Pharmacy & Therapeutics - April 2008 - (Page 202) Brief summary of prescribing information. INDICATIONS AND USAGE CUBICIN (daptomycin for injection) is indicated for the following infections (see also DOSAGE AND ADMINISTRATION and CLINICAL STUDIES in full prescribing information): Complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, S. agalactiae, S. dysgalactiae subsp equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only). Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative or anaerobic organisms. Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates. Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative or anaerobic organisms. The efficacy of CUBICIN in patients with left-sided infective endocarditis due to S. aureus has not been demonstrated. The clinical trial of CUBICIN in 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 in full prescribing information). CUBICIN has not been studied in patients with prosthetic valve endocarditis or meningitis. Patients with persisting or relapsing S. aureus infection or poor clinical response should have repeat blood cultures. If a culture is positive for S. aureus, MIC susceptibility testing of the isolate should be performed using a standardized procedure, as well as diagnostic evaluation to rule out sequestered foci of infection (see PRECAUTIONS). CUBICIN is not indicated for the treatment of pneumonia. Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to daptomycin. Empiric therapy may be initiated while awaiting test results. Antimicrobial therapy should be adjusted as needed based upon test results. To reduce the development of drug-resistant bacteria and maintain the effectiveness of CUBICIN and other antibacterial drugs, CUBICIN 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 are available, they 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. CONTRAINDICATIONS CUBICIN is contraindicated in patients with known hypersensitivity to daptomycin. WARNINGS Clostridium difficile–associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CUBICIN, and may range in severity from mild diarrhea to fatal colitis. 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 antibiotic use. Careful medical history is necessary because CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. PRECAUTIONS General The use of antibiotics may promote the selection of non-susceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken. Prescribing CUBICIN 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 drugresistant bacteria. Persisting or Relapsing S. aureus Infection Patients with persisting or relapsing S. aureus infection or poor clinical response should have repeat blood cultures. If a culture is positive for S. aureus, MIC susceptibility testing of the isolate should be performed using a standardized procedure, as well as diagnostic evaluation to rule out sequestered foci of infection. Appropriate surgical intervention (eg, debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of a change in antibiotic regimen may be required. Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the Adjudication Committee in 19/120 (15.8%) CUBICIN-treated patients (12 with MRSA and 7 with MSSA) and 11/115 (9.6%) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with antistaphylococcal semi-synthetic penicillin). Among all failures, 6 CUBICINtreated patients and 1 vancomycin-treated patient developed increasing MICs (reduced susceptibility) by central laboratory testing on 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 CLINICAL STUDIES in full prescribing information). Skeletal Muscle In a Phase 1 study examining doses up to 12 mg/kg q24h of CUBICIN for 14 days, no skeletal muscle effects or CPK elevations were observed. In Phase 3 cSSSI trials of CUBICIN at a dose of 4 mg/kg, elevations in CPK were reported as clinical adverse events in 15/534 (2.8%) CUBICIN-treated patients, compared with 10/558 (1.8%) comparator-treated patients. In the S. aureus bacteremia/endocarditis trial, at a dose of 6 mg / kg, elevations in CPK were reported as clinical adverse events in 8/120 (6.7%) CUBICIN-treated patients compared with 1/116 ( 500 U/L) at baseline, 2/19 (10.5%) treated with CUBICIN and 4/24 (16.7%) treated with comparator developed further increases in CPK while on therapy. In this same population, no patients developed myopathy. CUBICIN-treated patients with baseline CPK >500 U/L (N=19) did not experience an increased incidence of CPK elevations or myopathy relative to those treated with comparator (N=24). In the S. aureus bacteremia/endocarditis study, 3 (2.6%) CUBICIN-treated patients, including 1 with trauma associated with a heroin overdose and 1 with spinal cord compression, had an elevation in CPK >500 U/L with associated musculoskeletal symptoms. None of the patients in the comparator group had an elevation in CPK >500 U/L with associated musculoskeletal symptoms. CUBICIN should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevation >1,000 U/L (~5x ULN), or in patients without reported symptoms who have marked elevations in CPK >2,000 U/L (≥10x ULN). In addition, consideration should be given to temporarily suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, in patients receiving CUBICIN. In a Phase 1 study examining doses up to 12 mg/kg q24h of CUBICIN for 14 days, no evidence of nerve conduction deficits or symptoms of peripheral neuropathy was observed. In a small number of patients in Phase 1 and Phase 2 studies at doses up to 6 mg/kg, administration of CUBICIN was associated with decreases in nerve conduction velocity and with adverse events (eg, paresthesias, Bell’s palsy) possibly reflective of peripheral or cranial neuropathy. Nerve conduction deficits were also detected in a similar number of comparator subjects in these studies. In Phase 3 cSSSI and communityacquired pneumonia (CAP) studies, 7/989 (0.7%) CUBICIN-treated patients and 7/1,018 (0.7%) comparator-treated patients experienced paresthesias. New or worsening peripheral neuropathy was not diagnosed in any of these patients. In the S. aureus bacteremia/endocarditis trial, a total of 11/120 (9.2%) CUBICIN-treated patients had treatment-emergent adverse events related to the peripheral nervous system. All of the events were classified as mild to moderate in severity; most were of short duration and resolved during continued treatment with CUBICIN or were likely due to an alternative etiology. In animals, effects of CUBICIN on peripheral nerve were observed (see ANIMAL PHARMACOLOGY in full prescribing information). Therefore, physicians should be alert to the possibility of signs and symptoms of neuropathy in patients receiving CUBICIN. Drug Interactions Warfarin Concomitant administration of CUBICIN (6 mg/kg q24h for 5 days) and warfarin (25 mg single oral dose) had no significant effect on the pharmacokinetics of either drug, and the INR was not significantly altered. As experience with the concomitant administration of CUBICIN and warfarin is limited, anticoagulant activity in patients receiving CUBICIN and warfarin should be monitored for the first several days after initiating therapy with CUBICIN (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions in full prescribing information). HMG-CoA Reductase Inhibitors Inhibitors of HMG-CoA reductase may cause myopathy, which is manifested as muscle pain or weakness associated with elevated levels of CPK. There were no reports of skeletal myopathy in a placebo-controlled Phase 1 trial in which 10 healthy subjects on stable simvastatin therapy were treated concurrently with CUBICIN (4 mg/kg q24h) for 14 days. In the Phase 3 S. aureus bacteremia/endocarditis trial, 5/22 CUBICIN-treated patients who received prior or concomitant therapy with an HMG-CoA reductase inhibitor developed CPK elevations >500 U/L. Experience with co-administration
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