Cubicin RF

Name: Cubicin RF

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Uses of Cubicin RF

  • It is used to treat bacterial infections.

Dosage Forms and Strengths

For Injection: 500 mg daptomycin as a sterile, pale yellow to light brown lyophilized powder for reconstitution in a single-dose vial.

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)]
  • Peripheral neuropathy [see Warnings and Precautions (5.4)]
  • Increased International Normalized Ratio (INR)/prolonged prothrombin time [see Warnings and Precautions (5.9) and Drug Interactions (7.2)]

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 CUBICIN 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, CUBICIN 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 CUBICIN) are displayed in Table 7.

Table 7: Incidence of Adverse Reactions that Occurred in ≥2% of Adult Patients in the CUBICIN Treatment Group and ≥ the Comparator Treatment Group in Phase 3 cSSSI Trials
Adverse Reaction Adult Patients (%)
CUBICIN 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 CUBICIN 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, CUBICIN 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%) CUBICIN-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 CUBICIN) are displayed in Table 8.

Table 8: Incidence of Adverse Reactions that Occurred in ≥5% of Adult Patients in the CUBICIN Treatment Group and ≥ the Comparator Treatment Group in the S. aureus Bacteremia/Endocarditis Trial
Adverse Reaction* Adult Patients
n (%)
CUBICIN 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 CUBICIN-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 CUBICIN-treated patients than in comparator-treated patients. These differences were due to lack of therapeutic effectiveness of CUBICIN 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 CUBICIN at a dose of 4 mg/kg, elevations in CPK were reported as clinical adverse events in 15/534 (2.8%) CUBICIN-treated patients, compared with 10/558 (1.8%) comparator-treated patients. Of the 534 patients treated with CUBICIN, 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 9 summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI adult trials.

Table 9: Incidence of CPK Elevations from Baseline during Therapy in Either the CUBICIN Treatment Group or the Comparator Treatment Group in Phase 3 cSSSI Adult Trials
Change in CPK All Adult Patients Adult Patients with Normal CPK at Baseline
CUBICIN
4 mg/kg
(N=430)
Comparator*
(N=459)
CUBICIN
4 mg/kg
(N=374)
Comparator*
(N=392)
% n % n % n % n
Note: Elevations in CPK observed in adult patients treated with CUBICIN 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.
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%) CUBICIN-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 CUBICIN-treated patients, 4 had prior or concomitant treatment with an HMG-CoA reductase inhibitor. Three of these 11 CUBICIN-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 CUBICIN was evaluated in one clinical trial (in cSSSI), which included 256 pediatric patients (1 to 17 years of age) treated with intravenous CUBICIN 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: 10mg/kg for 1 to < 2 years, 9 mg/kg for 2 to 6 years, 7mg/kg for 7 to 11 years and 5 mg/kg for 12 to 17 years of age [see Clinical Studies (14)]. Patients treated with CUBICIN were (51%) male, (49%) female and (46 %) Caucasian and (32 %) Asian.

Adverse Reactions Leading to Discontinuation

In the cSSSI study, CUBICIN 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 10.

Table 10: Adverse Reactions that Occurred in ≥2% of Pediatric Patients in the CUBICIN Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the cSSSI Pediatric Trial
CUBICIN
(N = 256)
Comparator*
(N = 133)
Adverse Reaction 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 CUBICIN was evaluated in one clinical trial (in S. aureus bacteremia), which treated 55 pediatric patients with intravenous CUBICIN 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 CUBICIN 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, CUBICIN 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 11.

Table 11: Incidence of Adverse Reactions that Occurred in ≥5% of Pediatric Patients in the CUBICIN Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the Pediatric Bacteremia Trial
CUBICIN
(N = 55)
Comparator
(N = 26)
Adverse Reaction n (%) n (%)
*Comparators included intravenous therapy with either vancomycin, cefazolin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin)
Gastrointestinal disorders
  Vomiting 6 (10.9) 2 (7.7)
Investigations
  Blood CPK increased 4 (7.3) 0

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of CUBICIN. 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

General and administration site conditions: pyrexia

Immune System Disorders: anaphylaxis; hypersensitivity reactions, including angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia [see Contraindications (4), Warnings and Precautions (5.1)]

Infections and Infestations: Clostridium difficile–associated diarrhea [see Warnings and Precautions (5.6)]

Musculoskeletal Disorders: myoglobin increased; rhabdomyolysis (some reports involved patients treated concurrently with CUBICIN 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 (5.4)]

Skin and Subcutaneous Tissue Disorders: serious skin reactions, including Stevens-Johnson syndrome and vesiculobullous rash (with or without mucous membrane involvement), acute generalized exanthematous pustulosis

Gastrointestinal Disorders: nausea, vomiting

Renal and urinary disorders: acute kidney injury, renal insufficiency, and renal failure

Special Senses: visual disturbances

Overdosage

In the event of overdosage, supportive care is advised with maintenance of glomerular filtration. Daptomycin is cleared slowly from the body by hemodialysis (approximately 15% of the administered dose is removed over 4 hours) and by peritoneal dialysis (approximately 11% of the administered dose is removed over 48 hours). The use of high-flux dialysis membranes during 4 hours of hemodialysis may increase the percentage of dose removed compared with that removed by low-flux membranes.

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 Cubicin RF, should be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cubicin RF 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 Cubicin RF or other antibacterial drugs in the future.

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