warnings and cautions
5 WARNINGS AND PRECAUTIONS • Anaphylaxis/hypersensitivity reactions (including life-threatening): Discontinue daptomycin 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. ( 5.2 ) • Eosinophilic pneumonia: Discontinue daptomycin and consider treatment with systemic steroids. ( 5.3 ) • Peripheral neuropathy: Monitor for neuropathy and consider discontinuation. ( 5.4 ) • Potential nervous system and/or muscular system effects in pediatric patients younger than 12 months: Avoid use of daptomycin in this age group. ( 5.5 ) • Clostridium difficile –associated diarrhea: Evaluate patients if diarrhea occurs. ( 5.6 ) • Persisting or relapsing S. aureus bacteremia/endocarditis: Perform susceptibility testing and rule out sequestered foci of infection. ( 5.7 ) • Decreased efficacy was observed in adult patients with moderate baseline renal impairment. ( 5.8 ) 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. 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 HMGCoA 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 1 studies and Phase 2 clinical trials in adults, CPK elevations appeared to be more frequent when daptomycin was dosed more than once daily. Therefore, daptomycin should not be dosed more frequently than once a day. Daptomycin should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevations to levels >1,000 U/L (~5× ULN), and in patients without reported symptoms who have marked elevations in CPK, with levels >2,000 U/L (≥10× ULN). In addition, consideration should be given to suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, temporarily in patients receiving daptomycin [see Drug Interactions ( 7.1 )] . 5.3 Eosinophilic Pneumonia Eosinophilic pneumonia has been reported in patients receiving daptomycin [see Adverse Reactions ( 6.2 )] . In reported cases associated with daptomycin, patients developed fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates or organizing pneumonia. In general, patients developed eosinophilic pneumonia 2 to 4 weeks after starting daptomycin and improved when daptomycin 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 should undergo prompt medical evaluation, and daptomycin should be discontinued immediately. Treatment with systemic steroids is recommended. 5.4 Peripheral Neuropathy Cases of peripheral neuropathy have been reported during the daptomycin postmarketing experience [see Adverse Reactions ( 6.2 )] . Therefore, physicians should be alert to signs and symptoms of peripheral neuropathy in patients receiving daptomycin. Monitor for neuropathy and consider discontinuation. 5.5 Potential Nervous System and/or Muscular System Effects in Pediatric Patients Younger than 12 Months Avoid use of daptomycin 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 )] . 5.6 Clostridium difficile-Associated Diarrhea Clostridium difficile –associated diarrhea (CDAD) has been reported with the use of nearly all systemic antibacterial agents, including daptomycin, 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 A 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 2 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. 5.7 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 a blood culture is positive for S. aureus , minimum inhibitory concentration (MIC) susceptibility testing of the isolate should be performed using a 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 a 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 )] . 5.8 Decreased Efficacy in Patients with Moderate Baseline Renal Impairment Limited data are available from the two Phase 3 complicated skin and skin structure infection (cSSSI) trials regarding clinical efficacy of daptomycin treatment in adult patients with creatinine clearance (CL CR ) <50 mL/min; only 31/534 (6%) patients treated with daptomycin in the intent-to-treat (ITT) population had a baseline CL CR <50 mL/min. Table 3 shows the number of adult patients by renal function and treatment group who were clinical successes in the Phase 3 cSSSI trials. Table 3: Clinical Success Rates by Renal Function and Treatment Group in Phase 3 cSSSI Trials in Adult Patients (Population: ITT) CL CR Success Rate n/N (%) Daptomycin 4 mg/kg q24h Comparator 50 to 70 mL/min 25/38 (66%) 30/48 (63%) 30 to <50 mL/min 7/15 (47%) 20/35 (57%) In a subgroup analysis of the ITT population in the Phase 3 S. aureus bacteremia/endocarditis trial, clinical success rates, as determined by a treatment-blinded Adjudication Committee [see Clinical Studies ( 14.2 )] , in the daptomycin-treated adult patients were lower in patients with baseline CL CR <50 mL/min (see Table 4). A decrease of the magnitude shown in Table 4 was not observed in comparator treated patients. Table 4: 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 CL CR Success Rate n/N (%) Daptomycin 6 mg/kg q24h Comparator Bacteremia Right-Sided Infective Endocarditis Bacteremia Right-Sided Infective Endocarditis >80 mL/min 30/50 (60%) 7/14 (50%) 19/42 (45%) 5/11 (46%) 50 to 80 mL/min 12/26 (46%) 1/4 (25%) 13/31 (42%) 1/2 (50%) 30 to <50 mL/min 2/14 (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. 5.9 Drug-Laboratory Test Interactions Clinically relevant plasma concentrations of daptomycin have been observed to cause a 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 )]. 5.10 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 in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.