These highlights do not include all the information needed to use CUBICIN safely and effectively.  See full prescribing information for CUBICIN. CUBICIN (daptomycin for injection) for Intravenous UseInitial U.S. Approval: 2003

CUBICIN (daptomycin for injection)

CUBICIN is indicated for the treatment of the infections listed below.

Complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following Gram-positive bacteria: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only).

Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates.

CUBICIN is not indicated for the treatment of pneumonia.

CUBICIN is not indicated for the treatment of left-sided infective endocarditis due to S. aureus.  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 Trials (14.2) ].  CUBICIN has not been studied in patients with prosthetic valve endocarditis.

Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to daptomycin.

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 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.  Empiric therapy may be initiated while awaiting test results.

CUBICIN should be administered intravenously either by injection over a two (2) minute period or by infusion over a thirty (30) minute period.

CUBICIN 4 mg/kg should be administered intravenously in 0.9% sodium chloride injection once every 24 hours for 7 to 14 days.

CUBICIN 6 mg/kg should be administered intravenously in 0.9% sodium chloride injection once every 24 hours for 2 to 6 weeks.  There are limited safety data for the use of CUBICIN for more than 28 days of therapy.  In the Phase 3 trial, there were a total of 14 patients who were treated with CUBICIN for more than 28 days.

The recommended dosage regimen for patients with creatinine clearance (CL) <30 mL/min, including those on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), is 4 mg/kg (cSSSI) or 6 mg/kg (S. aureus bloodstream infections) once every 48 hours (Table 1).  When possible, CUBICIN should be administered following the completion of hemodialysis on hemodialysis days [see Warnings and Precautions (5.2, 5.7), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) ].

CUBICIN is supplied in single-use vials, each containing 500 mg daptomycin as a sterile, lyophilized powder.  The contents of a CUBICIN vial should be reconstituted, using aseptic technique, to 50 mg/mL as follows:

For intravenous (IV) injection over a period of 2 minutes, administer the appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL).

For IV infusion over a period of 30 minutes, the appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into a 50 mL IV infusion bag containing 0.9% sodium chloride injection.

Parenteral drug products should be inspected visually for particulate matter prior to administration.

No preservative or bacteriostatic agent is present in this product.  Aseptic technique must be used in the preparation of final IV solution.  Stability studies have shown that the reconstituted solution is stable in the vial for 12 hours at room temperature and up to 48 hours if stored under refrigeration at 2 to 8°C (36 to 46°F).

The diluted solution is stable in the infusion bag for 12 hours at room temperature and 48 hours if stored under refrigeration.  The combined storage time (reconstituted solution in vial and diluted solution in infusion bag) should not exceed 12 hours at room temperature or 48 hours under refrigeration.

CUBICIN vials are for single use only.

CUBICIN is compatible with 0.9% sodium chloride injection and lactated Ringer's injection.

CUBICIN is not compatible with dextrose-containing diluents.

CUBICIN should not be used in conjunction with ReadyMED elastomeric infusion pumps (Cardinal Health, Inc.).  Stability studies of CUBICIN solutions stored in ReadyMED elastomeric infusion pumps identified an impurity (2-mercaptobenzothiazole) leaching from this pump system into the CUBICIN solution.

Because only limited data are available on the compatibility of CUBICIN with other IV substances, additives and other medications should not be added to CUBICIN single-use vials or infusion bags, or infused simultaneously through the same IV line.  If the same IV line is used for sequential infusion of different drugs, the line should be flushed with a compatible intravenous solution before and after infusion with CUBICIN.

500 mg daptomycin as a sterile, pale yellow to light brown lyophilized powder for reconstitution in a single-use vial.

CUBICIN is contraindicated in patients with known hypersensitivity to daptomycin.

Anaphylaxis/hypersensitivity reactions have been reported with the use of antibacterial agents, including CUBICIN, and may be life-threatening.  If an allergic reaction to CUBICIN 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 CUBICIN.  Rhabdomyolysis, with or without acute renal failure, has been reported [see Adverse Reactions (6.2) ].

Patients receiving CUBICIN should be monitored for the development of muscle pain or weakness, particularly of the distal extremities.  In patients who receive CUBICIN, 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 CUBICIN.

In 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, CPK elevations appeared to be more frequent when CUBICIN was dosed more than once daily.  Therefore, CUBICIN should not be dosed more frequently than once a day.

CUBICIN 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 CUBICIN [see Drug Interactions (7.1) ].

Eosinophilic pneumonia has been reported in patients receiving CUBICIN [see Adverse Reactions (6.2) ].  In reported cases associated with CUBICIN, patients developed fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates.  In general, patients developed eosinophilic pneumonia 2 to 4 weeks after starting CUBICIN and improved when CUBICIN 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 CUBICIN should undergo prompt medical eva luation, and CUBICIN should be discontinued immediately.  Treatment with systemic steroids is recommended.

Cases of peripheral neuropathy have been reported during the CUBICIN postmarketing experience [see Adverse Reactions (6.2) ].  Therefore, physicians should be alert to signs and symptoms of peripheral neuropathy in patients receiving CUBICIN.

Clostridium difficile–associated diarrhea (CDAD) has been reported with the use of nearly all systemic antibacterial agents, including CUBICIN, 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 eva luation 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 eva luation 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 Trials (14.2) ].

There are limited data available from the cSSSI clinical trials regarding clinical efficacy of daptomycin treatment in patients with CrCL <50 mL/min; only 31/534 (6%) patients treated with daptomycin in the intent-to-treat (ITT) population had a baseline CrCL <50 mL/min.  Table 2 shows the number of patients by CrCL and treatment group who were clinical successes in the cSSSI trials.

In a subgroup analysis of the ITT population in the S. aureus bacteremia/endocarditis trial, clinical success rates, as determined by a treatment-blinded Adjudication Committee [see Clinical Trials (14.2) ], in the daptomycin-treated patients were lower in patients with baseline CrCL <50 mL/min (Table 3).  A decrease of the magnitude shown in Table 3 was not observed in comparator-treated patients.

Consider these data when selecting antibacterial therapy for use in 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-Laboratory Interactions (7.2) ].

The use of antibacterials may promote the overgrowth of non-susceptible microorganisms.  If superinfection occurs 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 drug-resistant bacteria.

The following adverse reactions are described, or described in greater detail, in other sections:

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 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 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.

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

Blood/Lymphatic System: leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased International Normalized Ratio (INR)

Cardiovascular System: supraventricular arrhythmia

Dermatologic System: eczema

Digestive System: abdominal distension, stomatitis, jaundice, increased serum lactate dehydrogenase

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

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

Nervous System: vertigo, mental status change, paresthesia

Special Senses: taste disturbance, eye irritation

S. aureus Bacteremia/Endocarditis Trial

In the S. aureus bacteremia/endocarditis trial, CUBICIN was discontinued in 20/120 (16.7%) patients due to an adverse reaction, while comparator was discontinued in 21/116 (18.1%) patients.

Serious Gram-negative infections (including bloodstream infections) were reported in 10/120 (8.3%) CUBICIN-treated 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.

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

Blood and Lymphatic System Disorders: eosinophilia, lymphadenopathy, thrombocythemia, thrombocytopenia

Cardiac Disorders: atrial fibrillation, atrial flutter, cardiac arrest

Ear and Labyrinth Disorders: tinnitus

Eye Disorders: vision blurred

Gastrointestinal Disorders: dry mouth, epigastric discomfort, gingival pain, hypoesthesia oral

Infections and Infestations: candidal infection NOS, vaginal candidiasis, fungemia, oral candidiasis, urinary tract infection fungal

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

Skin and Subcutaneous Tissue Disorders: pruritus generalized, rash vesicular

Other Trials

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 (1.3) ].

Laboratory Changes

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%) comparator-treated 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 (5.2) ].  Table 6 summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI trials.

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 CUBICIN-treated patients discontinued therapy due to CPK elevation, while the one comparator-treated patient did not discontinue therapy [see Warnings and Precautions (5.2) ].

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 pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia [see Contraindications (4), Warnings and Precautions (5.1) ]

Infections and Infestations: Clostridium difficile–associated diarrhea [see Warnings and Precautions (5.5) ]

Musculoskeletal Disorders: myoglobin increased; rhabdomyolysis (some reports involved patients treated concurrently with CUBICIN and HMG-CoA reductase inhibitors) [see Warnings and Precautions (5.2), Drug Interactions (7.1), and Clinical Pharmacology (12.3) ]

Respiratory, Thoracic, and Mediastinal Disorders: cough, eosinophilic pneumonia [see Warnings and Precautions (5.3) ]

Nervous System Disorders: peripheral neuropathy [see Warnings and Precautions (5.4) ]

Skin and Subcutaneous Tissue Disorders: serious skin reactions, including Stevens-Johnson syndrome and vesiculobullous rash (with or without mucous membrane involvement)

Gastrointestinal Disorders: nausea, vomiting

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 (12.3) ].

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 HMG-CoA reductase inhibitor developed elevated CPK [see Adverse Reactions (6.1) ].  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.

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:

Teratogenic Effects: Pregnancy Category B

Reproductive and teratology studies performed in rats and rabbits at doses of up to 75 mg/kg (2 and 4 times the 6 mg/kg human dose, respectively, on a body surface area basis) revealed no evidence of harm to the fetus due to daptomycin.  There are, however, no adequate and well-controlled trials in pregnant women.  Because animal reproduction studies are not always predictive of human response, CUBICIN should be used during pregnancy only if the potential benefit outweighs the possible risk.

It is not known whether daptomycin is excreted in human milk.  Because many drugs are excreted in human milk, caution should be exercised when CUBICIN is administered to nursing women.

Safety and effectiveness of CUBICIN in patients under the age of 18 years have not been established.

Of the 534 patients treated with CUBICIN in Phase 3 controlled clinical trials of complicated skin and skin structure infections (cSSSI), 27% were 65 years of age or older and 12% were 75 years of age or older.  Of the 120 patients treated with CUBICIN in the Phase 3 controlled clinical trial of S. aureus bacteremia/endocarditis, 25% were 65 years of age or older and 16% were 75 years of age or older.  In Phase 3 clinical trials of cSSSI and S. aureus bacteremia/endocarditis, clinical success rates were lower in patients ≥65 years of age than in patients <65 years of age.  In addition, treatment-emergent adverse events were more common in patients ≥65 years of age than in patients <65 years of age.

The exposure of daptomycin was higher in healthy elderly subjects than in healthy young subjects.  However, no adjustment of CUBICIN dosage is warranted for elderly patients with creatinine clearance (CL) ≥30 mL/min [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ].

Daptomycin is eliminated primarily by the kidneys; therefore, a modification of CUBICIN dosage is recommended for patients with CL <30 mL/min, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).  In patients with renal impairment, both renal function and creatine phosphokinase (CPK) should be monitored more frequently than once weekly [see Dosage and Administration (2.4) , Warnings and Precautions (5.2, 5.7), and Clinical Pharmacology (12.3) ].

In the event of overdosage, supportive care is advised with maintenance of glomerular filtration.  Daptomycin is cleared slowly from the body by hemodialysis (approximately 15% of the administered dose is removed over 4 hours) and by peritoneal dialysis (approximately 11% of the administered dose is removed over 48 hours).  The use of high-flux dialysis membranes during 4 hours of hemodialysis may increase the percentage of dose removed compared with that removed by low-flux membranes.

CUBICIN contains daptomycin, a cyclic lipopeptide antibacterial agent derived from the fermentation of Streptomyces roseosporus.  The chemical name is N-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine ε-lactone.  The chemical structure is:

The empirical formula is CHNO; the molecular weight is 1620.67.  CUBICIN is supplied in a single-use vial as a sterile, preservative-free, pale yellow to light brown, lyophilized cake containing approximately 500 mg of daptomycin for intravenous (IV) use following reconstitution with 0.9% sodium chloride injection [see Dosage and Administration (2.5) ].  The only inactive ingredient is sodium hydroxide, which is used in minimal quantities for pH adjustment.  Freshly reconstituted solutions of CUBICIN range in color from pale yellow to light brown.

Daptomycin is an antibacterial drug [see Microbiology (12.4) ].

Based on animal models of infection, the antimicrobial activity of daptomycin appears to correlate with the AUC/MIC (area under the concentration-time curve/minimum inhibitory concentration) ratio for certain pathogens, including S. aureus.  The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in

Manufacturer

Cubist Pharmaceuticals, Inc.

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
•  Last Updated: 2nd of March 2011