Daptomycinside effects

The following adverse reactions are described, or described in greater detail, in other sections: Anaphylaxis/Hypersensitivity Reactions Myopathy and Rhabdomyolysis Eosinophilic Pneumonia Drug Reaction with Eosinophilia and Systemic Symptoms Tubulointerstitial Nephritis Peripheral Neuropathy Increased International Normalized Ratio (INR)/Prolonged Prothrombin Time Adult cSSSI Patients: The most common adverse reactions that occurred in ≥2% of adult cSSSI patients receiving daptomycin for injection 4 mg/kg were diarrhea, headache, dizziness, rash, abnormal liver function tests, elevated creatine phosphokinase (CPK), urinary tract infections, hypotension, and dyspnea.

Pediatric cSSSI Patients: The most common adverse reactions that occurred in ≥2% of pediatric patients receiving daptomycin for injection were diarrhea, vomiting, abdominal pain, pruritus, pyrexia, elevated CPK, and headache. Adult S. aureus bacteremia/endocarditis Patients: The most common adverse reactions that occurred in ≥5% of S. aureus bacteremia/endocarditis patients receiving daptomycin for injection 6 mg/kg were sepsis, bacteremia, abdominal pain, chest pain, edema, pharyngolaryngeal pain, pruritus, increased sweating, insomnia, elevated CPK, and hypertension. Pediatric S. aureus bacteremia Patients: The most common adverse reactions that occurred in ≥5% of pediatric patients receiving daptomycin for injection were vomiting and elevated CPK. To report SUSPECTED ADVERSE REACTIONS, contact Sintetica US at 1-888-815-3345 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 Adverse Reaction Adult Patients (%) Daptomycin for Injection 4 mg/kg (N=534) Comparator 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). (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 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, 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 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 Adverse Reaction NOS, not otherwise specified. Adult Patients n (%) Daptomycin for Injection 6 mg/kg (N=120) Comparator 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. (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. 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. 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. Clinical Trial Experience in Pediatric Patients Complicated Skin and Skin Structure Infection Trial in Pediatric Patients The safety of daptomycin for injection was evaluated in one clinical trial (in cSSSI), which included 256 pediatric patients (1 to 17 years of age) treated with intravenous daptomycin for injection 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. Patients treated with daptomycin for injection were (51%) male, (49%) female and (46%) Caucasian and (32%) Asian. Adverse Reactions Leading to Discontinuation: In the cSSSI study, daptomycin for injection 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.

Table 9: Adverse Reactions that Occurred in ≥2% of Pediatric Patients in the Daptomycin for Injection Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the cSSSI Pediatric Trial Adverse Reaction Daptomycin for Injection (N=256) Comparator Comparators included intravenous therapy with either vancomycin, clindamycin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin) (N=133) n (%) n (%) Gastrointestinal disorders Diarrhea 18 7 Vomiting 7 1 Abdominal pain 5 0 Skin and subcutaneous tissue disorders Pruritus 8 2 General disorders and administration site conditions Pyrexia 10 4 Investigations Blood CPK increased 14 7 Nervous system disorders Headache 7 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 for injection was evaluated in one clinical trial (in S. aureus bacteremia), which treated 55 pediatric patients with intravenous daptomycin for injection 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. Patients treated with daptomycin for injection 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 for injection 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.

Table 10: Incidence of Adverse Reactions that Occurred in ≥5% of Pediatric Patients in the Daptomycin for Injection Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the Pediatric Bacteremia Trial Adverse Reaction Daptomycin for Injection (N=55) Comparator Comparators included intravenous therapy with either vancomycin, cefazolin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin) (N=26) n (%) n (%) Gastrointestinal disorders Vomiting 6 2 Investigations Blood CPK increased 4 0

6.2 Post-Marketing

Experience The following adverse reactions have been identified during post-approval use of daptomycin for injection. 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 Infections and Infestations: Clostridioides difficile –associated diarrhea Laboratory Investigations: platelet count decreased Musculoskeletal Disorders: myoglobin increased; rhabdomyolysis (some reports involved patients treated concurrently with daptomycin for injection and HMG-CoA reductase inhibitors) Respiratory, Thoracic, and Mediastinal Disorders: cough, eosinophilic pneumonia, organizing pneumonia Nervous System Disorders: peripheral neuropathy 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 Gastrointestinal Disorders: nausea, vomiting Renal and urinary disorders: acute kidney injury, renal insufficiency, renal failure, and tubulointerstitial nephritis (TIN) Special Senses: visual disturbances