Cubicin

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

• 500mg/vial

Staphylococcus Aureus Bacteremia

Indicated for treatment of adults with Staphylococcus aureus bacteremia, including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates

6 mg/kg IV infusion q24hr for at least 2-6 weeks 

Also see Administration for IV dilution and infusion rate instructions

Complicated Skin & Skin Structure Infections

Indicated for treatment of adults with Staphylococcus aureus bacteremia, including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates

4 mg/kg IV q24hr for 7-14 days 

Also see Administration for IV dilution and infusion rate instructions

Susceptible isolates

• Staphylococcus aureus (including MRSA)
• Streptococcus pyogenes
• Streptococcus agalactiae
• Streptococcus dysgalactiae ssp equisimilis
• Enterococcus faecalis (vancomycin-susceptible only)

Dosage Modifications

Renal impairment

• CrCl >30mL/min: No dosage adjustment necessary
• CrCl <30 mL/min: Give same dose q48hr
• Hemodialysis or continuous ambulatory peritoneal dialysis (CAPD): Give same dose on hemodialysis days after completion of hemodialysis

Dosing Considerations

Monitor creatine phosphokinase (CPK)

Limitations of use

• Not indicated for the treatment of pneumonia
• Not indicated for the treatment of left-sided infective endocarditis due to S aureus; the clinical trial in adults with S aureus bacteremia included limited data from patients with left-sided infective endocarditis; outcomes in these patients were poor
• Has not been studied in patients with prosthetic valve endocarditis

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

• 500mg/vial

Staphylococcus Aureus Bacteremia

Indicated for treatment of children aged 1-17 years with Staphylococcus aureus bacteremia

<1 year: Safety and efficacy not established (see Dosing Considerations)

≥1 year

• 12-17 years: 7 mg/kg IV q24hr
• 7-11 years: 9 mg/kg IV q24hr
• 1-6 years: 12 mg/kg IV q24hr
• Duration of therapy: Up to 42 days
• Also see Administration for IV dilution and infusion rate instructions

Complicated Skin & Skin Structure Infections

Indicated for the treatment of adult and pediatric patients (aged 1 to 17 yr) with complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of Gram-positive bacteria

<1 year: Safety and efficacy not established (see Dosing Considerations)

≥1 year

• 12-17 years: 5 mg/kg IV q24hr
• 7-11 years: 7 mg/kg IV q24hr
• 2-6 years: 9 mg/kg IV q24hr
• 1 to <2 years: 10 mg/kg IV q24hr
• Duration of therapy: Up to 14 days
• Also see Administration for IV dilution and infusion rate instructions

Susceptible isolates

• Staphylococcus aureus (including MRSA)
• Streptococcus pyogenes
• Streptococcus agalactiae
• Streptococcus dysgalactiae ssp equisimilis
• Enterococcus faecalis (vancomycin-susceptible only)

Dosage Modifications

Renal impairment: Dosage regimen in children with renal impairment has not been established

Dosing Considerations

Limitations of use

• Not indicated for pneumonia
• <1 year: Not recommended in children aged <1 yr owing to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs

Contraindications

Hypersensitivity

Cautions

Anaphylaxis/hypersensitivity reactions have been reported and may be life-threatening; discontinue the drug and institute appropriate therapy if allergic reaction occurs

May cause eosinophilic pneumonia characterized by fever, cough, shortness of breath, and difficulty breathing; may result in progressive respiratory failure and is potentially fatal; prompt medical evaluation, and treatment should be discontinued immediately if signs/symptoms develop; treatment with systemic steroids is recommended

Prolonged use may result in fungal or bacterial superinfection Perform susceptibility testing and rule out sequestered foci of infection if persisting or relapsing S. aureus bacteremia/endocarditis occurs

Avoid use in pediatric patients <12 months; potential nervous system or muscular system effects

Decreased efficacy reported in patients with moderate baseline renal impairment

Fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates or organizing pneumonia

Cases of peripheral neuropathy have been reported during the daptomycin postmarketing experience; monitor and consider discontinuation

Clostridium difficile-associated diarrhea (CDAD)

• CDAD has been reported and may range in severity from mild diarrhea to fatal; 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/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

Myopathy and rhabdomyolysis

• Use cautiously in patients with peripheral neuropathies and myopathy; monitor for neuropathy and consider discontinuation
• Discontinue with symptoms of myopathy and CPK >1000 U/L (>5x ULN), or no symptoms and CPK >2000 U/L (>10x ULN)
• CPK elevations more prevalent if dosed more frequently than q24hr
• Consider suspending statins during daptomycin therapy; theoretical risk of additive myopathy
• Renal function and CPK should be monitored more frequently than once weekly in adult patients with renal impairment

Cubicin is a prescription medication used to treat serious skin and blood infections caused by Staphylococcus aureus (a type of bacteria).

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Cubicin is part of the drug class:

• OTHER ANTIBACTERIALS

Cubicin comes in injectable form to be given directly into the vein (IV) by a healthcare professional. The injection will be over a 2 minute period or if infused, may last over 30 minutes.

Cubicin is usually administered by a healthcare provider in a medical setting making it unlikely for an overdose to occur. However, if overdose is suspected, seek emergency medical attention.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

Important Administration Duration Instructions

Adults

Administer the appropriate volume of the reconstituted Cubicin (concentration of 50 mg/mL) to adult patients intravenously either by injection over a two (2) minute period or by intravenous infusion over a thirty (30) minute period [see Dosage and Administration (2.2, 2.4, 2.7)].

Pediatric Patients (1 to 17 Years of Age)

Unlike in adults, do NOT administer Cubicin by injection over a two (2) minute period to pediatric patients.

• Pediatric Patients 7 to 17 years of Age: Administer Cubicin intravenously by infusion over a 30-minute period [see Dosage and Administration (2.3, 2.5, 2.7)].
• Pediatric Patients 1 to 6 years of Age: Administer Cubicin intravenously by infusion over a 60-minute period [see Dosage and Administration (2.3, 2.5, 2.7)].

Dosage in Adults for cSSSI

Administer Cubicin 4 mg/kg to adult patients intravenously in 0.9% sodium chloride injection once every 24 hours for 7 to 14 days.

Dosage in Pediatric Patients (1 to 17 Years of Age) for cSSSI

The recommended dosage regimens based on age for pediatric patients with cSSSI are shown in Table 1. Administer Cubicin intravenously in 0.9% sodium chloride injection once every 24 hours for up to 14 days.

Dosage in Adult Patients with Staphylococcus aureus Bloodstream Infections (Bacteremia), Including Those with Right-Sided Infective Endocarditis, Caused by Methicillin-Susceptible and Methicillin-Resistant Isolates

Administer Cubicin 6 mg/kg to adult patients 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 adult patients who were treated with Cubicin for more than 28 days.

Dosage in Pediatric Patients (1 to 17 Years of Age) with Staphylococcus aureus Bloodstream Infections (Bacteremia)

The recommended dosage regimens based on age for pediatric patients with S. aureus bloodstream infections (bacteremia) are shown in Table 2. Administer Cubicin intravenously in 0.9% sodium chloride injection once every 24 hours for up to 42 days.

Dosage in Patients with Renal Impairment

Adult Patients:

No dosage adjustment is required in adult patients with creatinine clearance (CLCR) greater than or equal to 30 mL/min. The recommended dosage regimen for Cubicin in adult patients with CLCR less than 30 mL/min, including adult patients 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 3). When possible, Cubicin should be administered following the completion of hemodialysis on hemodialysis days [see Warnings and Precautions (5.2, 5.8), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

Pediatric Patients:

The dosage regimen for Cubicin in pediatric patients with renal impairment has not been established.

Preparation and Administration of Cubicin

There are two formulations of daptomycin that have differences concerning storage and reconstitution. Carefully follow the reconstitution and storage procedures in labeling.

Reconstitution of Cubicin Vial

Cubicin is supplied in single-dose 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:

1. To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.
2. Remove the polypropylene flip-off cap from the Cubicin vial to expose the central portion of the rubber stopper.
3. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface.
4. Slowly transfer 10 mL of 0.9% sodium chloride injection through the center of the rubber stopper into the Cubicin vial, pointing the transfer needle toward the wall of the vial. It is recommended that a beveled sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device is used, pointing the transfer needle toward the wall of the vial.
5. Ensure that all of the Cubicin powder is wetted by gently rotating the vial.
   1. Allow the wetted product to stand undisturbed for 10 minutes.
   2. Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely reconstituted solution.

Administration Instructions

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

Slowly remove reconstituted liquid (50 mg daptomycin/mL) from the vial using a beveled sterile needle that is 21 gauge or smaller in diameter. Administer as an intravenous injection or infusion as described below:

Adults

Intravenous Injection over a period of 2 minutes

• For intravenous (IV) injection over a period of 2 minutes in adult patients only: Administer the appropriate volume of the reconstituted Cubicin (concentration of 50 mg/mL).

Intravenous Infusion over a period of 30 minutes

• For IV infusion over a period of 30 minutes in adult patients: 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.

Pediatric Patients (1 to 17 Years of Age)

Intravenous Infusion over a period of 30 or 60 minutes

• Unlike in Adults, do NOT administer Cubicin by injection over a two (2) minute period to pediatric patients [see Dosage and Administration (2.1)].
• For Intravenous infusion over a period of 60 minutes in pediatric patients 1 to 6 years of age: The appropriate volume of the reconstituted Cubicin (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into an intravenous infusion bag containing 25 mL of 0.9% sodium chloride injection. The infusion rate should be maintained at 0.42 mL/minute over the 60-minute period.
• For Intravenous infusion over a period of 30 minutes in pediatric patients 7 to 17 years of age: 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. The infusion rate should be maintained at 1.67 mL/minute over the 30-minute period.

No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the preparation of final IV solution. Do not exceed the In-Use storage conditions of the reconstituted and diluted solutions of Cubicin described below. Discard unused portions of Cubicin.

In-Use Storage Conditions for Cubicin Once Reconstituted in Acceptable Intravenous Diluents

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.

Compatible Intravenous Solutions

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

Incompatibilities

Cubicin is not compatible with dextrose-containing diluents.

Cubicin should not be used in conjunction with ReadyMED® elastomeric infusion pumps. 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-dose vials or infusion bags, or infused simultaneously with Cubicin 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.

Pregnancy

Risk Summary

Limited published data on use of Cubicin in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies performed in rats and rabbits daptomycin was administered intravenously during organogenesis at doses 2 and 4-times, respectively, the recommended 6 mg/kg human dose (on a body surface area basis). No evidence of adverse developmental outcomes was observed.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In pregnant rats, daptomycin was administered intravenously at doses of 5, 20, or 75 mg/kg/day during the gestation days 6 to 18. Maternal body weight gain was decreased at 75 mg/kg/day. No embryo/fetal effects were noted at the highest dose of 75 mg/kg/day, a dose approximately 2-fold higher than in humans at the recommended maximum dose of 6mg/kg (based on body surface area).

In pregnant rabbits, daptomycin was administered intravenously at doses of 5, 20, or 75 mg/kg/day during the gestation days 6 to 15. Maternal body weight gain and food consumption were decreased at 75 mg/kg/day. No embryo/fetal effects were noted at the highest dose of 75 mg/kg/day, a dose approximately 4-fold higher than in humans at the maximum recommended dose of 6mg/kg (based on body surface area).

In a combined fertility and pre/postnatal development study, daptomycin was administered intravenously to female rats at doses of 2, 25, 75 mg/kg/day from 14-days pre-mating through lactation/postpartum day 20). No effects on pre/postnatal development were observed up to the highest dose of 75 mg/kg/day, a dose approximately 2-fold higher than the maximum recommended human dose of 6 mg/kg (based on body surface area)1.

Lactation

Risk Summary

Limited published data report that daptomycin is present in human milk at infant doses of 0.1% of the maternal dose [see Data]2,3,4. There is no information on the effects of daptomycin on the breastfed infant or the effects of daptomycin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Cubicin and any potential adverse effects on the breastfed infant from Cubicin or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of Cubicin in the treatment of cSSSI and S. aureus bloodstream infections (bacteremia) have been established in the age groups 1 to 17 years of age. Use of Cubicin in these age groups is supported by evidence from adequate and well-controlled studies in adults, with additional data from pharmacokinetic studies in pediatric patients, and from safety, efficacy and PK studies in pediatric patients with cSSSI and S. aureus bloodstream infections [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

Safety and effectiveness in pediatric patients below the age of one year have not been established. Avoid use of Cubicin in pediatric patients younger than one year of age due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs [see Warnings and Precautions (5.5) and Nonclinical Toxicology (13.2)].

Cubicin is not indicated in pediatric patients with renal impairment because dosage has not been established in these patients.

Cubicin has not been studied in pediatric patients with other bacterial infections.

Geriatric Use

Of the 534 adult 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 adult 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 adult 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 adult subjects. However, no adjustment of Cubicin dosage is warranted for elderly patients with creatinine clearance (CLCR) ≥30 mL/min [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

Patients with Renal Impairment

Daptomycin is eliminated primarily by the kidneys; therefore, a modification of Cubicin dosage interval is recommended for adult patients with CLCR <30 mL/min, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). In adult patients with renal impairment, both renal function and creatine phosphokinase (CPK) should be monitored more frequently than once weekly [see Dosage and Administration (2.6), Warnings and Precautions (5.2, 5.8), and Clinical Pharmacology (12.3)].

The dosage regimen for Cubicin in pediatric patients with renal impairment has not been established.

Complicated Skin and Skin Structure Infections

Adults with cSSSI

Adult patients with clinically documented complicated skin and skin structure infections (cSSSI) (Table 17) were enrolled in two randomized, multinational, multicenter, investigator-blinded trials comparing Cubicin (4 mg/kg IV q24h) with either vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g IV per day). Patients could switch to oral therapy after a minimum of 4 days of IV treatment if clinical improvement was demonstrated. Patients known to have bacteremia at baseline were excluded. Patients with creatinine clearance (CLCR) between 30 and 70 mL/min were to receive a lower dose of Cubicin as specified in the protocol; however, the majority of patients in this subpopulation did not have the dose of Cubicin adjusted.

One trial was conducted primarily in the United States and South Africa (study 9801), and the second was conducted at non-US sites only (study 9901). The two trials were similar in design but differed in patient characteristics, including history of diabetes and peripheral vascular disease. There were a total of 534 adult patients treated with Cubicin and 558 treated with comparator in the two trials. The majority (89.7%) of patients received IV medication exclusively.

The efficacy endpoints in both trials were the clinical success rates in the intent-to-treat (ITT) population and in the clinically evaluable (CE) population. In study 9801, clinical success rates in the ITT population were 62.5% (165/264) in patients treated with Cubicin and 60.9% (162/266) in patients treated with comparator drugs. Clinical success rates in the CE population were 76.0% (158/208) in patients treated with Cubicin and 76.7% (158/206) in patients treated with comparator drugs. In study 9901, clinical success rates in the ITT population were 80.4% (217/270) in patients treated with Cubicin and 80.5% (235/292) in patients treated with comparator drugs. Clinical success rates in the CE population were 89.9% (214/238) in patients treated with Cubicin and 90.4% (226/250) in patients treated with comparator drugs.

The success rates by pathogen for microbiologically evaluable patients are presented in Table 18.

Pediatric Patients (1 to 17 Years of Age) with cSSSI

The cSSSI pediatric trial was a single prospective multi-center, randomized, comparative trial. A total of 396 pediatric patients aged 1 to 17 years with cSSSI caused by Gram positive pathogens were enrolled into the study. Patients known to have bacteremia, osteomyelitis, endocarditis, and pneumonia at baseline were excluded. Patients were enrolled in a stepwise approach into four age groups and given age-dependent doses of Cubicin once daily for up to 14 days. The different age groups and doses evaluated were as follows: Adolescents (12 to 17 years) treated with 5 mg/kg of Cubicin (n=113), Children (7 to 11 years) treated with 7 mg/kg of Cubicin (n=113), Children (2 to 6 years) treated with 9 mg/kg of Cubicin (n=125) and Infants (1 to <2 years) treated with 10 mg/kg (n= 45).

Patients were randomized 2:1 to receive Cubicin or a standard of care (SOC) comparator, which included intravenous therapy with either vancomycin, clindamycin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin, or cloxacillin). Patients could switch to oral therapy after clinical improvement was demonstrated (no minimum IV dosing was required).

The primary objective of this study was to evaluate the safety of Cubicin. The clinical outcome was determined by resolution or improvement of symptoms at the End-of-Treatment (EOT), 3 days after the last dose, and Test-of-Cure (TOC), 7-14 days after the last dose. Investigator observed outcomes were verified in a blinded fashion. Of the 396 subjects randomized in the study, 389 subjects were treated with Cubicin or comparator and included in the ITT population. Of these, 257 subjects were randomized to the Cubicin group and 132 subjects were randomized to the comparator group. Approximately 95% of subjects switched to oral therapy. The mean day of switch was day 4, and ranged from day 1 to day 14. The clinical success rates determined at 7–14 days after last dose of therapy (IV and oral) (TOC visit) were 88% (227/257) for Cubicin and 86% (114/132) for comparator.

S. aureus Bacteremia/Endocarditis

Adults with S.aureus Bacteremia/Endocarditis

The efficacy of Cubicin in the treatment of adult patients with S. aureus bacteremia was demonstrated in a randomized, controlled, multinational, multicenter, open-label trial. In this trial, adult patients with at least one positive blood culture for S. aureus obtained within 2 calendar days prior to the first dose of study drug and irrespective of source were enrolled and randomized to either Cubicin (6 mg/kg IV q24h) or standard of care [an anti-staphylococcal semi-synthetic penicillin 2 g IV q4h (nafcillin, oxacillin, cloxacillin, or flucloxacillin) or vancomycin 1 g IV q12h, each with initial gentamicin 1 mg/kg IV every 8 hours for first 4 days]. Of the patients in the comparator group, 93% received initial gentamicin for a median of 4 days, compared with 1 patient (<1%) in the Cubicin group. Patients with prosthetic heart valves, intravascular foreign material that was not planned for removal within 4 days after the first dose of study medication, severe neutropenia, known osteomyelitis, polymicrobial bloodstream infections, creatinine clearance <30 mL/min, and pneumonia were excluded.

Upon entry, patients were classified for likelihood of endocarditis using the modified Duke criteria (Possible, Definite, or Not Endocarditis). Echocardiography, including a transesophageal echocardiogram (TEE), was performed within 5 days following study enrollment. The choice of comparator agent was based on the oxacillin susceptibility of the S. aureus isolate. The duration of study treatment was based on the investigator's clinical diagnosis. Final diagnoses and outcome assessments at Test of Cure (6 weeks after the last treatment dose) were made by a treatment-blinded Adjudication Committee, using protocol-specified clinical definitions and a composite primary efficacy endpoint (clinical and microbiological success) at the Test of Cure visit.

A total of 246 patients ≥18 years of age (124 Cubicin, 122 comparator) with S. aureus bacteremia were randomized from 48 centers in the US and Europe. In the ITT population, 120 patients received Cubicin and 115 received comparator (62 received an anti-staphylococcal semi-synthetic penicillin and 53 received vancomycin). Thirty-five patients treated with an anti-staphylococcal semi-synthetic penicillin received vancomycin initially for 1 to 3 days, pending final susceptibility results for the S. aureus isolates. The median age among the 235 patients in the ITT population was 53 years (range: 21 to 91 years); 30/120 (25%) in the Cubicin group and 37/115 (32%) in the comparator group were ≥65 years of age. Of the 235 ITT patients, there were 141 (60%) males and 156 (66%) Caucasians across the two treatment groups. In addition, 176 (75%) of the ITT population had systemic inflammatory response syndrome (SIRS) at baseline and 85 (36%) had surgical procedures within 30 days prior to onset of the S. aureus bacteremia. Eighty-nine patients (38%) had bacteremia caused by methicillin-resistant S. aureus (MRSA). Entry diagnosis was based on the modified Duke criteria and comprised 37 (16%) Definite, 144 (61%) Possible, and 54 (23%) Not Endocarditis. Of the 37 patients with an entry diagnosis of Definite Endocarditis, all (100%) had a final diagnosis of infective endocarditis, and of the 144 patients with an entry diagnosis of Possible Endocarditis, 15 (10%) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee. Of the 54 patients with an entry diagnosis of Not Endocarditis, 1 (2%) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee.

In the ITT population, there were 182 patients with bacteremia and 53 patients with infective endocarditis as assessed by the Adjudication Committee, including 35 with right-sided endocarditis and 18 with left-sided endocarditis. The 182 patients with bacteremia comprised 121 with complicated S. aureus bacteremia and 61 with uncomplicated S. aureus bacteremia.

Complicated bacteremia was defined as S. aureus isolated from blood cultures obtained on at least 2 different calendar days, and/or metastatic foci of infection (deep tissue involvement), and classification of the patient as not having endocarditis according to the modified Duke criteria. Uncomplicated bacteremia was defined as S. aureus isolated from blood culture(s) obtained on a single calendar day, no metastatic foci of infection, no infection of prosthetic material, and classification of the patient as not having endocarditis according to the modified Duke criteria. The definition of right-sided infective endocarditis (RIE) used in the clinical trial was Definite or Possible Endocarditis according to the modified Duke criteria and no echocardiographic evidence of predisposing pathology or active involvement of either the mitral or aortic valve. Complicated RIE comprised patients who were not intravenous drug users, had a positive blood culture for MRSA, serum creatinine ≥2.5 mg/dL, or evidence of extrapulmonary sites of infection. Patients who were intravenous drug users, had a positive blood culture for methicillin-susceptible S. aureus (MSSA), had serum creatinine <2.5 mg/dL, and were without evidence of extrapulmonary sites of infection were considered to have uncomplicated RIE.

The coprimary efficacy endpoints in the trial were the Adjudication Committee success rates at the Test of Cure visit (6 weeks after the last treatment dose) in the ITT and Per Protocol (PP) populations. The overall Adjudication Committee success rates in the ITT population were 44.2% (53/120) in patients treated with Cubicin and 41.7% (48/115) in patients treated with comparator (difference = 2.4% [95% CI −10.2, 15.1]). The success rates in the PP population were 54.4% (43/79) in patients treated with Cubicin and 53.3% (32/60) in patients treated with comparator (difference = 1.1% [95% CI −15.6, 17.8]).

Adjudication Committee success rates are shown in Table 19.

Eighteen (18/120) patients in the Cubicin arm and 19/116 patients in the comparator arm died during the trial. These comprise 3/28 Cubicin-treated patients and 8/26 comparator-treated patients with endocarditis, as well as 15/92 Cubicin-treated patients and 11/90 comparator-treated patients with bacteremia. Among patients with persisting or relapsing S. aureus infections, 8/19 Cubicin-treated patients and 7/11 comparator-treated patients died.

Overall, there was no difference in time to clearance of S. aureus bacteremia between Cubicin and comparator. The median time to clearance in patients with MSSA was 4 days and in patients with MRSA was 8 days.

Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the Adjudication Committee in 19/120 (16%) Cubicin-treated patients (12 with MRSA and 7 with MSSA) and 11/115 (10%) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with an anti-staphylococcal semi-synthetic penicillin). Among all failures, isolates from 6 Cubicin-treated patients and 1 vancomycin-treated patient developed increasing MICs (reduced susceptibility) by central laboratory testing during 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 Warnings and Precautions (5.7)].

Pediatric Patients (1 to 17 Years of Age) with S.aureus Bacteremia

The pediatric S. aureus bacteremia study was designed as a prospective multi-center, randomized, comparative trial to treat pediatric patients aged 1 to 17 years with bacteremia. Patients known to have endocarditis or pneumonia at baseline were excluded. Patients were enrolled in a stepwise approach into three age groups and given age-dependent doses of Cubicin once daily for up to 42 days. The different age groups and doses evaluated were as follows: Adolescents (12 to 17 years, n=14 patients) treated with Cubicin dosed at 7 mg/kg once daily, Children (7 to 11 years, n=19 patients) treated with Cubicin dosed at 9 mg/kg once daily and Children (2 to 6 years, n=22 patients) treated with Cubicin dosed at 12 mg/kg once daily. No patients 1 to <2 years of age were enrolled.

Patients were randomized 2:1 to receive Cubicin or a standard of care comparator, which included intravenous therapy with vancomycin, semi-synthetic penicillin, first generation cephalosporin or clindamycin. Patients could switch to oral therapy after clinical improvement was demonstrated (no minimum IV dosing was required).

The primary objective of this study was to assess the safety of Cubicin. The clinical outcome was determined by resolution or improvement of symptoms at test-of-cure (TOC) visit, 7 to 14 days after the last dose, which was assessed by the site level Blinded Evaluator.

Of the 82 subjects randomized in the study, 81 subjects were treated with Cubicin or comparator and included in the safety population, and 73 had a proven S. aureus bacteremia at Baseline. Of these, 51 subjects were randomized to the Cubicin group and 22 subjects were randomized to the comparator group. The mean duration of IV therapy was 12 days, with a range of 1 to 44 days. Forty-eight subjects switched to oral therapy, and the mean duration of oral therapy was 21 days. The clinical success rates determined at 7 to 14 days after last dose of therapy (IV and oral) (TOC visit) were 88% (45/51) for Cubicin and 77% (17/22) for comparator.

Cubicin is injected into a vein through an IV. You may be shown how to use an IV at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

Cubicin must be given slowly, and the IV infusion can take 2 to 30 minutes to complete. When giving this medicine to a child or teenager, the infusion is even slower (30 to 60 minutes).

Use Cubicin for the full prescribed length of time. Some infections must be treated for up to 6 weeks. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Cubicin will not treat a viral infection such as the flu or a common cold.

Call your doctor if your symptoms do not improve, or if they get worse.

Cubicin is a powder medicine that must be mixed with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medication.

Do not shake the medication bottle or you may ruin the medicine. Gently swirl the medicine when mixing. Prepare your dose only when you are ready to give an injection. Do not use if the medicine has changed colors or has particles in it. Call your pharmacist for new medicine.

Each single-use vial (bottle) of Cubicin is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

While using Cubicin, you may need frequent blood and urine tests.

This medicine can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using Cubicin.

Store Cubicin powder in the refrigerator, do not freeze. After mixing Cubicin with a diluent, store in the refrigerator and use it within 48 hours. Do not freeze.

Mixed medicine must be used within 12 hours if you keep it at room temperature.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Summary of Use during Lactation

Limited information indicates that daptomycin produces low levels in milk and it would not be expected to cause any adverse effects in breastfed infants. No special precautions are required.

Drug Levels

Maternal Levels. A nursing mother received intravenous daptomycin 500 mg (6.7 mg/kg) and ertapenem 1 gram once daily for 28 days to treat a pelvic infection. On day 27 of therapy, expressed breastmilk was collected over six 4-hour intervals. Daptomycin milk concentrations were highest in the second sample with a concentration of 44.7 mcg/L. The fifth sample, ending at 20 hours after the dose, contained 29.2 mcg/L of daptomycin and the final sample had no detectable drug (<25 mcg/L).[1]

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Vancomycin

References

1. Buitrago MI, Crompton JA, Bertolami S et al. Extremely low excretion of daptomycin into breast milk of a nursing mother with methicillin-resistant Staphylococcus aureus pelvic inflammatory disease. Pharmacotherapy. 2009;29:347-51. PMID: 19249952