Daptomycin (Page 4 of 10)
5.11 Increased International Normalized Ratio (INR)/Prolonged Prothrombin Time
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)].
5.12 Development of Drug-Resistant Bacteria
Prescribing daptomycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication 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:
- Anaphylaxis/Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
- Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.2)]
- Eosinophilic Pneumonia [see Warnings and Precautions (5.3)]
- Drug Reaction with Eosinophilia and Systemic Symptoms [see Warnings and Precautions (5.4)]
- Tubulointerstitial Nephritis [see Warnings and Precautions (5.5)]
- Peripheral Neuropathy [see Warnings and Precautions (5.6)]
- Increased International Normalized Ratio (INR)/Prolonged Prothrombin Time [see Warnings and Precautions (5.11) and Drug Interactions (7.2)]
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 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 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) are displayed in Table 6.
| Adverse Reaction | Adult Patients (%) | |
|---|---|---|
| Daptomycin 4 mg/kg (N=534) | Comparator* (N=558) | |
| *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). | ||
| Gastrointestinal disorders | ||
| Diarrhea | 5.2 | 4.3 |
| Nervous system disorders | ||
| Headache | 5.4 | 5.4 |
| Dizziness | 2.2 | 2.0 |
| Skin/subcutaneous disorders | ||
| Rash | 4.3 | 3.8 |
| Diagnostic investigations | ||
| Abnormal liver function tests | 3.0 | 1.6 |
| Elevated CPK | 2.8 | 1.8 |
| 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 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 Adults
In the S. aureus bacteremia/endocarditis trial involving adult patients, daptomycin 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-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) are displayed in Table 7.
| Adverse Reaction* | Adult Patients n (%) | |
|---|---|---|
| Daptomycin 6 mg/kg (N=120) | Comparator † (N=116) | |
| *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. | ||
| Infections and infestations | ||
| Sepsis NOS | 6 (5%) | 3 (3%) |
| Bacteremia | 6 (5%) | 0 (0%) |
| Gastrointestinal disorders | ||
| Abdominal pain NOS | 7 (6%) | 4 (3%) |
| General disorders and administration site conditions | ||
| Chest pain | 8 (7%) | 7 (6%) |
| Edema NOS | 8 (7%) | 5 (4%) |
| Respiratory, thoracic and mediastinal disorders | ||
| Pharyngolaryngeal pain | 10 (8%) | 2 (2%) |
| Skin and subcutaneous tissue disorders | ||
| Pruritus | 7 (6%) | 6 (5%) |
| Sweating increased | 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-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 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-treated patients than in comparator-treated patients. These differences were due to lack of therapeutic effectiveness of daptomycin 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 at a dose of 4 mg/kg, elevations in CPK were reported as clinical adverse events in 15/534 (2.8%) daptomycin-treated patients, compared with 10/558 (1.8%) comparator-treated patients. Of the 534 patients treated with daptomycin, 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.
| Note: Elevations in CPK observed in adult patients treated with daptomycin 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 4 mg/kg (N=430) | Comparator* (N=459) | Daptomycin 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-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-treated patients, 4 had prior or concomitant treatment with an HMG-CoA reductase inhibitor. Three of these 11 daptomycin-treated patients discontinued therapy due to CPK elevation, while the one comparator-treated patient did not discontinue therapy [see Warnings and Precautions (5.2)].
Clinical Trial Experience in Pediatric Patients
Complicated Skin and Skin Structure Infection Trial in Pediatric Patients
The safety of daptomycin was evaluated in one clinical trial (in cSSSI), which included 256 pediatric patients (1 to 17 years of age) treated with intravenous daptomycin and 133 patients treated with comparator agents. Patients were given age-dependent doses once daily for a treatment period of up to 14 days (median treatment period was 3 days). The doses given by age group were as follows: 10 mg/kg for 1 to < 2 years, 9 mg/kg for 2 to 6 years, 7 mg/kg for 7 to 11 years and 5 mg/kg for 12 to 17 years of age [see Clinical Studies (14)]. Patients treated with daptomycin were (51%) male, (49%) female and (46%) Caucasian and (32%) Asian.
Adverse Reactions Leading to Discontinuation
In the cSSSI study, daptomycin was discontinued in 7/256 (2.7%) patients due to an adverse reaction, while comparator was discontinued in 7/133 (5.3%) patients.
Most Common Adverse Reactions
The rates of the most common adverse reactions, organized by body system, observed in these pediatric patients with cSSSI are displayed in Table 9.
| Adverse Reaction | Daptomycin (N = 256) | Comparator* (N = 133) |
|---|---|---|
| n (%) | n (%) | |
| *Comparators included intravenous therapy with either vancomycin, clindamycin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin) | ||
| Gastrointestinal disorders | ||
| Diarrhea | 18 (7.0) | 7 (5.3) |
| Vomiting | 7 (2.7) | 1 (0.8) |
| Abdominal Pain | 5 (2.0) | 0 |
| Skin and subcutaneous tissue disorders | ||
| Pruritus | 8 (3.1) | 2 (1.5) |
| General disorders and administration site conditions | ||
| Pyrexia | 10 (3.9) | 4 (3.0) |
| Investigations | ||
| Blood CPK increased | 14 (5.5) | 7 (5.3) |
| Nervous system disorders | ||
| Headache | 7 (2.7) | 3 (2.3) |
The safety profile in the clinical trial of cSSSI pediatric patients was similar to that observed in the cSSSI adult patients.
S. aureus Bacteremia Trial in Pediatric Patients
The safety of daptomycin was evaluated in one clinical trial (in S. aureus bacteremia), which treated 55 pediatric patients with intravenous daptomycin and 26 patients with comparator agents. Patients were given age-dependent doses once daily for a treatment period of up to 42 days (mean duration of IV treatment was 12 days). The doses by age group were as follows: 12 mg/kg for 1 to <6 years, 9 mg/kg for 7 to 11 years and 7 mg/kg for 12 to 17 years of age [see Clinical Studies (14)]. Patients treated with daptomycin were (69%) male and (31%) female. No patients 1 to <2 years of age were enrolled.
Adverse Reactions Leading to Discontinuation
In the bacteremia study, daptomycin was discontinued in 3/55 (5.5%) patients due to an adverse reaction, while comparator was discontinued in 2/26 (7.7%) patients.
Most Common Adverse Reactions
The rates of the most common adverse reactions, organized by body system, observed in these pediatric patients with bacteremia are displayed in Table 10.
| *Comparators included intravenous therapy with either vancomycin, cefazolin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin) | ||
| Adverse Reaction | Daptomycin (N = 55) | Comparator (N = 26) |
| n (%) | n (%) | |
| Gastrointestinal disorders | ||
| Vomiting | 6 (10.9) | 2 (7.7) |
| Investigations | ||
| Blood CPK increased | 4 (7.3) | 0 |
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