Daptomycin: Package Insert and Label Information (Page 2 of 6)

5.3 Eosinophilic Pneumonia

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

5.4 Peripheral Neuropathy

Cases of peripheral neuropathy have been reported during the Daptomycin for Injection post-marketing experience [see Adverse Reactions (6.2)]. Therefore, physicians should be alert to signs and symptoms of peripheral neuropathy in patients receiving Daptomycin for Injection. Monitor for neuropathy and consider discontinuation.

5.5 Potential Nervous System and/or Muscular System Effects in Pediatric Patients Younger than 12 Months

Avoid use of Daptomycin for Injection in pediatric patients younger than 12 months due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs with intravenous daptomycin [see Nonclinical Toxicology (13.2) ].

5.6 Clostridium difficile –Associated Diarrhea

Clostridium difficile –associated diarrhea (CDAD) has been reported with the use of nearly all systemic antibacterial agents, including Daptomycin for Injection, 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 evaluation should be instituted as clinically indicated.

5.7 Persisting or Relapsing S. aureus Bacteremia/Endocarditis

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 evaluation 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)].

5.8 Decreased Efficacy in Patients with Moderate Baseline Renal Impairment

Limited data are available from the two Phase 3 complicated skin and skin structure infection (cSSSI) trials regarding clinical efficacy of Daptomycin for Injection treatment in adult patients with creatinine clearance (CLCR ) <50 mL/min; only 31/534 (6%) patients treated with Daptomycin for Injection in the intent-to-treat (ITT) population had a baseline CLCR <50 mL/min. Table 4 shows the number of adult patients by renal function and treatment group who were clinical successes in the Phase 3 cSSSI trials.

Table 4. Clinical Success Rates by Renal Function and Treatment Group in Phase 3 cSSSI Trials in Adult Patients (Population: ITT)

CLCR

Success Rate n/N (%)

Daptomycin for Injection 4 mg/kg q24h

Comparator

50-70 mL/min

25/38 (66%)

30/48 (63%)

30–< 50 mL/min

7/15 (47%)

20/35 (57%)

In a subgroup analysis of the ITT population in the Phase 3 S. aureus bacteremia/endocarditis trial, clinical success rates, as determined by a treatment-blinded Adjudication Committee [see Clinical Trials (14.2)], in the Daptomycin for Injection-treated adult patients were lower in patients with baseline CLCR <50 mL/min (see Table 5). A decrease of the magnitude shown in Table 5 was not observed in comparator-treated patients.

Table 5: Adjudication Committee Clinical Success Rates at Test of Cure by Baseline Creatinine Clearance and Treatment Subgroup in the S. aureus Bacteremia/Endocarditis Trial in Adult Patients (Population: ITT)

Baseline CLCR

Success Rate n/N (%)

Daptomycin for Injection 6 mg/kg q24h

Comparator

Bacteremia

Right-Sided Infective Endocarditis

Bacteremia

Right-Sided Infective Endocarditis

>80 mL/min

30/50 (60%)

7/14 (50%)

19/42 (45%)

5/11 (46%)

50-80 mL/min

12/26 (46%)

1/4 (25%)

13/31 (42%)

1/2 (50%)

30-<50 mL/min

2/14 (14%)

0/1 (0%)

7/17 (41%)

1/1 (100%)

Consider these data when selecting antibacterial therapy for use in adult patients with baseline moderate to severe renal impairment.

5.9 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 [see Drug Interactions (7.2)].

5.10 Non-Susceptible Microorganisms

The use of antibacterials may promote the overgrowth of non-susceptible microorganisms. If these infections occur during therapy, appropriate measures should be taken.

Prescribing Daptomycin for Injection 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.

6 ADVERSE REACTIONS

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

6.1 Clinical Trials Experience

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 Trial Experience in Adult Patients

Clinical trials enrolled 1,864 adult patients treated with Daptomycin for Injection and 1,416 treated with comparator.

Complicated Skin and Skin Structure Infection Trials in Adults

In Phase 3 complicated skin and skin structure infection (cSSSI) trials in adult patients, Daptomycin for Injection 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 adult patients with cSSSI (receiving 4 mg/kg Daptomycin for Injection) are displayed in Table 6.

Table 6: Incidence of Adverse Reactions that Occurred in ≥2% of Adult Patients in the Daptomycin for Injection Treatment Group and ≥ the Comparator Treatment Group in Phase 3 cSSSI Trials
*
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).

Adverse Reaction

Adult Patients (%)

Daptomycin for Injection 4 mg/kg (N=534)

Comparator * (N=558)

Gastrointestinal disorders Diarrhea

5.2

4.3

Nervous system disorders Headache Dizziness

5.42.2

5.42.0

Skin/subcutaneous disorders Rash

4.3

3.8

Diagnostic investigations Abnormal liver function tests Elevated CPK

3.02.8

1.61.8

Infections Urinary tract infections

2.4

0.5

Vascular disorders Hypotension

2.4

1.4

Respiratory disorders Dyspnea

2.1

1.6

Drug-related adverse reactions (possibly or probably drug-related) that occurred in <1% of adult patients receiving Daptomycin for Injection 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, paresthesiaSpecial Senses: taste disturbance, eye irritation

S. aureus Bacteremia/Endocarditis Trial in Adults

In the S. aureus bacteremia/endocarditis trial involving adult patients, Daptomycin for Injection 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%) Daptomycin for Injection-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 adult patients with S. aureus bacteremia/endocarditis (receiving 6 mg/kg Daptomycin for Injection) are displayed in Table 7.

Table 7: Incidence of Adverse Reactions that Occurred in ≥5% of Adult Patients in the Daptomycin for Injection Treatment Group and ≥ the Comparator Treatment Group in the S. aureus Bacteremia/Endocarditis Trial
*
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 q4h), each with initial low-dose gentamicin.

Adverse Reaction *

Adult Patients n (%)

Daptomycin for Injection 6 mg/kg (N=120)

Comparator (N=116)

Infections and infestations

Sepsis NOS Bacteremia

6 (5%)

6 (5%)

3 (3%)

0 (0%)

Gastrointestinal disorders

Abdominal pain NOS

7 (6%)

4 (3%)

General disorders and administration site conditions

Chest pain Edema NOS

8 (7%)

8 (7%)

7 (6%)

5 (4%)

Respiratory, thoracic and mediastinal disorders

Pharyngolaryngeal pain

10 (8%)

2 (2%)

Skin and subcutaneous tissue disorders

Pruritus Sweating increased

7 (6%)

6 (5%)

6 (5%)

0 (0%)

Psychiatric disorders

Insomnia

11 (9%)

8 (7%)

Investigations Blood creatine phosphokinase increased

8 (7%)

1 (1%)

Vascular disorders

Hypertension NOS

7 (6%)

3 (3%)

The following reactions, not included above, were reported as possibly or probably drug-related in the Daptomycin for Injection-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 NOSSkin and Subcutaneous Tissue Disorders: pruritus generalized, rash vesicular

Other Trials in Adults

In Phase 3 trials of community-acquired pneumonia (CAP) in adult patients, the death rate and rates of serious cardiorespiratory adverse events were higher in Daptomycin for Injection-treated patients than in comparator-treated patients. These differences were due to lack of therapeutic effectiveness of Daptomycin for Injection in the treatment of CAP in patients experiencing these adverse events [see Indications and Usage (1.4)].

Laboratory Changes in Adults

Complicated Skin and Skin Structure Infection Trials in Adults

In Phase 3 cSSSI trials of adult patients receiving Daptomycin for Injection at a dose of 4 mg/kg, elevations in CPK were reported as clinical adverse events in 15/534 (2.8%) Daptomycin for Injection-treated patients, compared with 10/558 (1.8%) comparator-treated patients. Of the 534 patients treated with Daptomycin for Injection, 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 8 summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI adult trials.

Table 8: Incidence of CPK Elevations from Baseline during Therapy in Either the Daptomycin for Injection Treatment Group or the Comparator Treatment Group in Phase 3 cSSSI Adult Trials
Note: Elevations in CPK observed in adult patients treated with Daptomycin for Injection or comparator were not clinically or statistically significantly different.
*
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.

Change in CPK

All Adult Patients

Adult Patients with Normal CPK

at Baseline

Daptomycin for

Injection

4 mg/kg

(N=430)

Comparator *

(N=459)

Daptomycin for

Injection

4 mg/kg

(N=374)

Comparator *

(N=392)

%

n

%

n

%

n

%

n

No Increase

90.7

390

91.1

418

91.2

341

91.1

357

Maximum

Value >1× ULN

9.3

40

8.9

41

8.8

33

8.9

35

>2× ULN

4.9

21

4.8

22

3.7

14

3.1

12

>4× ULN

1.4

6

1.5

7

1.1

4

1.0

4

>5× ULN

1.4

6

0.4

2

1.1

4

0.0

0

>10× ULN

0.5

2

0.2

1

0.2

1

0.0

0

S. aureus Bacteremia/Endocarditis Trial in Adults

In the S. aureus bacteremia/endocarditis trial in adult patients, at a dose of 6 mg/kg, 11/120 (9.2%) Daptomycin for Injection-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 Daptomycin for Injection-treated patients, 4 had prior or concomitant treatment with an HMG-CoA reductase inhibitor. Three of these 11 Daptomycin for Injection-treated patients discontinued therapy due to CPK elevation, while the one comparator-treated patient did not discontinue therapy [see Warnings and Precautions (5.2)].

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.

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