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The following adverse reactions are described, or described in greater detail, in other sections:
- Anaphylaxis/hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
- Myopathy and rhabdomyolysis [see WARNINGS AND PRECAUTIONS]
- Eosinophilic pneumonia [see WARNINGS AND PRECAUTIONS]
- Peripheral neuropathy [see WARNINGS AND PRECAUTIONS]
- Increased International Normalized Ratio (INR)/prolonged prothrombin time [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials Experience
Clinical trials enrolled 1,864 patients treated with CUBICIN and 1,416 treated with comparator.
Complicated Skin And Skin Structure Infection Trials
In Phase 3 complicated skin and skin structure infection (cSSSI) trials, CUBICIN 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 cSSSI (4 mg/kg CUBICIN) patients are displayed in Table 4.
Table 4: Incidence of Adverse Reactions that Occurred
in ≥ 2% of Patients in the CUBICIN Treatment Group and ≥ the
Comparator Treatment Group in Phase 3 cSSSI Trials
|Adverse Reaction||Patients (%)|
|CUBICIN 4 mg/kg
|Nervous system disorders|
|Abnormal liver function tests||3.0||1.6|
|Urinary tract infections||2.4||0.5|
|*Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g/day IV in divided doses).|
Drug-related adverse reactions (possibly or probably drug-related) that occurred in < 1% of patients receiving CUBICIN in the cSSSI trials are as follows:
Body as a Whole: fatigue, weakness, rigors, flushing, hypersensitivity
Cardiovascular System: supraventricular arrhythmia
Dermatologic System: eczema
Special Senses: taste disturbance, eye irritation
S. Aureus Bacteremia/Endocarditis Trial
Serious Gram-negative infections (including bloodstream infections) were reported in 10/120 (8.3%) CUBICIN-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 S. aureus bacteremia/endocarditis (6 mg/kg CUBICIN) patients are displayed in Table 5.
Table 5: Incidence of Adverse Reactions that Occurred
in ≥ 5% of Patients in the CUBICIN Treatment Group and ≥ the
Comparator Treatment Group in the S. aureus Bacteremia/Endocarditis
|Adverse Reaction*||Patients n (%)|
|CUBICIN 6 mg/kg
|Infections and infestations|
|Sepsis NOS||6 (5%)||3 (3%)|
|Bacteremia||6 (5%)||0 (0%)|
|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%)|
|Insomnia||11 (9%)||8 (7%)|
|Blood creatine phosphokinase increased||8 (7%)||1 (1%)|
|Hypertension NOS||7 (6%)||3 (3%)|
|*NOS, not otherwise specified.
†Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 2 g IV q4 h), each with initial low-dose gentamicin.
The following reactions, not included above, were reported as possibly or probably drug-related in the CUBICIN-treated group:
Ear and Labyrinth Disorders: tinnitus
Eye Disorders: vision blurred
Gastrointestinal Disorders: dry mouth, epigastric discomfort, gingival pain, hypoesthesia oral
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
In Phase 3 trials of community-acquired pneumonia (CAP), the death rate and rates of serious cardiorespiratory adverse events were higher in CUBICIN-treated patients than in comparator-treated patients. These differences were due to lack of therapeutic effectiveness of CUBICIN in the treatment of CAP in patients experiencing these adverse events [see INDICATIONS AND USAGE].
Complicated Skin and Skin Structure Infection Trials
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%) comparatortreated patients. Of the 534 patients treated with CUBICIN, 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]. Table 6 summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI trials.
Table 6: Incidence of CPK Elevations from Baseline
during Therapy in Either the CUBICIN Treatment Group or the Comparator
Treatment Group in Phase 3 cSSSI Trials
|Change in CPK||All Patients||Patients with Normal CPK at Baseline|
|CUBICIN 4 mg/kg (N=430)||Comparator* (N=459)||CUBICIN 4 mg/kg (N=374)||Comparator* (N=392)|
|Maximum Value > 1x ULN†||9.3||40||8.9||41||8.8||33||8.9||35|
|> 2x ULN||4.9||21||4.8||22||3.7||14||3.1||12|
|> 4x ULN||1.4||6||1.5||7||1.1||4||1.0||4|
|> 5x ULN||1.4||6||0.4||2||1.1||4||0.0||0|
|> 10x ULN||0.5||2||0.2||1||0.2||1||0.0||0|
|Note: Elevations in CPK observed in patients treated with
CUBICIN or comparator were not clinically or statistically significantly
*Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 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 the S. aureus bacteremia/endocarditis trial, at a dose of 6 mg/kg, 11/120 (9.2%) CUBICIN-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 CUBICIN-treated patients, 4 had prior or concomitant treatment with an HMG-CoA reductase inhibitor. Three of these 11 CUBICINtreated patients discontinued therapy due to CPK elevation, while the one comparator-treated patient did not discontinue therapy [see WARNINGS AND PRECAUTIONS].
The following adverse reactions have been identified during postapproval use of CUBICIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure.
Immune System Disorders: anaphylaxis; hypersensitivity reactions, including angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]
Infections and Infestations: Clostridium difficile–associated diarrhea [see WARNINGS AND PRECAUTIONS]
Musculoskeletal Disorders: myoglobin increased; rhabdomyolysis (some reports involved patients treated concurrently with CUBICIN and HMG-CoA reductase inhibitors) [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY]
Respiratory, Thoracic, and Mediastinal Disorders: cough, eosinophilic pneumonia [see WARNINGS AND PRECAUTIONS]
Gastrointestinal Disorders: nausea, vomiting
Special Senses: visual disturbances
Read the Cubicin (daptomycin injection) Side Effects Center for a complete guide to possible side effects
HMG-CoA Reductase Inhibitors
In healthy subjects, concomitant administration of CUBICIN and simvastatin had no effect on plasma trough concentrations of simvastatin, and there were no reports of skeletal myopathy [see CLINICAL PHARMACOLOGY].
However, inhibitors of HMG-CoA reductase may cause myopathy, which is manifested as muscle pain or weakness associated with elevated levels of creatine phosphokinase (CPK). In the Phase 3 S. aureus bacteremia/endocarditis trial, some patients who received prior or concomitant treatment with an HMGCoA reductase inhibitor developed elevated CPK [see ADVERSE REACTIONS]. Experience with the coadministration of HMG-CoA reductase inhibitors and CUBICIN in patients is limited; therefore, consideration should be given to suspending use of HMG-CoA reductase inhibitors temporarily in patients receiving CUBICIN.
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. The possibility of an erroneously elevated PT/INR result due to interaction with a recombinant thromboplastin reagent may be minimized by drawing specimens for PT or INR testing near the time of trough plasma concentrations of daptomycin. However, sufficient daptomycin concentrations may be present at trough to cause interaction.
If confronted with an abnormally high PT/INR result in a patient being treated with CUBICIN, it is recommended that clinicians:
- Repeat the assessment of PT/INR, requesting that the specimen be drawn just prior to the next CUBICIN dose (i.e., at trough concentration). If the PT/INR value obtained at trough remains substantially elevated above what would otherwise be expected, consider evaluating PT/INR utilizing an alternative method.
- Evaluate for other causes of abnormally elevated PT/INR results.
Read the Cubicin Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 7/25/2016
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