(daptomycin for injection)
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 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 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) are displayed in Table 4.
| Adverse Reaction | Adult Patients n (%) | |
|---|---|---|
| Daptomycin for Injection 4 mg/kg (N=534) | Comparator* (N=558) | |
| ||
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 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) are displayed in Table 5.
| Adverse Reaction* | Adult Patients n (%) | |
|---|---|---|
| Daptomycin for Injection 6 mg/kg (N=120) | Comparator† (N=116) | |
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 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 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 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 (1.3)].
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, 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 adult trials.
| Change in CPK | All Adult Patients | Adult Patients with Normal CPK at Baseline | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Daptomycin for Injection 4 mg/kg | Comparator* (N=459) | Daptomycin for Injection 4 mg/kg | Comparator* (N=392) | ||||||
| (N=430) | % | n | (N=374) | % | n | ||||
| % | n | % | n | ||||||
| Note: Elevations in CPK observed in adult patients treated with daptomycin for injection or comparator were not clinically or statistically significantly different. | |||||||||
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)].
The following adverse reactions have been identified during post-approval use of daptomycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: anemia, thrombocytopenia
General and administration site conditions: pyrexia
Immune System Disorders: anaphylaxis; hypersensitivity reactions, including angioedema, pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia [see Contraindications (4) and Warnings and Precautions (5.1)]
Infections and Infestations: Clostridioides difficile–associated diarrhea [see Warnings and Precautions (5.8)]
Laboratory Investigations: platelet count decreased
Musculoskeletal Disorders: myoglobin increased; rhabdomyolysis (some reports involved patients treated concurrently with daptomycin 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, organizing pneumonia [see Warnings and Precautions (5.3)]
Nervous System Disorders: peripheral neuropathy [see Warnings and Precautions (5.6)]
Skin and Subcutaneous Tissue Disorders: serious skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), vesiculobullous rash (with or without mucous membrane involvement, including Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]), and acute generalized exanthematous pustulosis [see Warnings and Precautions (5.4)]
Gastrointestinal Disorders: nausea, vomiting
Metabolic and Nutritional Disorders: hyperkalemia
Renal and urinary disorders: acute kidney injury, renal insufficiency, renal failure, and tubulointerstitial nephritis (TIN) [see Warnings and Precautions (5.5)]
Special Senses: visual disturbances
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