects with moderate hepatic impairment. No dosage adjustment is warranted when daptomycin for injection is administered to patients with mild to moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh Class C) have not been evaluated.GenderNo clinically significant gender-related differences in daptomycin pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when daptomycin for injection is administered. GeriatricThe pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects (>=75 years of age) and 11 healthy young adult controls (18 to 30 years of age). Following administration of single mg/kg dose of daptomycin for injection by IV infusion over 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0-was approximately 58% higher in elderly subjects than in healthy young adult subjects. There were no differences in Cmax [see Use in Specific Populations (8.5)].ObesityThe pharmacokinetics of daptomycin were evaluated in moderately obese (Body Mass Index [BMI] 25 to 39.9 kg/m2) and extremely obese (BMI >=40 kg/m2) adult subjects and controls matched for age, gender, and renal function. Following administration of daptomycin for injection by IV infusion over 30-minute period as single mg/kg dose based on total body weight, the total plasma clearance of daptomycin normalized to total body weight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects than in nonobese controls. The AUC0- of daptomycin was approximately 30% higher in moderately obese subjects and 31% higher in extremely obese subjects than in nonobese controls. The differences were most likely due to differences in the renal clearance of daptomycin. No adjustment of daptomycin for injection dosage is warranted in obese patients. Pediatric The pharmacokinetics of daptomycin in pediatric subjects was evaluated in single-dose pharmacokinetic studies. In general, body weight-normalized total body clearance in pediatric patients was higher than in adults and increased with decrease of age, whereas elimination half-life tends to decrease with decrease of age. Body weight-normalized total body clearance and elimination half-life of daptomycin in children to years of age were similar at different doses. study was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in pediatric patients (1 to 17 years old, inclusive) with cSSSI caused by Gram-positive pathogens. Patients were enrolled into age groups [see Clinical Studies (14.1)], and intravenous daptomycin doses of to 10 mg/kg once daily were administered. Following administration of multiple doses, daptomycin exposure (AUCss and Cmax,ss) was similar across different age groups after dose adjustment based on body weight and age (Table 13). Table 13: Mean (SD) Daptomycin Population Pharmacokinetic Parameters in cSSSI Pediatric PatientsAgePharmacokinetic ParametersDose (mg/kg) Infusion Duration (min) AUCss (mcgoh/mL) t1/2 (h) Vss (mL) CLT (mL/h/kg) Cmax,ss (mcg/mL) 12 to 17 years (N=6) 30 434 (67.9) 7.1 (0.9) 8200 (3250) 11.8 (2.15) 76.4 (6.75) to 11 years (N=2) 30 543 6.8 4470 13.2 92.4 to years (N=7) 60 452 (93.1) 4.6 (0.8) 2750 (832) 20.8 (4.29) 90.3 (14.0) to less than years (N=27) 10 60 462 (138) 4.8 (0.6) 1670 (446) 23.1 (5.43) 81.6 (20.7) AUCss, area under the concentration-time curve at steady state; CLT, clearance normalized to body weight; Vss, volume of distribution at steady state; 1/2 terminal half-life Mean is calculated from N=2 study was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in pediatric patients with S. aureus bacteremia. Patients were enrolled into age groups [see Clinical Studies (14.2)], and intravenous doses of to 12 mg/kg once daily were administered. Following administration of multiple doses, daptomycin exposure (AUCss and Cmax,ss) was similar across different age groups after dose adjustment based on body weight and age (Table 14). Table 14: Mean (SD) of Daptomycin Pharmacokinetics in Bacteremia Pediatric PatientsAge Pharmacokinetic Parameters Dose (mg/kg) Infusion Duration (min) AUCss (mcgoh/mL) t1/2 (h) Vss (mL) CLT (mL/h/kg) Cmax,ss (mcg/mL) 12 to 17 years(N=13)7 30 656 (334) 7.5 (2.3) 6420 (1980)12.4 (3.9) 104 (35.5) to 11 years(N=19)9 30 579 (116) 6.0 (0.8) 4510 (1470)15.9 (2.8) 104 (14.5) to years(N=19)12 60 620 (109) 5.1 (0.6) 2200 (570) 19.9 (3.4) 106 (12.8) AUCss, area under the concentration-time curve at steady state; CLT, clearance normalized to body weight; Vss, volume of distribution at steady state; 1/2 terminal half-life No patients to <2 years of age were enrolled in the study. Simulation using population pharmacokinetic model demonstrated that the AUCss of daptomycin in pediatric patients to <2 years of age receiving 12 mg/kg once daily would be comparable to that in adult patients receiving mg/kg once daily.Drug-Drug InteractionsIn Vitro Studies In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the P450 system. AztreonamIn study in which 15 healthy adult subjects received single dose of daptomycin for injection mg/kg IV and combination dose of daptomycin for injection mg/kg IV and aztreonam g IV, administered over 30-minute period, the Cmax and AUC0- of daptomycin were not significantly altered by aztreonam. TobramycinIn study in which healthy adult males received single dose of daptomycin for injection mg/kg IV, tobramycin mg/kg IV, and both in combination, administered over 30-minute period, the mean Cmax and AUC0- of daptomycin were 12.7% and 8.7% higher, respectively, when daptomycin for injection was coadministered with tobramycin. The mean Cmax and AUC0- of tobramycin were 10.7% and 6.6% lower, respectively, when tobramycin was coadministered with daptomycin for injection. These differences were not statistically significant. The interaction between daptomycin and tobramycin with clinical dose of daptomycin for injection is unknown.WarfarinIn 16 healthy adult subjects, administration of daptomycin for injection mg/kg q24h by IV infusion over 30-minute period for days, with coadministration of single oral dose of warfarin (25 mg) on the 5th day, had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR (International Normalized Ratio). SimvastatinIn 20 healthy adult subjects on stable daily dose of simvastatin 40 mg, administration of daptomycin for injection mg/kg q24h by IV infusion over 30-minute period for 14 days (N=10) had no effect on plasma trough concentrations of simvastatin and was not associated with higher incidence of adverse events, including skeletal myopathy, than in subjects receiving placebo once daily (N=10) [see Warnings and Precautions (5.2) and Drug Interactions (7.1)]. ProbenecidConcomitant administration of probenecid (500 mg times daily) and single dose of daptomycin for injection mg/kg by IV infusion over 30-minute period in adults did not significantly alter the Cmax or AUC0- of daptomycin.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryLimited published data on use of daptomycin for injection in pregnant women are insufficient to inform drug-associated risk for major birth defects and miscarriage. In animal reproduction studies performed in rats and rabbits daptomycin was administered intravenously during organogenesis at doses and 4-times, respectively, the recommended mg/kg human dose (on body surface area basis). No evidence of adverse developmental outcomes was observed. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. Data Animal DataIn pregnant rats, daptomycin was administered intravenously at doses of 5, 20, or 75 mg/kg/day during the gestation days to 18. Maternal body weight gain was decreased at 75 mg/kg/day. No embryo/fetal effects were noted at the highest dose of 75 mg/kg/day, dose approximately 2-fold higher than in humans at the recommended maximum dose of 6mg/kg (based on body surface area). In pregnant rabbits, daptomycin was administered intravenously at doses of 5, 20, or 75 mg/kg/day during the gestation days to 15. Maternal body weight gain and food consumption were decreased at 75 mg/kg/day. No embryo/fetal effects were noted at the highest dose of 75 mg/kg/day, dose approximately 4-fold higher than in humans at the maximum recommended dose of 6mg/kg (based on body surface area). In combined fertility and pre/postnatal development study, daptomycin was administered intravenously to female rats at doses of 2, 25, 75 mg/kg/day from 14-days pre-mating through lactation/postpartum day 20). No effects on pre/postnatal development were observed up to the highest dose of 75 mg/kg/day, dose approximately 2-fold higher than the maximum recommended human dose of mg/kg (based on body surface area)1. 8.2 Lactation Risk Summary Limited published data report that daptomycin is present in human milk at infant doses of 0.1% of the maternal dose [see Data]2,3,4. There is no information on the effects of daptomycin on the breastfed infant or the effects of daptomycin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for daptomycin and any potential adverse effects on the breastfed infant from daptomycin for injection or from the underlying maternal condition. 8.4 Pediatric Use. The safety and effectiveness of daptomycin in the treatment of cSSSI and S. aureus bloodstream infections (bacteremia) have been established in the age groups to 17 years of age. Use of daptomycin in these age groups is supported by evidence from adequate and well-controlled studies in adults, with additional data from pharmacokinetic studies in pediatric patients, and from safety, efficacy and PK studies in pediatric patients with cSSSI and S. aureus bloodstream infections [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].Safety and effectiveness in pediatric patients below the age of one year have not been established. Avoid use of daptomycin in pediatric patients younger than one year of age due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs [see Warnings and Precautions (5.7) and Nonclinical Toxicology (13.2)].Daptomycin is not indicated in pediatric patients with renal impairment because dosage has not been established in these patients. Daptomycin has not been studied in pediatric patients with other bacterial infections.. 8.5 Geriatric Use. Of the 534 adult patients treated with daptomycin for injection in Phase controlled clinical trials of complicated skin and skin structure infections (cSSSI), 27% were 65 years of age or older and 12% were 75 years of age or older. Of the 120 adult patients treated with daptomycin for injection in the Phase controlled clinical trial of S. aureus bacteremia/endocarditis, 25% were 65 years of age or older and 16% were 75 years of age or older. In Phase adult clinical trials of cSSSI and S. aureus bacteremia/endocarditis, clinical success rates were lower in patients >=65 years of age than in patients <65 years of age. In addition, treatment-emergent adverse events were more common in patients >=65 years of age than in patients <65 years of age. The exposure of daptomycin was higher in healthy elderly subjects than in healthy young adult subjects. However, no adjustment of daptomycin for injection dosage is warranted for elderly patients with creatinine clearance (CLCR) >=30 mL/min [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].. 8.6 Patients with Renal Impairment Daptomycin is eliminated primarily by the kidneys; therefore, modification of daptomycin for injection dosage interval is recommended for adult patients with CLCR <30 mL/min, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). In adult patients with renal impairment, both renal function and creatine phosphokinase (CPK) should be monitored more frequently than once weekly [see Dosage and Administration (2.6), Warnings and Precautions (5.2, 5.10), and Clinical Pharmacology (12.3)]. The dosage regimen for daptomycin in pediatric patients with renal impairment has not been established.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Anaphylaxis/hypersensitivity reactions (including life-threatening): Discontinue daptomycin for injection and treat signs/symptoms. (5.1) Myopathy and rhabdomyolysis: Monitor CPK levels and follow muscle pain or weakness; if elevated CPK or myopathy occurs, consider discontinuation of daptomycin for injection. (5.2) Eosinophilic pneumonia: Discontinue daptomycin for injection and consider treatment with systemic steroids. (5.3) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue daptomycin for injection and institute appropriate treatment. (5.4) Tubulointerstitial Nephritis (TIN): Discontinue daptomycin for injection and institute appropriate treatment. (5.5)Peripheral neuropathy: Monitor for neuropathy and consider discontinuation. (5.6) Potential nervous system and/or muscular system effects in pediatric patients younger than 12 months: Avoid use of daptomycin for injection in this age group. (5.7) Clostridioides difficile-associated diarrhea: Evaluate patients if diarrhea occurs. (5.8) Persisting or relapsing S. aureus bacteremia/endocarditis: Perform susceptibility testing and rule out sequestered foci of infection. (5.9)Decreased efficacy was observed in adult patients with moderate baseline renal impairment. (5.10) Anaphylaxis/hypersensitivity reactions (including life-threatening): Discontinue daptomycin for injection and treat signs/symptoms. (5.1) Myopathy and rhabdomyolysis: Monitor CPK levels and follow muscle pain or weakness; if elevated CPK or myopathy occurs, consider discontinuation of daptomycin for injection. (5.2) Eosinophilic pneumonia: Discontinue daptomycin for injection and consider treatment with systemic steroids. (5.3) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue daptomycin for injection and institute appropriate treatment. (5.4) Tubulointerstitial Nephritis (TIN): Discontinue daptomycin for injection and institute appropriate treatment. (5.5). Peripheral neuropathy: Monitor for neuropathy and consider discontinuation. (5.6) Potential nervous system and/or muscular system effects in pediatric patients younger than 12 months: Avoid use of daptomycin for injection in this age group. (5.7) Clostridioides difficile-associated diarrhea: Evaluate patients if diarrhea occurs. (5.8) Persisting or relapsing S. aureus bacteremia/endocarditis: Perform susceptibility testing and rule out sequestered foci of infection. (5.9). Decreased efficacy was observed in adult patients with moderate baseline renal impairment. (5.10) 5.1 Anaphylaxis/Hypersensitivity Reactions Anaphylaxis/hypersensitivity reactions have been reported with the use of antibacterial agents, including daptomycin for injection, and may be life-threatening. If an allergic reaction to daptomycin for injection occurs, discontinue the drug and institute appropriate therapy [see Adverse Reactions (6.2)].. 5.2 Myopathy and Rhabdomyolysis Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal (ULN), has been reported with the use of daptomycin for injection. Rhabdomyolysis, with or without acute renal failure, has been reported [see Adverse Reactions (6.2)]. Patients receiving daptomycin for injection should be monitored for the development of muscle pain or weakness, particularly of the distal extremities. In patients who receive daptomycin for injection, CPK levels should be monitored weekly, and more frequently in patients who received recent prior or concomitant therapy with an HMG-CoA reductase inhibitor or in whom elevations in CPK occur during treatment with daptomycin for injection. In adult patients with renal impairment, both renal function and CPK should be monitored more frequently than once weekly [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].In Phase studies and Phase clinical trials in adults, CPK elevations appeared to be more frequent when daptomycin for injection was dosed more than once daily. Therefore, daptomycin for injection should not be dosed more frequently than once day. Daptomycin for injection should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevations to levels >1,000 U/L (~5x ULN), and in patients without reported symptoms who have marked elevations in CPK, with levels >2,000 U/L (>=10x ULN). In addition, consideration should be given to suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, temporarily in patients receiving daptomycin for injection [see Drug Interactions (7.1)].. 5.3 Eosinophilic Pneumonia Eosinophilic pneumonia has been reported in patients receiving daptomycin for injection [see Adverse Reactions (6.2)]. In reported cases associated with daptomycin for injection, patients developed fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates or organizing pneumonia. In general, patients developed eosinophilic pneumonia to weeks after starting daptomycin for injection and improved when daptomycin for injection was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving daptomycin for injection should undergo prompt medical evaluation, and daptomycin for injection should be discontinued immediately. Treatment with systemic steroids is recommended.. 5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). DRESS has been reported in post-marketing experience with daptomycin for injection [see Adverse Reactions (6.2)]. Patients who develop skin rash, fever, peripheral eosinophilia, and systemic organ (for example, hepatic, renal, pulmonary) impairment while receiving daptomycin for injection should undergo medical evaluation. If DRESS is suspected, discontinue daptomycin for injection promptly and institute appropriate treatment. 5.5 Tubulointerstitial Nephritis (TIN) TIN has been reported in post-marketing experience with daptomycin for injection [see Adverse Reactions (6.2)]. Patients who develop new or worsening renal impairment while receiving daptomycin for injection should undergo medical evaluation. If TIN is suspected, discontinue daptomycin for injection promptly and institute appropriate treatment.. 5.6 Peripheral Neuropathy. Cases of peripheral neuropathy have been reported during the daptomycin for injection postmarketing experience [see Adverse Reactions (6.2)]. Therefore, physicians should be alert to signs and symptoms of peripheral neuropathy in patients receiving daptomycin for injection.Monitor for neuropathy and consider discontinuation. 5.7 Potential Nervous System and/or Muscular System Effects in Pediatric Patients Younger than 12 Months Avoid use of daptomycin for injection in pediatric patients younger than 12 months due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs with intravenous daptomycin [see Nonclinical Toxicology (13.2)].. 5.8 Clostridioides difficile-Associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has been reported with the use of nearly all systemic antibacterial agents, including daptomycin for injection, and may range in severity from mild diarrhea to fatal colitis [see Adverse Reactions (6.2)]. Treatment with antibacterial agents alters the normal flora of the colon, leading to 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, since these infections can be refractory to antimicrobial 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 may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.. 5.9 Persisting or Relapsing S. aureus Bacteremia/Endocarditis Patients with persisting or relapsing S. aureus bacteremia/endocarditis or poor clinical response should have repeat blood cultures. If blood culture is positive for S. aureus, minimum inhibitory concentration (MIC) susceptibility testing of the isolate should be performed using standardized procedure, and diagnostic evaluation of the patient should be performed to rule out sequestered foci of infection. Appropriate surgical intervention (e.g., debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of change in antibacterial regimen may be required.Failure of treatment due to persisting or relapsing S. aureus bacteremia/endocarditis may be due to reduced daptomycin susceptibility (as evidenced by increasing MIC of the S. aureus isolate) [see Clinical Studies (14.2)].. 5.10 Decreased Efficacy in Patients with Moderate Baseline Renal Impairment Limited data are available from the two Phase complicated skin and skin structure infection (cSSSI) trials regarding clinical efficacy of daptomycin for injection treatment in adult patients with creatinine clearance (CLCR) <50 mL/min; only 31/534 (6%) patients treated with daptomycin for injection in the intent-to-treat (ITT) population had baseline CLCR <50 mL/min. Table shows the number of adult patients by renal function and treatment group who were clinical successes in the Phase cSSSI trials. Table 4. Clinical Success Rates by Renal Function and Treatment Group in Phase cSSSI Trials in Adult Patients (Population: ITT) CLCR Success Rate n/N (%)Daptomycin for Injection4 mg/kg q24hComparator50 to 70 mL/min25/38 (66%)30/48 (63%)30 to <50 mL/min7/15 (47%)20/35 (57%)In subgroup analysis of the ITT population in the Phase S. aureus bacteremia/endocarditis trial, clinical success rates, as determined by treatment-blinded Adjudication Committee [see Clinical Studies (14.2)], in the daptomycin for injection-treated adult patients were lower in patients with baseline CLCR <50 mL/min (see Table 5). decrease of the magnitude shown in Table was not observed in comparator-treated patients. Table 5. Adjudication Committee Clinical Success Rates at Test of Cure by Baseline Creatinine Clearance and Treatment Subgroup in the S. aureus Bacteremia/Endocarditis Trial in Adult Patients (Population: ITT)Baseline CLCR Success Rate n/N (%)Daptomycin For Injection6 mg/kg q24hComparatorBacteremiaRight-Sided Infective EndocarditisBacteremiaRight-Sided Infective Endocarditis>80 mL/min30/50 (60%)7/14 (50%)19/42 (45%)5/11 (46%)50 to 80 mL/min12/26 (46%)1/4 (25%)13/31 (42%)1/2 (50%)30 to <50 mL/min2/14 (14%)0/1 (0%)7/17 (41%)1/1 (100%)Consider these data when selecting antibacterial therapy for use in adult patients with baseline moderate to severe renal impairment.. 5.11 Drug-Laboratory Test Interactions Clinically relevant plasma concentrations of daptomycin have been observed to cause significant concentration-dependent false prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay [see Drug Interactions (7.2)].. 5.12 Non-Susceptible Microorganisms The use of antibacterials may promote the overgrowth of non-susceptible microorganisms. If these infections occur during therapy, appropriate measures should be taken. Prescribing daptomycin for injection in the absence of proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug- resistant bacteria.