(daptomycin for injection)
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)].
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 1 studies and Phase 2 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 a 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 (~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 for Injection [see Drug Interactions (7.1)].
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 2 to 4 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.
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.
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.
Cases of peripheral neuropathy have been reported during the daptomycin for injection post-marketing 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.
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)].
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 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.
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)].
Limited data are available from the two Phase 3 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 a baseline CLCR <50 mL/min. Table 2 shows the number of adult patients by renal function and treatment group who were clinical successes in the Phase 3 cSSSI trials.
| CLCR | Success Rate n/N (%) | |
|---|---|---|
| Daptomycin for Injection 4 mg/kg every 24h | Comparator | |
50–70 mL/min | 25/38 (66%) | 30/48 (63%) |
30–<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 for injection-treated adult patients were lower in patients with baseline CLCR <50 mL/min (see Table 3). A decrease of the magnitude shown in Table 3 was not observed in comparator-treated patients.
| Baseline CLCR | Success Rate n/N (%) | |||
|---|---|---|---|---|
| Daptomycin for Injection 6 mg/kg every 24h | 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%) |
50–80 mL/min | 12/26 (46%) | 1/4 (25%) | 13/31 (42%) | 1/2 (50%) |
30–<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.
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)].
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