Daptomycin: Package Insert and Label Information (Page 5 of 5)

14.2 S. aureus Bacteremia/Endocarditis

Adults with S. aureus Bacteremia/Endocarditis

The efficacy of daptomycin for injection 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 daptomycin for injection (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 daptomycin for injection 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 daptomycin for injection, 122 comparator) with S . aureus bacteremia were randomized from 48 centers in the US and Europe. In the ITT population, 120 patients received daptomycin for injection 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 daptomycin for injection 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 daptomycin for injection 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 daptomycin for injection 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 11.

Table 11: Adjudication Committee Success Rates at Test of Cure in the S. aureus Bacteremia/Endocarditis Trial in Adult Patients (Population: ITT)
*
Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 2 g IV q4h), each with initial low-dose gentamicin.
95% Confidence Interval
97.5% Confidence Interval (adjusted for multiplicity)
§
According to the modified Duke criteria
99% Confidence Interval (adjusted for multiplicity)

Population

Success Rate n/N (%)

Difference:

Daptomycin for injection Comparator (Confidence Interval)

Daptomycin for injection 6 mg/kg

Comparator *

Overall

53/120 (44%)

48/115 (42%)

2.4% (-10.2, 15.1)

Baseline Pathogen

Methicillin-susceptible S. aureus

Methicillin-resistant S. aureus

33/74 (45%)

20/45 (44%)

34/70 (49%)

14/44 (32%)

-4.0% (-22.6, 14.6)

12.6% (-10.2, 35.5)

Entry Diagnosis §

Definite or Possible Infective Endocarditis

Not Infective Endocarditis

41/90 (46%)

12/30 (40%)

37/91 (41%)

11/24 (46%)

4.9% (-11.6, 21.4)

-5.8% (-36.2, 24.5)

Final Diagnosis

Uncomplicated Bacteremia

Complicated Bacteremia

18/32 (56%)

26/60 (43%)

16/29 (55%)

23/61 (38%)

1.1% (-31.7, 33.9)

5.6% (-17.3, 28.6)

Right-Sided Infective Endocarditis

8/19 (42%)

7/16 (44%)

-1.6% (-44.9, 41.6)

Uncomplicated Right-Sided Infective Endocarditis

3/6 (50%)

1/4 (25%)

25.0% (-51.6, 100.0)

Complicated Right-Sided Infective Endocarditis

5/13 (39%)

6/12 (50%)

-11.5% (-62.4, 39.4)

Left-Sided Infective Endocarditis

1/9 (11%)

2/9 (22%)

-11.1% (-55.9, 33.6)

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

Overall, there was no difference in time to clearance of S. aureus bacteremia between daptomycin for injection 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%) daptomycin for injection-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 daptomycin for injection-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 use information is approved for Merck & Co., Inc.’s Cubicin (daptomycin for injection). However, due to Merck & Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

15 REFERENCES

  1. Liu SL, Howard LC, Van Lier RBL, Markham JK: Teratology studies with daptomycin administered intravenously (iv) to rats and rabbits. Teratology 37(5):475, 1988.
  2. Stroup JS, Wagner J, Badzinski T: Use of daptomycin in a pregnant patient with Staphylococcus aureus endocarditis. Ann Pharmacother 44(4):746-749, 2010.
  3. Buitrago MI, Crompton JA, Bertolami S, North DS, Nathan RA. Extremely low excretion of daptomycin into breast milk of a nursing mother with methicillin-resistant Staphylococcus aureus pelvic inflammatory disease. Pharmacotherapy 2009;29(3):347–351.
  4. Klibanov OM, Vickery S, Nortey C: Successful treatment of infective panniculitis with daptomycin in a pregnant, morbidly obese patient. Ann Pharmacother 48(5):652-655, 2014.
  5. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr, Ryan T, Bashore T, Corey GR. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30:633–638.

16 HOW SUPPLIED/STORAGE AND HANDLING

Daptomycin for Injection is supplied as a sterile pale yellow to light brown lyophilized cake in a single-dose 15 mL vial containing 350 mg of daptomycin: Package of 1 (NDC 70594-053-01).

Store original packages at refrigerated temperatures, 2 to 8°C (36 to 46°F); avoid excessive heat [see Dosage and Administration (2.5)].

17 PATIENT COUNSELING INFORMATION

Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Patients should report any previous allergic reactions to daptomycin [see Warnings and Precautions (5.1)] .

Advise patients to report muscle pain or weakness, especially in the forearms and lower legs, as well as tingling or numbness [see Warnings and Precautions (5.2, 5.4)].

Advise patients to report any symptoms of cough, breathlessness, or fever [see Warnings and Precautions (5.3)].

Advise patients that diarrhea is a common problem caused by antibacterials that usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever), even as late as 2 or more months after having received the last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.6) ].

Counsel patients that antibacterial drugs, including Daptomycin for Injection, should be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Daptomycin for Injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be administered exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Daptomycin for Injection or other antibacterial drugs in the future.

Manufactured for:

Xellia Pharmaceuticals USA, LLC
Buffalo Grove, IL 60089

Made in India

LEA-020125-03

Code No: AP/DRUGS/103/97

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL — 350 mg Vial Label

NDC 45932-0039-1 Rx Only

Daptomycin for Injection

350 mg/vial

MUST BE REFRIGERATED

For Intravenous Infusion.

Single-Dose VialDiscard Unused Portion

xellia-label
(click image for full-size original)

PRINCIPAL DISPLAY PANEL — 350 mg Vial Carton

NDC 45932-0039-1

Daptomycin for Injection

350 mg/vial

MUST BE REFRIGERATED

For Intravenous Infusion.

Use 0.9% Sodium Chloride Injection for reconstitution only.

One Single-Dose Vial

Discard Unused Portion

Rx Only

xellia-carton
(click image for full-size original)
DAPTOMYCIN daptomycin injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:45932-0039
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DAPTOMYCIN (DAPTOMYCIN) DAPTOMYCIN 350 mg in 7 mL
Inactive Ingredients
Ingredient Name Strength
SODIUM HYDROXIDE
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:45932-0039-1 1 VIAL in 1 CARTON contains a VIAL
1 7 mL in 1 VIAL This package is contained within the CARTON (45932-0039-1)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA209949 07/19/2018
Labeler — Xellia Pharmaceuticals USA, LLC (305814345)

Revised: 10/2019 Xellia Pharmaceuticals USA, LLC

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