Daptomycin In Sodium Chloride

1 INDICATIONS AND USAGE Daptomycin in Sodium Chloride Injection is a 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) for whom appropriate dosing can be achieved ( 1.1 ) and, • Staphylococcus aureus bloodstream infections (bacteremia), in adult patients for whom appropriate dosing can be achieved, including those with right-sided infective endocarditis, ( 1.2 ) • Staphylococcus aureus bloodstream infections (bacteremia) in pediatric patients (1 to 17 years of age) for whom appropriate dosing can be achieved. ( 1.3 ) Limitations of Use • Daptomycin in Sodium Chloride Injection is not indicated for the treatment of pneumonia. ( 1.4 ) • Daptomycin in Sodium Chloride Injection is not indicated for the treatment of left-sided infective endocarditis due to S. aureus. ( 1.4 ) • Daptomycin in Sodium Chloride 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 in Sodium Chloride Injection and other antibacterial drugs, Daptomycin in Sodium Chloride Injection should be used to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.5 ) 1.1 Complicated Skin and Skin Structure Infections (cSSSI) Daptomycin in Sodium Chloride Injection is indicated for the treatment of adult and pediatric patients (1 to 17 years of age) for whom appropriate dosing can be achieved, 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 in Sodium Chloride Injection is indicated for the treatment of adult patients for whom appropriate dosing can be achieved, 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 in Sodium Chloride Injection is indicated for the treatment of pediatric patients (1 to 17 years of age) for whom appropriate dosing can be achieved with Staphylococcus aureus bloodstream infections (bacteremia). 1.4 Limitations of Use Daptomycin in Sodium Chloride Injection is not indicated for the treatment of pneumonia. Daptomycin in Sodium Chloride 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 Studies (14.2) ]. Daptomycin for injection has not been studied in patients with prosthetic valve endocarditis. Daptomycin in Sodium Chloride Injection is not recommended in pediatric patients younger than 1 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 in Sodium Chloride Injection and other antibacterial drugs, Daptomycin in Sodium Chloride Injection should be used only to treat or prevent 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.

2 DOSAGE AND ADMINISTRATION If a dose of Daptomycin in Sodium Chloride Injection is required that does not equal 350 mg, 500 mg, 700 mg or 1,000 mg, this product is not recommended for use and an alternative formulation of daptomycin should be considered. ( 2.1 ) Adult Patients • Administer to adult patients intravenously by infusion over a 30-minute period. ( 2.1 , 2.7 ) • Recommended dosage regimen for adult patients ( 2.2 , 2.4 , 2.6 ): Creatinine Clearance (CL CR ) Dosage Regimen cSSSI For 7 to 14 days S. aureus Bacteremia For 2 to 6 weeks ≥30 mL/min 4 mg/kg once every 24 hours 6 mg/kg once every 24 hours <30 mL/min, including hemodialysis and CAPD 4 mg/kg once every 48 hours* 6 mg/kg once every 48 hours* *Administered following hemodialysis on hemodialysis days. Pediatric Patients • Administer to pediatric patients intravenously by infusion over a 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 5 mg/kg once every 24 hours infused over 30 minutes Up to 14 days 7 to 11 years 7 mg/kg once every 24 hours infused over 30 minutes 2 to 6 years 9 mg/kg once every 24 hours infused over 60 minutes 1 to less than 2 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 7 mg/kg once every 24 hours infused over 30 minutes Up to 42 days 7 to 11 years 9 mg/kg once every 24 hours infused over 30 minutes 1 to 6 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. 2.1 Important Administration Duration Instructions If a dose of Daptomycin in Sodium Chloride Injection is required that does not equal 350 mg, 500 mg, 700 mg or 1,000 mg, this product is not recommended for use and an alternative formulation of daptomycin should be considered. Adult Patients: Administer the appropriate dose of Daptomycin in Sodium Chloride Injection to adult patients by intravenous infusion over a thirty (30) minute period [see Dosage and Administration (2.2 , 2.4 , 2.7) ] . Pedatric Patients (1 to 17 Years of Age) • Pediatric Patients 7 to 17 years of Age: Administer Daptomycin in Sodium Chloride Injection intravenously by infusion over a 30-minute period [see Dosage and Administration (2.3 , 2.5 , 2.7) ]. • Pediatric Patients 1 to 6 years of Age: Administer Daptomycin in Sodium Chloride Injection intravenously by infusion over a 60-minute period [see Dosage and Administration (2.3 , 2.5 , 2.7) ]. 2.2 Dosage in Adults for cSSSI Administer Daptomycin in Sodium Chloride Injection 4 mg/kg to adult patients intravenously once every 24 hours for 7 to 14 days. 2.3 Dosage in Pediatric Patients (1 to 17 Years of Age) for cSSSI If a dose of Daptomycin in Sodium Chloride Injection is required that does not equal 350 mg, 500 mg, 700 mg or 1,000 mg, this product is not recommended for use and an alternative formulation of daptomycin should be considered. The recommended dosage regimens based on age for pediatric patients with cSSSI are shown in Table 1 . Administer Daptomycin in Sodium Chloride Injection intravenously once every 24 hours for up to 14 days. Table 1. Recommended Dosage of Daptomycin in Sodium Chloride Injection in Pediatric Patients (1 to 17 Years of Age) with cSSSI, Based on Age Age Range Dosage Regimen* Duration of therapy 12 to 17 years 5 mg/kg once every 24 hours infused over 30 minutes Up to 14 days 7 to 11 years 7 mg/kg once every 24 hours infused over 30 minutes 2 to 6 years 9 mg/kg once every 24 hours infused over 60 minutes 1 to less than 2 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 in Sodium Chloride Injection 6 mg/kg to adult patients intravenously once every 24 hours for 2 to 6 weeks. There are limited safety data for the use of daptomycin for injection for more than 28 days of therapy. In the Phase 3 trial, there were a 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) If a dose of Daptomycin in Sodium Chloride Injection is required that does not equal 350 mg, 500 mg, 700 mg or 1,000 mg, this product is not recommended for use and an alternative formulation of daptomycin should be considered. The recommended dosage regimens based on age for pediatric patients with S. aureus bloodstream infections (bacteremia) are shown in Table 2 . Administer Daptomycin in Sodium Chloride Injection intravenously once every 24 hours for up to 42 days. Table 2. Recommended Dosage of Daptomycin in Sodium Chloride Injection in Pediatric Patients (1 to 17 Years of Age) with S. aureus Bacteremia, Based on Age Age Dosage* Duration of therapy 12 to 17 years 7 mg/kg once every 24 hours infused over 30 minutes Up to 42 days 7 to 11 years 9 mg/kg once every 24 hours infused over 30 minutes 1 to 6 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 (CL CR ) greater than or equal to 30 mL/min. The recommended dosage regimen for Daptomycin in Sodium Chloride Injection in adult patients with CL CR less than 30 mL/min, including adult patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), is 4 mg/kg (cSSSI) or 6 mg/kg ( S. aureus bloodstream infections) once every 48 hours ( Table 3 ). When possible, Daptomycin in Sodium Chloride 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 in Sodium Chloride Injection in Adult Patients Creatinine Clearance (CL CR ) Dosage Regimen in Adults cSSSI S. aureus Bloodstream Infections Greater than or equal to 30 mL/min 4 mg/kg once every 24 hours 6 mg/kg once every 24 hours Less than 30 mL/min, including hemodialysis and CAPD 4 mg/kg once every 48 hours* 6 mg/kg once every 48 hours* *When possible, administer Daptomycin in Sodium Chloride Injection following the completion of hemodialysis on hemodialysis days. Pediatric Patients: The dosage regimen for Daptomycin in Sodium Chloride Injection in pediatric patients with renal impairment has not been established. 2.7 Preparation and Administration of Daptomycin in Sodium Chloride Injection Thawing of Plastic Container • Thaw frozen container at room temperature 20°C to 25°C (68°F to 77°F) or under refrigeration 2°C to 8°C (36°F to 46°F). Product should not be thawed by immersion in water baths or by microwave irradiation. Do not force thaw. • No further dilution is necessary. • Check for minute leaks by squeezing container firmly. If leaks are detected, discard solution as sterility may be impaired. • Do not add supplementary medication. • The container should be visually inspected. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. • Thaw and equilibrate container to a room temperature. • Agitate after solution has reached room temperature. If after visual inspection the solution remains cloudy or if an insoluble precipitate is noted or if any seals are not intact, the container should be discarded. • Solution should be clear and slightly yellow in color. • The thawed solution is stable for 30 days under refrigeration (5°C/41°F) or 48 hours at room temperature (25°C/77°F). Do not refreeze thawed antibacterial drugs . Preparation for Administration • Suspend container from support. • Remove protector from outlet port at bottom of container. • Attach Intravenous administration set to outlet port. Refer to the manufacturer’s instructions accompanying the administration set for complete directions. Administration Instructions Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Adults Intravenous Infusion over a period of 30 minutes • For intravenous infusion over a period of 30 minutes in adult patients: The appropriate dose of Daptomycin in Sodium Chloride Injection should be used, based on patient weight. Pediatric Patients (1 to 17 Years of Age) Intravenous Infusion over a period of 30 or 60 minutes • For Intravenous infusion over a period of 60 minutes in pediatric patients 1 to 6 years of age: The appropriate dose of Daptomycin in Sodium Chloride Injection should be used, based on patient weight. The infusion rate should be maintained at 0.83 mL/min for a 50 mL GALAXY container and 1.67 mL/min for a 100 mL GALAXY container over the 60-minute period. • For Intravenous infusion over a period of 30 minutes in pediatric patients 7 to 17 years of age : The appropriate dose of Daptomycin in Sodium Chloride Injection should be used, based on patient weight. The infusion rate should be maintained at 1.67 mL/min for a 50 mL GALAXY container and 3.33 mL/min for a 100 mL GALAXY container over the 30-minute period. Do not exceed the In-Use storage conditions of Daptomycin in Sodium Chloride Injection described below. Discard unused portions of Daptomycin in Sodium Chloride Injection. In-Use Storage Conditions for Daptomycin in Sodium Chloride Injection The thawed solution is stable for 30 days under refrigeration (5°C/41°F) or 48 hours at 25°C/77°F. Do not refreeze thawed antibacterial drugs . 2.8 Incompatibilities Because only limited data are available on the compatibility of daptomycin with other intravenous substances, additives and other medications should not be added to Daptomycin in Sodium Chloride Injection ready to use infusion bags, or infused simultaneously with Daptomycin in Sodium Chloride Injection through the same IV line. If the same intravenous line is used for sequential infusion of different drugs, the line should be flushed with a compatible intravenous solution before and after infusion with Daptomycin in Sodium Chloride Injection.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • 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 for injection 4 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 for injection 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 for injection 6 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 for injection were vomiting and elevated CPK. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trial Experience in Adult Patients Clinical trials enrolled 1,864 adult patients treated with daptomycin for injection and 1,416 treated with comparator. Complicated Skin and Skin Structure Infection Trials in Adults In Phase 3 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 (3.0%) patients. The rates of the most common adverse reactions, organized by body system, observed in adult patients with cSSSI (receiving 4 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 3 cSSSI Trials Adverse Reaction Adult Patients (%) Daptomycin for Injection 4 mg/kg (N=534) Comparator Comparator: vancomycin (1 g IV every 12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g/day IV in divided doses). (N=558) Gastrointestinal disorders Diarrhea 5.2 4.3 Nervous system disorders Headache 5.4 5.4 Dizziness 2.2 2.0 Skin/subcutaneous disorders Rash 4.3 3.8 Diagnostic investigations Abnormal liver function tests 3.0 1.6 Elevated CPK 2.8 1.8 Infections Urinary tract infections 2.4 0.5 Vascular disorders Hypotension 2.4 1.4 Respiratory disorders Dyspnea 2.1 1.6 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 a Whole: fatigue, weakness, rigors, flushing, hypersensitivity Blood/Lymphatic System: leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased International Normalized Ratio (INR) Cardiovascular System: supraventricular arrhythmia Dermatologic System: eczema Digestive System: abdominal distension, stomatitis, jaundice, increased serum lactate dehydrogenase Metabolic/Nutritional System: hypomagnesemia, increased serum bicarbonate, electrolyte disturbance Musculoskeletal System: myalgia, muscle cramps, muscle weakness, arthralgia Nervous System: vertigo, mental status change, paresthesia Special Senses: taste disturbance, eye irritation S. aureus Bacteremia/Endocarditis Trial in Adults In 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 4 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 Crohn’s disease, recurrent line sepsis, and recurrent urosepsis caused by a 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 6 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 Trial Adverse Reaction NOS, not otherwise specified. Adult Patients n (%) Daptomycin for Injection 6 mg/kg (N=120) Comparator Comparator: vancomycin (1 g IV every 12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 2 g IV every 4h), each with initial low-dose gentamicin. (N=116) Infections and infestations Sepsis NOS 6 (5%) 3 (3%) Bacteremia 6 (5%) 0 (0%) Gastrointestinal disorders Abdominal pain NOS 7 (6%) 4 (3%) General disorders and administration site conditions Chest pain 8 (7%) 7 (6%) Edema NOS 8 (7%) 5 (4%) Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain 10 (8%) 2 (2%) Skin and subcutaneous tissue disorders Pruritus 7 (6%) 6 (5%) Sweating increased 6 (5%) 0 (0%) Psychiatric disorders Insomnia 11 (9%) 8 (7%) Investigations Blood creatine phosphokinase increased 8 (7%) 1 (1%) Vascular disorders Hypertension NOS 7 (6%) 3 (3%) 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, thrombocytopenia Cardiac Disorders: atrial fibrillation, atrial flutter, cardiac arrest Ear and Labyrinth Disorders: tinnitus Eye Disorders: vision blurred Gastrointestinal Disorders: dry mouth, epigastric discomfort, gingival pain, hypoesthesia oral Infections and Infestations: candidal infection NOS, vaginal candidiasis, fungemia, oral candidiasis, urinary tract infection fungal Investigations: blood phosphorous increased, blood alkaline phosphatase increased, INR increased, liver function test abnormal, alanine aminotransferase increased, aspartate aminotransferase increased, prothrombin time prolonged Metabolism and Nutrition Disorders: appetite decreased NOS Musculoskeletal and Connective Tissue Disorders: myalgia Nervous System Disorders: dyskinesia, paresthesia Psychiatric Disorders: hallucination NOS Renal and Urinary Disorders: proteinuria, renal impairment NOS Skin and Subcutaneous Tissue Disorders: pruritus generalized, rash vesicular Other Trials in Adults In Phase 3 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 Adults Complicated Skin and Skin Structure Infection Trials in Adults In Phase 3 cSSSI trials of adult patients receiving daptomycin for injection at a dose of 4 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, 1 (0.2%) had symptoms of muscle pain or weakness associated with CPK elevations to greater than 4 times the upper limit of normal (ULN). The symptoms resolved within 3 days and CPK returned to normal within 7 to 10 days after treatment was discontinued [see Warnings and Precautions (5.2) ] . Table 8 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 3 cSSSI Adult Trials All Adult Patients Adult Patients with Normal CPK at Baseline Change in CPK Daptomycin for Injection 4 mg/kg (N=430) Comparator Comparator: vancomycin (1 g IV every 12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g/day IV in divided doses). (N=459) Daptomycin for Injection 4 mg/kg (N=374) Comparator (N=392) % n % n % n % n No Increase 90.7 390 91.1 418 91.2 341 91.1 357 Maximum Value>1× ULN ULN (Upper Limit of Normal) is defined as 200 U/L. 9.3 40 8.9 41 8.8 33 8.9 35 >2× ULN 4.9 21 4.8 22 3.7 14 3.1 12 >4× ULN 1.4 6 1.5 7 1.1 4 1.0 4 >5× ULN 1.4 6 0.4 2 1.1 4 0.0 0 >10× ULN 0.5 2 0.2 1 0.2 1 0.0 0 Note: Elevations in CPK observed in adult patients treated with daptomycin or comparator were not clinically or statistically significantly different. S. aureus Bacteremia/Endocarditis Trial in Adults In the S. aureus bacteremia/endocarditis trial in adult patients, at a dose of 6 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, 4 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 for injection was evaluated in one clinical trial (in cSSSI), which included 256 pediatric patients (1 to 17 years of age) treated with intravenous daptomycin for injection and 133 patients treated with comparator agents. Patients were given age-dependent doses once daily for a treatment period of up to 14 days (median treatment period was 3 days). The doses given by age group were as follows: 10 mg/kg for 1 to < 2 years, 9 mg/kg for 2 to 6 years, 7 mg/kg for 7 to 11 years and 5 mg/kg for 12 to 17 years of age [see Clinical Studies (14) ] . Patients treated with daptomycin for injection were (51%) male, (49%) female and (46%) Caucasian and (32%) Asian. Adverse Reactions Leading to Discontinuation In the cSSSI study, daptomycin for injection 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 for Injection Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the cSSSI Pediatric Trial Adverse Reaction Daptomycin for Injection (N = 256) Comparator Comparators included intravenous therapy with either vancomycin, clindamycin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin) (N = 133) n (%) n (%) Gastrointestinal disorders Diarrhea 18 (7.0) 7 (5.3) Vomiting 7 (2.7) 1 (0.8) Abdominal Pain 5 (2.0) 0 Skin and subcutaneous tissue disorders Pruritus 8 (3.1) 2 (1.5) General disorders and administration site conditions Pyrexia 10 (3.9) 4 (3.0) Investigations Blood CPK increased 14 (5.5) 7 (5.3) Nervous system disorders Headache 7 (2.7) 3 (2.3) 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 for injection was evaluated in one clinical trial (in S. aureus bacteremia), which treated 55 pediatric patients with intravenous daptomycin for injection and 26 patients with comparator agents. Patients were given age-dependent doses once daily for a 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 1 to <6 years, 9 mg/kg for 7 to 11 years and 7 mg/kg for 12 to 17 years of age [see Clinical Studies (14) ] . Patients treated with daptomycin for injection were (69%) male and (31%) female. No patients 1 to <2 years of age were enrolled. Adverse Reactions Leading to Discontinuation In the bacteremia study, daptomycin for injection 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 for Injection Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the Pediatric Bacteremia Trial Adverse Reaction Daptomycin for Injection (N = 55) Comparator (N = 26) n (%) n (%) Gastrointestinal disorders Vomiting 6 (10.9) 2 (7.7) Investigations Blood CPK increased 4 (7.3) 0 *Comparators included intravenous therapy with either vancomycin, cefazolin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin) 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of daptomycin for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: anemia, thrombocytopenia General and administration site conditions: pyrexia Immune System Disorders: anaphylaxis; hypersensitivity reactions, including angioedema, pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia [see Contraindications (4) and Warnings and Precautions (5.1) ] Infections and Infestations: Clostridioides difficile –associated diarrhea [see Warnings and Precautions (5.8) ] Laboratory Investigations: platelet count decreased Musculoskeletal 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), vesiculobullous rash (with or without mucous membrane involvement, including Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]), and acute generalized exanthematous pustulosis [see Warnings and Precautions (5.4) ] Gastrointestinal Disorders: nausea, vomiting Metabolic and Nutritional Disorders : hyperkalemia 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

12.3 Pharmacokinetics Daptomycin for Injection Administered over a 30-Minute Period in Adults The mean and standard deviation (SD) pharmacokinetic parameters of daptomycin at steady-state following intravenous (IV) administration of daptomycin for injection over a 30-minute period at 4 to 12 mg/kg every 24h to healthy young adults are summarized in Table 11 . Table 11. Mean (SD) Daptomycin Pharmacokinetic Parameters in Healthy Adult Volunteers at Steady-State Dose Daptomycin was administered by IV infusion over a 30-minute period. Doses of Daptomycin in excess of 6 mg/kg have not been approved. (mg/kg) Pharmacokinetic Parameters AUC 0-24 , area under the concentration-time curve from 0 to 24 hours; t 1/2 , elimination half-life; V ss , volume of distribution at steady-state; CL T , total plasma clearance; C max , maximum plasma concentration. AUC 0-24 (mcg•h/mL) t 1/2 (h) V ss (L/kg) CL T (mL/h/kg) C max (mcg/mL) 4 (N=6) 494 (75) 8.1 (1.0) 0.096 (0.009) 8.3 (1.3) 57.8 (3.0) 6 (N=6) 632 (78) 7.9 (1.0) 0.101 (0.007) 9.1 (1.5) 93.9 (6.0) 8 (N=6) 858 (213) 8.3 (2.2) 0.101 (0.013) 9.0 (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) 9.0 (2.8) 183.7 (25.0) Daptomycin pharmacokinetics were generally linear and time-independent at daptomycin for injection doses of 4 to 12 mg/kg every 24h administered by IV infusion over a 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 every 24h 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. Distribution Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a 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 a trend toward decreasing serum protein binding among subjects with CL CR <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 (V ss ) of daptomycin in healthy adult subjects was approximately 0.1 L/kg and was independent of dose. Elimination Metabolism In in vitro studies, daptomycin was not metabolized by human liver microsomes. In 5 healthy adults after infusion of radiolabeled 14 C-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 a separate study, no metabolites were observed in plasma on Day 1 following the administration of daptomycin for injection at 6 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. Excretion Daptomycin is excreted primarily by the kidneys. In a mass balance study of 5 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 9 days) based on total radioactivity. Specific Populations Patients with Renal Impairment Population-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 (CL T ), elimination half-life (t 1/2 ), and volume of distribution at steady-state (V ss ) in patients with cSSSI were similar to those in patients with S. aureus bacteremia. Following administration of daptomycin for injection 4 mg/kg every 24h by IV infusion over a 30-minute period, the mean CL T was 9%, 22%, and 46% lower among subjects and patients with mild (CL CR 50–80 mL/min), moderate (CL CR 30–<50 mL/min), and severe (CL CR <30 mL/min) renal impairment, respectively, than in those with normal renal function (CL CR >80 mL/min). The mean steady-state systemic exposure (AUC), t 1/2 , and V ss increased with decreasing renal function, although the mean AUC for patients with CL CR 30–80 mL/min was not markedly different from the mean AUC for patients with normal renal function. The mean AUC for patients with CL CR <30 mL/min and for patients on dialysis (CAPD and hemodialysis dosed post-dialysis) was approximately 2 and 3 times higher, respectively, than for patients with normal renal function. The mean C max ranged from 60 to 70 mcg/mL in patients with CL CR ≥30 mL/min, while the mean C max for patients with CL CR <30 mL/min ranged from 41 to 58 mcg/mL. After administration of daptomycin for injection 6 mg/kg every 24h by IV infusion over a 30-minute period, the mean C max 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 4 mg/kg or 6 mg/kg to Infected Adult Patients and Noninfected Adult Subjects with Various Degrees of Renal Function Renal Function Pharmacokinetic Parameters CL CR , creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; CAPD, continuous ambulatory peritoneal dialysis; AUC 0-∞ , area under the concentration-time curve extrapolated to infinity; AUC ss , area under the concentration-time curve calculated over the 24-hour dosing interval at steady-state; C min,ss , trough concentration at steady-state; NA, not applicable. t 1/2 Parameters obtained following a single dose from patients with complicated skin and skin structure infections and healthy subjects. (h) 4 mg/kg V ss (L/kg) 4 mg/kg CL T (mL/h/kg) 4 mg/kg AUC 0-∞ (mcg•h/mL) 4 mg/kg AUC ss Parameters obtained at steady-state from patients with S. aureus bacteremia. (mcg•h/mL) 6 mg/kg C min,ss (mcg/mL) 6 mg/kg Normal (CL CR >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 (CL CR 50– 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 (CL CR 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 19.0 (9.0) N=14 Severe Renal Impairment (CL CR <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 was administered over a 30-minute period. Because renal excretion is the primary route of elimination, adjustment of Daptomycin in Sodium Chloride Injection dosage interval is necessary in adult patients with severe renal impairment (CL CR <30 mL/min) [see Dosage and Administration (2.6) ]. Patients with Hepatic Impairment The 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 in Sodium Chloride 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. Gender No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when Daptomycin in Sodium Chloride Injection is administered. Geriatric Patients The 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 a single 4 mg/kg dose of daptomycin for injection by IV infusion over a 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC 0-∞ was approximately 58% higher in elderly subjects than in healthy young adult subjects. There were no differences in C max [see Use in Specific Populations (8.5) ]. Obese Patients The pharmacokinetics of daptomycin were evaluated in 6 moderately obese (Body Mass Index [BMI] 25 to 39.9 kg/m 2 ) and 6 extremely obese (BMI ≥40 kg/m 2 ) adult subjects and controls matched for age, gender, and renal function. Following administration of daptomycin for injection by IV infusion over a 30-minute period as a single 4 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 AUC 0-∞ 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 in Sodium Chloride Injection dosage is warranted in obese patients. Pediatric Patients The pharmacokinetics of daptomycin in pediatric subjects was evaluated in 3 single-dose pharmacokinetic studies. In general, body weight-normalized total body clearance in pediatric patients was higher than in adults and increased with a decrease of age, whereas elimination half-life tends to decrease with a decrease of age. Body weight-normalized total body clearance and elimination half-life of daptomycin in children 2 to 6 years of age were similar at different doses. A 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 4 age groups [see Clinical Studies (14.1) ] , and intravenous daptomycin for injection doses of 5 to 10 mg/kg once daily were administered. Following administration of multiple doses, daptomycin exposure (AUC ss and C max,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 Patients Age Pharmacokinetic Parameters Dose (mg/kg) Infusion Duration (min) AUC ss (mcg•h/mL) t 1/2 (h) V ss (mL) CL T (mL/h/kg) C max,ss (mcg/mL) 12 to 17 years (N=6) 5 30 434 (67.9) 7.1 (0.9) 8200 (3250) 11.8 (2.15) 76.4 (6.75) 7 to 11 years (N=2) 7 30 543 Mean is calculated from N=2 6.8 4470 13.2 92.4 2 to 6 years (N=7) 9 60 452 (93.1) 4.6 (0.8) 2750 (832) 20.8 (4.29) 90.3 (14.0) 1 to less than 2 years (N=27) 10 60 462 (138) 4.8 (0.6) 1670 (446) 23.1 (5.43) 81.6 (20.7) AUC ss , area under the concentration-time curve at steady state; CL T , clearance normalized to body weight; V ss , volume of distribution at steady state; t ½ , terminal half-life A study was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in pediatric patients with S. aureus bacteremia. Patients were enrolled into 3 age groups [see Clinical Studies (14.2) ] , and intravenous doses of 7 to 12 mg/kg once daily were administered. Following administration of multiple doses, daptomycin exposure (AUC ss and C max,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 Patients Pharmacokinetic Parameters Age Dose (mg/kg) Infusion Duration (min) AUC ss (mcg•h/mL) t 1/2 (h) V ss (mL) CL T (mL/h/kg) C max,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) 7 to 11 years (N=19) 9 30 579 (116) 6.0 (0.8) 4510 (1470) 15.9 (2.8) 104 (14.5) 2 to 6 years (N=19) 12 60 620 (109) 5.1 (0.6) 2200 (570) 19.9 (3.4) 106 (12.8) AUC ss , area under the concentration-time curve at steady state; CL T , clearance normalized to body weight; V ss , volume of distribution at steady state; t ½ , terminal half-life No patients 1 to <2 years of age were enrolled in the study. Simulation using a population pharmacokinetic model demonstrated that the AUC ss of daptomycin in pediatric patients 1 to <2 years of age receiving 12 mg/kg once daily would be comparable to that in adult patients receiving 6 mg/kg once daily. Drug Interaction Studies In 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. Aztreonam In a study in which 15 healthy adult subjects received a single dose of daptomycin for injection 6 mg/kg IV and a combination dose of daptomycin for injection 6 mg/kg IV and aztreonam 1 g IV, administered over a 30-minute period, the C max and AUC 0-∞ of daptomycin were not significantly altered by aztreonam. Tobramycin In a study in which 6 healthy adult males received a single dose of daptomycin for injection 2 mg/kg IV, tobramycin 1 mg/kg IV, and both in combination, administered over a 30-minute period, the mean C max and AUC 0-∞ of daptomycin were 12.7% and 8.7% higher, respectively, when daptomycin for injection was coadministered with tobramycin. The mean C max and AUC 0-∞ 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 a clinical dose of Daptomycin in Sodium Chloride Injection is unknown. Warfarin In 16 healthy adult subjects, administration of daptomycin for injection 6 mg/kg every 24h by IV infusion over a 30-minute period for 5 days, with coadministration of a 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). Simvastatin In 20 healthy adult subjects on a stable daily dose of simvastatin 40 mg, administration of daptomycin for injection 4 mg/kg every 24h by IV infusion over a 30-minute period for 14 days (N=10) had no effect on plasma trough concentrations of simvastatin and was not associated with a 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) ]. Probenecid Concomitant administration of probenecid (500 mg 4 times daily) and a single dose of daptomycin for injection 4 mg/kg by IV infusion over a 30-minute period in adults did not significantly alter the C max or AUC 0-∞ of daptomycin.