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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Clinical studies sponsored by Cubist enrolled 1,667 patients treated with CUBICIN and 1,319 treated with comparator. Most adverse events reported in Cubist-sponsored Phase 1, 2, and 3 clinical studies were described as mild or moderate in intensity. In Phase 3 cSSSI trials, CUBICIN was discontinued in 15/534 (2.8%) patients due to an adverse event, while comparator was discontinued in 17/558 (3.0%) patients. In the S. aureus bacteremia/endocarditis trial, CUBICIN was discontinued in 20/120 (16.7%) patients due to an adverse event, while comparator was discontinued in 21/116 (18.1%) patients.

Gram-Negative Infections

In the S. aureus bacteremia/endocarditis trial, serious Gram-negative infections and nonserious Gram-negative bloodstream infections were reported in 10/120 (8.3%) CUBICIN-treated and 0/115 comparator-treated patients. Comparator patients received dual therapy that included initial gentamicin for 4 days. Events 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 organisms. One patient with sternal osteomyelitis following mitral valve repair developed S. aureus endocarditis with a 2 cm mitral vegetation and had a course complicated with bowel infarction, polymicrobial bacteremia, and death.

Other Adverse Reactions

The rates of most common adverse events, organized by body system, observed in cSSSI patients are displayed in Table 5.

Table 5. Incidence (%) of Adverse Events that Occurred in ≥ 2% of Patients in Either CUBICIN or Comparator Treatment Groups in Phase 3 cSSSI Studies

Additional adverse events that occurred in 1 to 2% of patients in either CUBICIN (4 mg/kg) or comparator treatment groups in the cSSSI studies are as follows: edema, cellulitis, hypoglycemia, elevated alkaline phosphatase, cough, back pain, abdominal pain, hypokalemia, hyperglycemia, decreased appetite, anxiety, chest pain, sore throat, cardiac failure, confusion, and Candida infections. These events occurred at rates ranging from 0.2 to 1.7% in CUBICIN-treated patients and at rates of 0.4 to 1.8% in comparator-treated patients.

Additional drug-related adverse events (possibly or probably related) that occurred in < 1% of patients receiving CUBICIN in the cSSSI trials are as follows:

Body as a Whole: fatigue, weakness, rigors, discomfort, jitteriness, 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, flatulence, stomatitis, jaundice, increased serum lactate dehydrogenase

Metabolic/Nutritional System: hypomagnesemia, increased serum bicarbonate, electrolyte disturbance

Musculoskeletal System: myalgia, muscle cramps, muscle weakness, osteomyelitis

Nervous System: vertigo, mental status change, paraesthesia

Special Senses: taste disturbance, eye irritation

The rates of most common adverse events, organized by System Organ Class (SOC), observed in S. aureus bacteremia/endocarditis (6 mg/kg CUBICIN) patients are displayed in Table 6.

Table 6. Incidence (%) of Adverse Events that Occurred in ≥ 5% of Patients in Either CUBICIN or Comparator Treatment Groups in the S. aureus Bacteremia/Endocarditis Study

The following events, not included above, were reported as possibly or probably drug-related in the CUBICIN-treated group:

Blood and Lymphatic System Disorders: eosinophilia (1.7%), lymphadenopathy ( < 1%), thrombocythaemia ( < 1%), thrombocytopenia ( < 1%)

Cardiac Disorders: atrial fibrillation ( < 1%), atrial flutter ( < 1%), cardiac arrest ( < 1%)

Ear and Labyrinth Disorders: tinnitus ( < 1%)

Eye Disorders: vision blurred ( < 1%)

Gastrointestinal Disorders: dry mouth ( < 1%), epigastric discomfort ( < 1%), gingival pain ( < 1%), hypoaesthesia oral ( < 1%)

Infections and Infestations: candidal infection NOS (1.7%), vaginal candidiasis (1.7%), fungaemia ( < 1%), oral candidiasis ( < 1%), urinary tract infection fungal ( < 1%)

Investigations: blood phosphorous increased (2.5%), blood alkaline phosphatase increased (1.7%), INR increased (1.7%), liver function test abnormal (1.7%), alanine aminotransferase increased ( < 1%), aspartate aminotransferase increased ( < 1%), prothrombin time prolonged ( < 1%)

Metabolism and Nutrition Disorders: appetite decreased NOS ( < 1%)

Musculoskeletal and Connective Tissue Disorders: myalgia ( < 1%)

Nervous System Disorders: dyskinesia ( < 1%), paraesthesia ( < 1%)

Psychiatric Disorders: hallucination NOS ( < 1%)

Renal and Urinary Disorders: proteinuria ( < 1%), renal impairment NOS ( < 1%)

Skin and Subcutaneous Tissue Disorders: heat rash ( < 1%), pruritus generalized ( < 1%), rash vesicular ( < 1%)

In Phase 3 studies 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).

Laboratory Changes

In Phase 3 comparator-controlled cSSSI and CAP studies, there was no clinically or statistically significant difference (p < 0.05) in the incidence of CPK elevations between patients treated with CUBICIN and those treated with comparator. CPK elevations in both groups were generally related to medical conditions—for example, skin and skin structure infection, surgical procedures, or intramuscular injections—and were not associated with muscle symptoms.

In the Phase 3 cSSSI studies, 0.2% of patients treated with CUBICIN had symptoms of muscle pain or weakness associated with CPK elevations to greater than 4X ULN. The symptoms resolved within 3 days and CPK returned to normal within 7 to 10 days after discontinuing treatment (see PRECAUTIONS, Skeletal Muscle). Table 7 summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI trials.

Table 7. Incidence (%) of Creatine Phosphokinase (CPK) Elevations from Baseline while on Therapy in Either CUBICIN or Comparator Treatment Groups in Phase 3 cSSSI Studies

In the S. aureus bacteremia/endocarditis study, a total of 11 CUBICIN-treated patients (9.2%) had treatment-emergent elevations in CPK to > 500 U/L, including 4 patients with elevations > 10X ULN. Three of these 11 patients had CPK levels return to the normal range during continued CUBICIN treatment, 6 had values return to the normal range during follow-up, 1 had values returning toward baseline at the last assessment, and 1 did not have follow-up values reported. Three patients discontinued CUBICIN due to CPK elevation.

There was more renal dysfunction in comparator-treated patients than in CUBICIN-treated patients. The incidence of decreased renal function, defined as the proportion of patients with a creatinine clearance level < 50 mL/min if baseline clearance was ≥ 50 mL/min or with a decrease of ≥ 10 mL/min if baseline clearance was < 50 mL/min, is shown in Table 8.

Table 8. Incidence of Decreased Renal Function Based on Creatinine Clearance Levels

Post-Marketing Experience

The following adverse reactions have been reported with CUBICIN in worldwide post-marketing experience. Because these events are reported voluntarily from a population of unknown size, estimates of frequency cannot be made and causal relationship cannot be precisely established.

Immune System Disorders: anaphylaxis; hypersensitivity reactions, including pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia.

Musculoskeletal System: rhabdomyolysis; some reports involved patients treated concurrently with CUBICIN and HMG-CoA reductase inhibitors.

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).

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 coadministration of HMG-CoA reductase inhibitors and CUBICIN in patients is limited; therefore, consideration should be given to temporarily suspending use of HMG-CoA reductase inhibitors in patients receiving CUBICIN (see ADVERSE REACTIONS, Post-Marketing Experience).

Drug-Laboratory Test Interactions

Clinically relevant plasma levels 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 levels 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:

1. 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 drawn at trough remains substantially elevated over what would otherwise be expected, consider evaluating PT/INR utilizing an alternative method.
2. Evaluate for other causes of abnormally elevated PT/INR results.

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