Cubicin: Indications, Dosage, Precautions, Adverse Effects
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Cubicin - Product Information

Manufacture: Sunovion Pharmaceuticals Inc.
Country: Canada
Condition: Bacteremia, Endocarditis, Methicillin-Resistant Staphylococcus Aureus Infection, Skin and Structure Infection, Skin or Soft Tissue Infection
Class: Miscellaneous antibiotics
Form: Liquid solution, Intravenous (IV)
Ingredients: daptomycin, sodium hydroxide

(Daptomycin for Injection)

Summary Product Information

Route of Administration Dosage Form/Strength Clinically Relevant Nonmedicinal Ingredients
intravenous 10 mL vial, 500 mg/vial Sodium hydroxide
For a complete listing see Dosage Forms, Composition and Packaging section.

Indications And Clinical Use

CUBICIN (daptomycin for injection) is indicated for the following infections in adults:

Complicated skin and skin structure infections (cSSSI) caused by susceptible strains of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillinresistant strains), Streptococcus pyogenes and Streptococcus agalactiae.

Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative and/or anaerobic organisms. Skin and soft tissues infections are considered complicated when they involve deeper skin structures, such as fascia or muscle layers, require significant surgical intervention or arise in the presence of significant comorbidity.

Staphylococcus aureus bloodstream infections (bacteremia) including those with right-sided

Staphylococcus aureus infective endocarditis (native valve) caused by methicillin-susceptible and methicillin-resistant strains.

Patients with prosthetic valves, meningitis, known osteomyelitis, polymicrobial bloodstream infections or with intravascular foreign material not planned for removal within 4 days of dosing (except vascular stents in place for > 6 months or permanent pacemakers) were not enrolled in clinical trials.

The efficacy of CUBICIN in patients with left-sided infective endocarditis due to Staphylococcus aureus has not been demonstrated. The clinical trial of daptomycin in patients with Staphylococcus aureus bloodstream infections included limited data from patients with left-sided infective endocarditis; outcomes in these patients were poor.

Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative and/or anaerobic organisms.

CUBICIN® is not indicated for the treatment of pneumonia.

Patients with persisting or relapsing Staphylococcus aureus infection or poor clinical response should have repeat blood cultures. Appropriate surgical intervention (e.g., debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of a change in antibiotic regimen may be required.

Pediatrics (<18 years of age): The safety and efficacy of CUBICIN in patients under the age of 18 have not been established. Based on the very limited pharmacokinetic data currently available, no recommendation on a posology can be made. Therefore, use of CUBICIN in this age group is not recommended until further data are available (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Pediatrics, DETAILED PHARMACOLOGY, Animal Pharmacology, Juvenile Animals and TOXICOLOGY).

Contraindications

CUBICIN (daptomycin for injection) is contraindicated in patients with known hypersensitivity to daptomycin.

Warnings And Precautions

General

The use of antibiotics may promote the overgrowth of non-susceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.

Prescribing CUBICIN (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.

CUBICIN is inactive against Gram-negative bacteria.

Because daptomycin activity is inhibited in the presence of pulmonary surfactant, CUBICIN is not indicated for use in pneumonia.

The safety and efficacy of CUBICIN has not been established in patients with co-morbidities of meningitis, musculopathies, neuropathies or severe renal impairment.

Immune System

Hypersensitivity

Anaphylaxis and hypersensitivity reactions (including angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema and pulmonary eosinophilia) have been reported with CUBICIN use. If an allergic reaction occurs, administration of CUBICIN should be discontinued and appropriate therapy should be initiated.

Persisting or Relapsing Staphylococcus aureus Infection

Patients with persisting or relapsing Staphylococcus aureus infection or poor clinical response should have repeat blood cultures. If a culture is positive for Staphylococcus aureus, MIC susceptibility testing of the isolate should be performed using a standardized procedure, as well as diagnostic evaluation 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 antibiotic regimen may be required.

In the Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) trial, failure of treatment due to persisting or relapsing Staphylococcus aureus infections was assessed in 19/120 (15.8%) CUBICIN-treated patients [12 with methicillinresistant Staphylococcus aureus (MRSA) and 7 with methicillin-susceptible Staphylococcus aureus (MSSA)] and 11/115 (9.6%) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with anti-staphylococcal semi-synthetic penicillin). Among all failures, 6 CUBICIN-treated patients and 1 vancomycin-treated patient developed increasing MICs (reduced susceptibility) on or following therapy. Most patients who failed due to persisting or relapsing Staphylococcus aureus infection had deep-seated infection and did not receive necessary surgical intervention.

Musculoskeletal

Myopathy and Creatine Phosphokinase (CPK)

Myopathy [muscular pains, weakness, and/or rhabdomyolysis (with or without acute renal failure)] associated with creatine phosphokinase (CPK) elevations has been observed with the use of daptomycin in human and animal studies and during post-marketing use (see ADVERSE REACTIONS, DETAILED PHARMACOLOGY and TOXICOLOGY).

Therefore, in patients receiving CUBICIN it is recommended that:

  • Patients should be monitored regularly for any signs and symptoms that might represent myopathy including muscle pain or weakness, particularly in the distal extremities.
  • Any patient who develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days.
  • Plasma CPK levels should be measured at baseline and at least once weekly during therapy in all patients.
  • Patients who develop unexplained elevations in CPK should be monitored more frequently than once weekly.
  • Consideration should be given prior to initiation of CUBICIN therapy in patients with increased baseline CPK as these patients may be at increased risk of further increases of CPK during CUBICIN therapy. If CUBICIN is given, these patients should be monitored more frequently than once weekly.
  • CPK should be measured more frequently than once weekly in patients who are at higher risk of developing myopathy. These patients include but are not limited to those with renal impairment, and those who recently received or are currently taking other medications known to be associated with myopathy (e.g., HMG-CoA reductase inhibitors).

CUBICIN should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevation > 1000 U/L (approximately 5 times ULN), or in patients without reported symptoms who have marked elevations in CPK (≥ 10 times ULN). In addition, consideration should be given to temporarily suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, in patients receiving CUBICIN.

In Phase 3 complicated skin and skin structure infection trials (cSSSI) of CUBICIN, at a dose of 4 mg/kg, elevations in serum CPK were reported as clinical adverse events in 15/534 (2.8%) CUBICIN-treated patients, compared to 10/558 (1.8%) comparator-treated patients.

In the Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) trial, at a dose of 6 mg/kg, elevations in CPK were reported as clinical adverse events in 8/120 (6.7%) of CUBICIN- treated patients, compared to 1/116 (< 1%) of the comparator-treated patients. There were a total of 11 patients who experienced CPK elevations to above 500 U/L (2.5 times ULN). Of these 11 patients, 5 had recent prior or concomitant treatment with an HMG-CoA reductase inhibitor. Three (2.6%) CUBICIN-treated patients, including 1 with trauma associated with heroin overdose, 1 with spinal cord compression and 1 with concomitant HMG-CoA reductase inhibitor, had an elevation in CPK > 500 U/L with associated musculoskeletal symptoms. None of the patients in the comparator group had an elevation of CPK > 500 U/L with associated musculoskeletal symptoms.

In a Phase 1 study in healthy volunteers examining doses up to 12 mg/kg q24h of CUBICIN for 14 days, no skeletal muscle effects or CPK elevations were observed.

Skeletal muscle effects associated with CUBICIN were observed in animals (see DETAILED PHARMACOLOGY, Animal Pharmacology and TOXICOLOGY).

Neurologic

Neuropathy

Cases of peripheral neuropathy have been reported during post-marketing therapy with CUBICIN (see ADVERSE REACTIONS).

Direct effects on the central nervous system have not been investigated.

In a small number of patients in Phase 1 and Phase 2 studies at doses up to 6 mg/kg, administration of CUBICIN® was associated with decreases in nerve conduction velocity and with adverse events (e.g., paresthesias, Bell’s palsy) possibly reflective of peripheral or cranial neuropathy. In the Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) trial, a total of 11/120 (9.2%) CUBICIN-treated patients had treatment-emergent adverse events related to the peripheral nervous system. All of the events were classified as mild to moderate in severity; most were of short duration and resolved during continued treatment with CUBICIN or were likely due to an alternative etiology.

In a Phase 1 study in healthy volunteers examining doses up to 12 mg/kg q24h of CUBICIN for 14 days, no evidence of peripheral nerve conduction deficits or symptoms of peripheral neuropathy were observed.

In adult animals, effects of CUBICIN® on peripheral nerve were observed. In juvenile dogs, peripheral and spinal cord nerve effects were noted.

Pediatric patients younger than 12 months should not be given CUBICIN® due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs (see INDICATIONS AND CLINICAL USE, Pediatrics, DETAILED PHARMACOLOGY, Animal Pharmacology and TOXICOLOGY).

Renal

The safety and efficacy of CUBICIN in patients with severe renal impairment (creatinine clearance < 30 mL/min) have not been established. CUBICIN should only be considered for use in patients with severe renal impairment when the expected clinical benefit outweighs the potential risk and there are no further available therapeutic options. In these patients, a dose adjustment is required (see DOSAGE AND ADMINISTRATION, Patients with Renal Impairment). Response to treatment, renal function and creatine phosphokinase (CPK) should be closely monitored.

No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 mL/min). However, due to limited clinical experience, response to treatment, renal function and creatine phosphokinase (CPK) should be closely monitored in all patients with some degree of renal impairment (creatinine clearance < 80 mL/min).

Consideration should be given to monitoring renal function in patients treated with CUBICIN. Renal impairment has been reported during treatment with CUBICIN although the relationship to daptomycin remains unclear (see ADVERSE REACTIONS>).

Caution is advised prior to commencing therapy with CUBICIN® in patients who already have some degree of renal impairment (creatinine clearance < 80 mL/min).

Regular monitoring of renal function is advised during the concomitant administration of potentially nephrotoxic agents, regardless of the patient’s underlying renal function.

In the Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) trial, at a dose of CUBICIN® 6 mg/kg/day, a lower clinical success rate and an increase in serious adverse events were seen in patients with moderately impaired renal function (creatinine clearance 30 to < 50 mL/min).

Carcinogenesis and Mutagenesis

Long-term carcinogenicity studies in animals have not been conducted to evaluate the carcinogenic potential of daptomycin. However, neither mutagenic nor clastogenic potential was found in a battery of genotoxicity tests (see TOXICOLOGY).

Gastrointestinal

Clostridium difficile-Associated Disease

Clostridium difficile-associated disease (CDAD) has been reported with the use of many antibacterial agents, including CUBICIN. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of the colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases (see ADVERSE REACTIONS).

Respiratory

Community-Acquired Pneumonia

In Phase 3 studies of community-acquired pneumonia, the death rate and rates of serious cardiorespiratory adverse events were higher in CUBICIN-treated patients than in comparatortreated patients. These differences were due to lack of therapeutic effectiveness of CUBICIN in the treatment of community-acquired pneumonia in patients experiencing these adverse events (see INDICATIONS AND CLINICAL USE). Daptomycin’s activity in vitro is inhibited by the presence of pulmonary surfactant.

Eosinophilic Pneumonia

Eosinophilic pneumonia has been reported in patients receiving CUBICIN®. In reported cases associated with CUBICIN, patients developed fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates. In general, patients developed eosinophilic pneumonia 2 to 4 weeks after starting CUBICIN and improved when CUBICIN was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon reexposure has been reported. Patients who develop these signs and symptoms while receiving CUBICIN should undergo prompt medical evaluation, and CUBICIN® should be discontinued immediately. Treatment with systemic steroids is recommended.

Special Populations

Pregnant Women

No clinical studies have been performed in pregnant women. CUBICIN should not be used during pregnancy unless clearly necessary and the benefits to the mother outweigh the potential risks to the fetus. Animal studies have not demonstrated harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.

Nursing Women

Data from a single case indicated that daptomycin is present in human milk. Daptomycin is poorly bioavailable orally. Due to limited data, breastfeeding should be discontinued during treatment with CUBICIN.

Pediatrics (<18 years of age)

The safety and efficacy of CUBICIN in patients under the age of 18 have not been established. Based on the very limited pharmacokinetic data currently available, no recommendation on a posology can be made. Therefore, use of CUBICIN in this age group is not recommended until further data are available.

Pediatric patients younger than 12 months should not be given CUBICIN® due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs (see INDICATIONS AND CLINICAL USE, Pediatrics, ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Pediatrics, DETAILED PHARMACOLOGY, Animal Pharmacology, and TOXICOLOGY).

Geriatrics (≥ 65 years of age)

In the Phase 3 clinical studies, lower clinical success rates were seen in patients ≥ 65 years of age compared to those < 65 years of age. In addition, treatmentemergent adverse events were more common in patients ≥ 65 years old than in patients < 65 years of age. Of the 534 patients treated with CUBICIN in Phase 3 controlled clinical trials of complicated skin and skin structure infection (cSSSI), 27.0% were 65 years of age or older and 12.4% were 75 years or older. Of the 120 patients treated with CUBICIN in the Phase 3 Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) controlled clinical trial, 25.0% were 65 years of age or older and 15.8% were 75 years or older.

Monitoring and Laboratory Tests

Creatine Phosphokinase (CPK)

Patients should be monitored regularly for any signs and symptoms that might represent myopathy including muscle pain or weakness, particularly in the distal extremities. Any patient who develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days.

Plasma CPK levels should be measured at baseline and at least once weekly during CUBICIN therapy in all patients. Patients who develop unexplained elevations in CPK should be monitored more frequently than once weekly. Consideration should be given prior to initiation of CUBICIN therapy in patients with increased baseline CPK as these patients may be at increased risk of further increases of CPK during CUBICIN therapy. If CUBICIN is given, these patients should be monitored more frequently than once weekly.

CPK should be measured more frequently than once weekly in patients who are at higher risk of developing myopathy. These patients include but are not limited to those with renal impairment, and those who recently received or are currently taking other medications known to be associated with myopathy (e.g., HMG-CoA reductase inhibitors) [see WARNINGS AND PRECAUTIONS, Musculoskeletal, Myopathy and Creatine Phosphokinase (CPK)].

Renal

Consideration should be given to monitoring renal function in patients treated with CUBICIN.

In patients with renal impairment (creatinine clearance < 80 mL/min) response to treatment, renal function and creatine phosphokinase (CPK) should be closely monitored.

The safety and efficacy of CUBICIN in patients with severe renal impairment (creatinine clearance < 30 mL/min) have not been established.

Neuropathy

Patients should be monitored for signs and symptoms of neuropathy during therapy with CUBICIN.

Warfarin

As experience with the concomitant administration of CUBICIN and warfarin is limited, anticoagulant activity in patients receiving CUBICIN and warfarin should be monitored for the first several days after initiating therapy with CUBICIN.

Adverse Reactions

Adverse Drug Reaction Overview

Clinical studies enrolled 1,667 patients treated with CUBICIN and 1,319 treated with comparator. Overall, at least one adverse event was reported by 51.3% of CUBICIN-treated subjects and by 52.5% of comparator-treated subjects in two Phase 3, double-blind, controlled complicated skin and skin structure infection (cSSSI) trials. In the randomized, comparative, open-label Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) trial, the majority of patients experienced at least one treatment emergent adverse event during the study, including 95.8% and 94.8% of patients in the CUBICIN and comparator groups, respectively. The majority of adverse events reported in the Phase 1, 2 and 3 clinical studies were described as mild or moderate in intensity.

In the cSSSI trials, CUBICIN was discontinued in 15/534 (2.8%) patients due to an adverse event while comparator was discontinued in 17/558 (3.0%) patients. In the SAB/SAIE trial, CUBICIN was discontinued in 20/120 (16.7%) patients due to an adverse event while comparator was discontinued in 21/116 (18.1%) patients.

In the cSSSI trials, CUBICIN was discontinued in 15/534 (2.8%) patients due to an adverse event while comparator was discontinued in 17/558 (3.0%) patients. In the SAB/SAIE trial, CUBICIN was discontinued in 20/120 (16.7%) patients due to an adverse event while comparator was discontinued in 21/116 (18.1%) patients.

The most frequent adverse events observed in the cSSSI trials were: constipation, nausea, injection site reactions, headache and diarrhea. In the SAB/SAIE trial, the most frequent adverse events were: diarrhea, vomiting, constipation and nausea.

The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy volunteers. Based on these study results, both methods of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had a similar safety and tolerability profile. There was no relevant difference in local tolerability or in the nature and frequency of adverse reactions.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Complicated Skin and Skin Structure Infection (cSSSI) Trials

Most Common Clinical Trial Adverse Drug Reactions in Two Phase 3 cSSSI Studies

The rates of the most common treatment emergent adverse events irrespective of causality, organized by body system, observed in the cSSSI clinical trials are displayed in Table 1.


Table 1. Incidence (%) of Treatment Emergent Adverse Events Irrespective of Causality that Occurred in ≥ 2% of Patients in Either CUBICIN or Comparator Treatment Groups in the Phase 3 cSSSI Studies1 (Population: Safety2)

Adverse Event CUBICIN 4 mg/kg
(N=534)
Comparator3
(N=558)
Gastrointestinal Disorders
Constipation 6.2% 6.8%
Nausea 5.8% 9.5%
Diarrhea 5.2% 4.3%
Vomiting 3.2% 3.8%
Dyspepsia 0.9% 2.5%
General Disorders
Injection site reactions 5.8% 7.7%
Fever 1.9% 2.5%
Nervous System Disorders
Headache 5.4% 5.4%
Insomnia 4.5% 5.4%
Dizziness 2.2% 2.0%
Skin/Subcutaneous Disorders
Rash 4.3% 3.8%
Pruritus 2.8% 3.8%
Diagnostic Investigations
Abnormal liver function tests 3.0% 1.6%
Elevated CPK 2.8% 1.8%
Infections
Fungal infections 2.6% 3.2%
Urinary tract infections 2.4% 0.5%
Vascular Disorders
Hypotension 2.4% 1.4%
Hypertension 1.1% 2.0%
Renal/Urinary Disorders
Renal failure 2.2% 2.7%
Blood/Lymphatic Disorders
Anemia 2.1% 2.3%
Respiratory Disorders
Dyspnea 2.1% 1.6%
Musculoskeletal Disorders
Limb pain 1.5% 2.0%
Arthralgia 0.9% 2.2%
1 This table includes Adverse Events from both cSSSI Phase 3 trials. The first trial was conducted in the U.S. and South Africa, the second in Europe, South Africa, Australia and Israel

2 Safety population includes all subjects who received at least one dose of CUBICIN or comparator according to treatment actually received during the trials

3 Comparators included vancomycin (1 g IV q12h), which was used in patients with known or suspected penicillin allergy or with methicillinresistant Staphylococcus aureus infection, and anti-staphylococcal semi-synthetic penicillin (i.e. nafcillin, oxacillin, cloxacillin, flucloxacillin 4-12 g/day IV), which were selected based on the standard therapy in each country.


Additional adverse events that occurred in < 1 to 2% of patients in either CUBICIN (4 mg/kg) or comparator treatment groups in the cSSSI studies are as follows: edema, cellulitis, hypoglycemia, elevated alkaline phosphatase, cough, back pain, abdominal pain, hypokalemia, hyperglycemia, decreased appetite, anxiety, chest pain, sore throat, cardiac failure, confusion and Candida infections. These events occurred at rates ranging from 0.2 to 1.7% in CUBICIN- treated patients and at rates of 0.4 to 1.8% in comparator-treated patients.

The most common possibly or probably drug-related treatment emergent adverse events organized by body system, observed in the cSSSI trials are displayed in Table 2.


Table 2. Incidence (%) of Possibly or Probably Drug-Related Treatment Emergent Adverse Events Occurring in ≥ 1% of Patients in Either CUBICIN or Comparator Treatment Groups in the Phase 3 cSSSI Studies (Population: Safety)

Adverse Event CUBICIN 4 mg/kg
(N=534)
Comparator
(N=558)
Gastrointestinal Disorders
Nausea 2.2% 3.4%
Investigations
Blood creatine phosphokinase increased 2.1% 1.4%

Less Common Clinical Trial Adverse Drug Reactions (<1%) in Two Phase 3 cSSSI Studies

Additional drug-related adverse events (possibly or probably related) that occurred in < 1% of patients receiving CUBICIN in the complicated skin and skin structure infection (cSSSI) trials are as follows:

Body as a Whole: fatigue, weakness, rigors, discomfort, tremor, 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, flatulence, stomatitis, jaundice, increased serum lactate dehydrogenase

Metabolic/Nutritional System: hypomagnesemia, increased serum bicarbonate, electrolyte disturbance

Musculoskeletal System: myalgia, muscle cramps, muscle weakness, osteomyelitis

Nervous System: vertigo, mental status change, paraesthesia

Special Senses: taste disturbance, eye irritation

Reproductive System and Breast Disorders: vaginitis

Abnormal Hematologic and Clinical Chemistry Findings in Two Phase 3 cSSSI Studies

In the two Phase 3 comparator-controlled complicated skin and skin structure (cSSSI) studies, there was no clinically or statistically significant difference (p<0.05) in the incidence of creatine phosphokinase (CPK) elevations between patients treated with CUBICIN and those treated with comparator. CPK elevations in both groups were generally related to medical conditions, for example, skin and skin structure infection, surgical procedures, or intramuscular injections; and were not associated with muscle symptoms.

Table 3 summarizes the CPK shifts from Baseline through End of Treatment in the cSSSI trials.


Table 3. Incidence (%) of Creatine Phosphokinase (CPK) Elevations From Baseline Through End of Treatment in either CUBICIN or Comparator Treatment Groups in Phase 3 cSSSI Studies

Change All Patients Patients with Normal CPK at Baseline
CUBICIN
(N=430)
Comparator
(N=459)
CUBICIN
(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
>1x ULN*
9.3% 40 8.9% 41 8.8% 33 8.9% 35
>2x ULN 4.9% 21 4.8% 22 3.7% 14 3.1% 12
>4x ULN 1.4% 6 1.5% 7 1.1% 4 1.0% 4
>5x ULN 1.4% 6 0.4% 2 1.1% 4 0.0% 0
>10x ULN 0.5% 2 0.2% 1 0.2% 1 0.0% 0
* ULN (Upper Limit of Normal) is defined as 200 U/L.

In the cSSSI studies, 0.2% of patients treated with CUBICIN had symptoms of muscle pain or weakness associated with CPK elevations to greater than 4 times the upper limit of normal. The symptoms resolved within 3 days and CPK returned to normal within 7 to 10 days after discontinuing treatment [see WARNINGS AND PRECAUTIONS, Musculoskeletal, Myopathy and Creatine Phosphokinase (CPK)].

Staphylococcus aureus Bacteremia/Staphylococcus aureus Infective Endocarditis (SAB/SAIE) Trial

Most Common Clinical Trial Adverse Drug Reactions in the SAB/SAIE Trial

The rates of the most common treatment emergent adverse events irrespective of causality and organized by body system observed in the Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) trial are displayed in Table 4.


Table 4. Incidence (%) of Treatment Emergent Adverse Events Irrespective of Causality that Occurred in ≥ 5% of Patients in CUBICIN or Comparator Treatment Groups in the SAB/SAIE Study (Population: Safetya)

Adverse Events CUBICIN 6 mg/kg
(N=120)
Comparatorb
(N=116)
Infections and Infestations 54.2% 48.3%
Urinary tract infection NOSc 6.7% 9.5%
Osteomyelitis NOS 5.8% 6.0%
Sepsis NOS 5.0% 2.6%
Bacteremia 5.0% 0%
Pneumonia NOS 3.3% 7.8%
Gastrointestinal Disorders 50.0% 58.6%
Diarrhea NOS 11.7% 18.1%
Vomiting NOS 11.7% 12.9%
Constipation 10.8% 12.1%
Nausea 10.0% 19.8%
Abdominal pain NOS 5.8% 3.4%
Dyspepsia 4.2% 6.9%
Loose stools 4.2% 5.2%
Gastrointestinal hemorrhage NOS 1.7% 5.2%
General Disorders and Administration Site Conditions 44.2% 59.5%
Edema peripheral 6.7% 13.8%
Pyrexia 6.7% 8.6%
Chest pain 6.7% 6.0%
Edema NOS 6.7% 4.3%
Asthenia 5.0% 5.2%
Injection site erythema 2.5% 6.0%
Respiratory, Thoracic and Mediastinal Disorders 31.7% 37.1%
Pharyngolaryngeal pain 8.3% 1.7%
Pleural effusion 5.8% 6.9%
Cough 3.3% 6.0%
Dyspnea 3.3% 5.2%
Skin and Subcutaneous Tissue Disorders 30.0% 34.5%
Rash NOS 6.7% 8.6%
Pruritus 5.8% 5.2%
Erythema 5.0% 5.2%
Sweating increased 5.0% 0%
Musculoskeletal and Connective Tissue Disorders 29.2% 36.2%
Pain in extremity 9.2% 9.5%
Back pain 6.7% 8.6%
Arthralgia 3.3% 11.2%
Psychiatric Disorders 29.2% 24.1%
Insomnia 9.2% 6.9%
Anxiety 5.0% 5.2%
Nervous System Disorders 26.7% 27.6%
Headache 6.7% 10.3%
Dizziness 5.8% 6.0%
Investigations 25.0% 28.4%
Blood creatine phosphokinase increased 6.7% <1%
Blood and Lymphatic System Disorders 24.2% 20.7%
Anemia NOS 12.5% 15.5%
Metabolism and Nutrition Disorders 21.7% 32.8%
Hypokalemia 9.2% 12.9%
Hyperkalemia 5.0% 8.6%
Vascular Disorders 17.5% 17.2%
Hypertension NOS 5.8% 2.6%
Hypotension NOS 5.0% 7.8%
Injury, Poisoning and Procedural Complications 15.8% 15.5%
Renal and Urinary Disorders 15.0% 22.4%
Renal failure NOS 3.3% 9.5%
Renal failure acute 3.3% 6.0%
Cardiac Disorders 11.7% 15.5%
Reproductive System and Breast Disorders 5.0% 6.9%
Eye Disorders 4.2% 8.6%
a Safety population includes all subjects who received at least one dose of CUBICIN or comparator according to treatment actually received during the trials

b Comparator: vancomycin (1 g IV q12h), which was used in patients with known or suspected penicillin allergy or with methicillinresistant Staphylococcus aureus, or anti-staphylococcal semi-synthetic penicillins (i.e., nafcillin, oxacillin, cloxacillin, flucloxacillin; 2 g IV q4h), which were selected based on the standard therapy in each country, each with initial synergistic gentamicin.

c NOS: Not Otherwise Specified


Note: p-values by body system were as follows: infections p=0.435; gastrointestinal p=0.194; general and administration site p=0.020; respiratory, thoracic, mediastinal p=0.412; skin and subcutaneous tissue p=0.488; musculoskeletal and connective tissue p=0.269; psychiatric p=0.462; nervous system p=0.885; investigations p=0.560; blood and lymphatic system p=0.537; metabolism and nutrition p=0.059; vascular p>0.999; injury, poisoning p>0.999; renal and urinary p=0.181; cardiac disorders p=0.449; reproductive system p=0.591; eye disorders p=0.189


The most common possibly or probably drug-related treatment emergent adverse events, organized by body system, observed in the SAB/SAIE trial are displayed in Table 5.


Table 5. Incidence (%) of Possibly or Probably Drug-Related Treatment Emergent Adverse Events Occurring in ≥ 1% of Patients in Either CUBICIN or Comparator Treatment Groups in the Phase 3 SAB/SAIE Study (Population: Safety)

Adverse Events CUBICIN 6 mg/kg
(N=120)
Comparator
(N=116)
Investigations
Blood creatine phosphokinase (CPK) increased 5.0% 0%
Blood phosphorus increased 2.5% <1%
Blood alkaline phosphatase increased 1.7% 0%
International normalized ratio increased 1.7% 0%
Liver function test abnormal 1.7% <1%
Blood creatinine increased 0% 2.6%
Gastrointestinal Disorders
Loose stools 3.3% 1.7%
Dyspepsia 2.5% <1%
Diarrhea NOS 1.7% 9.5%
Nausea 1.7% 5.2%
Vomiting <1% 1.7%
Skin and Subcutaneous Tissue Disorders
Rash NOS 2.5% 2.6%
Renal and Urinary Disorders
Renal failure NOS 1.7% 6.0%
Renal impairment NOS <1% 1.7%
Renal failure acute 0% 2.6%
Infections and Infestations
Candidal infection NOS 1.7% 0%
Vaginal candidiasis 1.7% 0%
General Disorders and Administration Site Conditions
Chest pain 1.7% 0%
Pyrexia 0% 2.6%
Blood and Lymphatic System Disorders
Eosinophilia 1.7% 0%
Nervous System Disorders
Dysgeusia 0% 2.6%
Vascular Disorders
Hypotension NOS 0% 2.6%
Musculoskeletal and Connective Tissue Disorders
Arthralgia 0% 1.7%
Weakness in extremity 1.7% 0%

Less Common Clinical Trial Adverse Drug Reactions in the SAB/SAIE Trial (< 1%)

The following events, not included above in Table 5, were reported as possibly or probably drugrelated in the Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) CUBICIN-treated group:

Blood and Lymphatic System Disorders: 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: fungemia, oral candidiasis, urinary tract infection fungal

Investigations: 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: heat rash, pruritus generalized, rash vesicular

Abnormal Hematologic and Clinical Chemistry Findings in the SAB/SAIE Trial

In the Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) trial, a total of 11 CUBICIN patients (9.2%) had treatment-emergent elevations in creatine phosphokinase (CPK) to > 500 U/L, including 4 patients with elevations > 10X ULN. Three of these 11 patients had CPK levels return to the normal range during continued CUBICIN treatment, 6 had values return to the normal range during follow-up, 1 had values returning toward baseline at the last assessment, and 1 did not have follow-up values reported.

Six of the 11 patients with treatment-emergent CPK elevations > 500 U/L had medical or surgical reasons for the elevated CPK. Three patients discontinued CUBICIN due to CPK elevation. Table 6 presents the incidence of CPK elevations from baseline in all patients and in patients with normal CPK levels through the end of treatment with CUBICIN and comparator in the SAB/SAIE trial.


Table 6. Incidence (%) of Creatine Phosphokinase (CPK) Elevations from Baseline through End of Treatment in either CUBICIN or Comparator Treatment Groups in the SAB/SAIE Study

Change All Patients Patients with Normal CPK at
Baseline
CUBICIN
(N=116)
Comparator
(N=111)
CUBICIN
(N=92)
Comparator
(N=96)
% N % N % N % N
No Increase 75.9 88 87.4 97 75.0 69 87.5 84
Maximum Value > 1X ULN* 24.1 28 12.6 14 25.0 23 12.5 12
> 2X ULN 13.8 16 6.3 7 12.0 11 5.2 5
> 4X ULN 8.6 10 0.9 1 7.6 7 0.0 0
> 5X ULN 6.9 8 0.9 1 5.4 5 0.0 0
> 10X ULN 3.4 4 0.9 1 2.2 2 0.0 0
* ULN (Upper Limit of Normal) is laboratory specific.

Note: CPK evaluations through 3 days post-treatment are included in the analysis.


There was more renal dysfunction in comparator-treated patients than in CUBICIN-treated patients. The incidence of decreased renal function, defined as the proportion of patients with a creatinine clearance level < 50 mL/min if baseline clearance was ≥ 50 mL/min or with a decrease of ≥ 10 mL/min if baseline clearance was < 50 mL/min, is shown in Table 7.


Table 7. Incidence of Decreased Renal Function Based on Creatinine Clearance Levels

Study Interval CUBICIN 6 mg/kg
(N=120)
n/N (%)
Comparatora
(N=116)
n/N (%)
Days 2 to 4 2/96 (2.1%) 6/90 (6.7%)
Days 2 to 7 6/115 (5.2%) 16/113 (14.2%)
Days 2 to End of Study 13/118 (11.0%) 30/114 (26.3%)
a Comparator: vancomycin (1 g IV q12h) or anti-staphylococcal semi-synthetic penicillin (i.e. nafcillin, oxacillin, cloxacillin, flucloxacillin; 2 g IV q4h), each with initial low-dose gentamicin.

Post-Market Adverse Drug Reactions

The following adverse reactions have been reported with CUBICIN® in worldwide postmarketing experience. Because these events are reported voluntarily from a population of unknown size, estimates of frequency cannot be made and causal relationship cannot be precisely established.

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.

Infections and Infestations: Clostridium difficile-associated diarrhea.

Musculoskeletal Disorders: myoglobin increased; rhabdomyolysis (some reports involved patients treated concurrently with CUBICIN and HMG-CoA reductase inhibitors).

Neurologic Disorders: one case of coma post-anaesthesia/surgery; peripheral neuropathy.

Respiratory, Thoracic, and Mediastinal Disorders: cough; eosinophilic pneumonia (see WARNINGS AND PRECAUTIONS Respiratory, Eosinophilic Pneumonia).

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

Drug Interactions

Overview

There is limited experience regarding concomitant administration of CUBICIN (daptomycin for injection) with other medicinal products that may trigger myopathy (e.g., HMG-CoA reductase inhibitors). However, some cases of marked rises in creatine phosphokinase (CPK) levels and cases of rhabdomyolysis occurred in patients taking one of these medications at the same time as CUBICIN. It is recommended that other medications associated with myopathy should, if possible, be temporarily discontinued during treatment with CUBICIN unless the benefits of concomitant administration outweigh the risk. If co-administration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients should be closely monitored for any signs or symptoms that might represent myopathy.

Daptomycin is primarily cleared by renal filtration and, therefore, plasma levels may be increased during co-administration with medicinal products that reduce renal filtration (e.g., NSAIDs and COX-2 inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-administration due to additive renal effects. Therefore, caution is advised when CUBICIN is co-administered with any other medicinal product known to reduce renal filtration.

Drug-Drug Interactions

Drug-drug interaction studies were performed with CUBICIN and other drugs that are likely to either be co-administered or associated with overlapping toxicity as shown in Table 8.


Table 8. Established or Potential Drug-Drug Interactions with CUBICIN

Drug Name Ref Effect Clinical comment
Aztreonam CT In a study in which 15 healthy adult subjects received a single dose of CUBICIN 6 mg/kg IV and a combination dose of CUBICIN 6 mg/kg IV and aztreonam 1 g IV, the Cmax and AUC0-∞ of daptomycin were not significantly altered by aztreonam. No dosage adjustment of CUBICIN is warranted when CUBICIN is coadministered with aztreonam.
HMG-CoA Reductase Inhibitors CT In 20 healthy subjects on a stable daily dose of oral simvastatin 40 mg, administration of CUBICIN® 4 mg/kg IV q24h for 14 days (N=10) was not associated with a higher incidence of adverse events than subjects receiving placebo once daily (N=10).Inhibitors of HMG-CoA reductase may cause myopathy, which is manifested as muscle pain or weakness associated with elevated levels of CPK. Experience with co-administration of HMG-CoA reductase inhibitors and CUBICIN in patients is limited, therefore, consideration should be given to temporarily suspending use of HMG-CoA reductase inhibitors in patients receiving CUBICIN (see WARNINGS AND PRECAUTIONS, Musculoskeletal).
Probenecid CT Concomitant administration of oral probenecid (500 mg four times daily) and a single dose of CUBICIN 4 mg/kg IV did not significantly alter the Cmax and AUC0-∞ of daptomycin. No dosage adjustment of CUBICIN is warranted when CUBICIN is coadministered with probenecid.
Tobramycin CT In a study in which 6 healthy adult males received a single dose of CUBICIN 2 mg/kg IV, tobramycin 1 mg/kg IV, and both in combination, the mean Cmax and AUC0-∞ of daptomycin increased 12.7% and 8.7%, respectively, when administered with tobramycin. The mean Cmax and AUC0-∞ of tobramycin decreased 10.7% and 6.6%, respectively, when administered with CUBICIN. These differences were not statistically significant. The interaction between CUBICIN and tobramycin with a clinical dose of CUBICIN is unknown. Caution is warranted when CUBICIN is coadministered with tobramycin.
Nonclinical In rats, mild skeletal muscle degeneration and/or regeneration was observed with 20 mg/kg IV CUBICIN when administered alone. During concurrent administration with tobramycin 10 mg/kg SC b.i.d., mild skeletal muscle changes were observed with 5 mg/kg IV CUBICIN. Tobramycin may have a weak potentiating effect on muscle damage caused by CUBICIN.
Warfarin CT In 16 healthy subjects, concomitant administration of CUBICIN 6 mg/kg IV q24h for 5 days followed by a single oral dose of warfarin (25 mg) had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR (International Normalized Ratio). As experience with the concomitant administration of CUBICIN and warfarin is limited, anticoagulant activity in patients receiving CUBICIN and warfarin should be monitored for the first several days after initiating therapy with CUBICIN.
Gentamicin Nonclinical An increase in nephrotoxicity was apparent upon combination treatment with daptomycin 30 mg/kg/day IV and a high dose of gentamicin (30 mg/kg/day IM) in dogs. No meaningful difference in nephrotoxicity was observed in animals receiving daptomycin in combination with a more clinically relevant dose of gentamicin (9 mg/kg/day IM). Concurrent administration of daptomycin and clinical levels of gentamicin is unlikely to alter the nephrotoxic potential of gentamicin in humans. However, caution should be used when administering the combination to renally impaired patients.
CT: Clinical Trial

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Clinically relevant plasma levels 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. The possibility of an erroneously elevated PT/INR result due to interaction with a recombinant thromboplastin reagent may be minimized by drawing specimens for PT or INR testing near the time of trough plasma concentrations of daptomycin. However, sufficient daptomycin levels may be present at trough to cause interaction.

If confronted with an abnormally high PT/INR result in a patient being treated with CUBICIN, it is recommended that clinicians:

  1. Repeat the assessment of PT/INR, requesting that the specimen be drawn just prior to the next CUBICIN dose (i.e., at trough concentration). If the PT/INR value drawn at trough remains substantially elevated over what would otherwise be expected, consider evaluating PT/INR utilizing an alternative method.
  2. Evaluate for other causes of abnormally elevated PT/INR results.

Dosage And Administration

Complicated Skin and Skin Structure Infections

CUBICIN (daptomycin for injection) 4 mg/kg should be administered intravenously in 0.9% sodium chloride injection, USP, once every 24 hours for 7 to 14 days, either by injection over a 2-minute period or by infusion over a 30-minute period.

Staphylococcus aureus Bloodstream Infections (Bacteremia) including those with Right-Sided Staphylococcus aureus Infective Endocarditis (Native Valve)

CUBICIN 6 mg/kg should be administered intravenously in 0.9% sodium chloride injection, USP, once every 24 hours, either by injection over a 2-minute period or by infusion over a 30-minute period. Duration of treatment should be based on the treating physician’s working diagnosis. In the clinical trial, duration ranged from 10 days to 42 days with an option for an additional 14 days. There are limited safety data for the use of CUBICIN for more than 28 days.

Clinical studies in patients employed infusion of daptomycin over 30 minutes. There is no clinical experience in patients with the administration of daptomycin as an injection over 2 minutes. This mode of administration was only studied in healthy subjects. However, when compared with the same doses given as intravenous infusions over 30 minutes, there were no clinically important differences in the pharmacokinetics and safety profile of daptomycin (see also ADVERSE REACTIONS, Adverse Drug Reaction Overview and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Dosing and Administration Considerations

General

  • CUBICIN should not be dosed more frequently than once a day. In Phase 1 and 2 clinical studies, creatine phosphokinase (CPK) elevations appeared to be more frequent when CUBICIN was dosed more frequently than once daily.
  • Clinical studies have shown that dosing adjustments based on age alone, gender, race or obesity are not required (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).
  • Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to daptomycin. Empiric therapy may be initiated while awaiting test results. Antimicrobial therapy should be adjusted as needed based upon test results.
  • To reduce the development of drug-resistant bacteria and maintain the effectiveness of CUBICIN and other antibacterial drugs, CUBICIN should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

The recommended dosing schedule for adult patients including those with creatinine clearance ≥30 mL/min is presented in Table 9.


Table 9. Recommended Dosage of CUBICIN (daptomycin for injection) in Adult Patients including those with Creatinine Clearance ≥ 30 mL/min

Creatinine
Clearance
Indication Dosage Regimen Duration
≥ 30 mL/min Complicated Skin and Skin Structure Infections 4 mg/kg once every 24 hours 7 to 14 days
Staphylococcus aureus Bloodstream Infections (Bacteremia) including those with Right-Sided Staphylococcus aureus Infective Endocarditis (Native Valve) 6 mg/kg once every 24 hours 10 to 42 days with an option for an additional 14 days

Patients with Renal Impairment

Daptomycin is eliminated primarily by the kidney.

No dose adjustment is required in patients whose creatinine clearance is ≥30 mL/min (see Table 9).

Patients with Creatinine Clearance < 30 mL/min

CUBICIN should only be used in patients whose creatinine clearance is < 30 mL/min when it is considered that the expected clinical benefit outweighs the potential risk and for whom there are no further therapeutic options.

Clinical efficacy and safety of CUBICIN have not been established in patients with severe renal impairment (creatinine clearance < 30 mL/min).

The dose interval adjustment guidance presented below in Table 10 is based on pharmacokinetic modeling data.

Response to treatment, renal function and creatine phosphokinase (CPK) should be closely monitored in these patients.

Whenever possible, CUBICIN should be administered following the completion of dialysis on dialysis days. The use of high-flux dialysis membranes during 4 hours of hemodialysis may increase the percentage of dose removed compared with low-flux membranes.


Table 10. Dosage Adjustment of CUBICIN® (daptomycin for injection) in Adult Patients with Severe Renal Impairment (creatinine clearance < 30 mL/min)

Creatinine
Clearance
Indication Dosage Regimen Duration
< 30 mL/min Complicated Skin and Skin Structure Infections 4 mg/kg once every 24 hours 7 to 14 days
Staphylococcus aureus Bloodstream Infections (Bacteremia) including those with Right-Sided Staphylococcus aureus Infective Endocarditis (Native Valve) 6 mg/kg once every 24 hours 10 to 42 days with an option for an additional 14 days

Patients with Hepatic Insufficiency

No dose adjustment is necessary when administering CUBICIN to patients with mild or moderate hepatic insufficiency (Child-Pugh Class B). No data are available in patients with severe hepatic insufficiency (Child-Pugh Class C).

Pediatrics

The safety and efficacy of CUBICIN in patients under the age of 18 have not been established. Use of CUBICIN in this age group is not recommended until further data are available (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Pediatrics, DETAILED PHARMACOLOGY, Animal Pharmacology, Juvenile Animals and TOXICOLOGY).

Reconstitution

CUBICIN is supplied in single-use vials containing 500 mg daptomycin as a sterile, lyophilized powder. The contents of a CUBICIN® 500 mg vial should be reconstituted with 10 mL of 0.9% sodium chloride for injection to 50 mg/mL. Since no preservative or bacteriostatic agent is present in the product, aseptic technique must be used in preparation of the product.

Procedure

  • Prior to reconstitution, remove the CUBICIN vials from refrigeration and allow the product to sit at room temperature for a few minutes. CUBICIN vials do not need to be warmed to room temperature prior to reconstitution.
  • Remove the polypropylene flip-off cap from the CUBICIN vial to expose the central portions of the rubber stoppers. Gently tap vial twice on counter to settle/loosen the lyophilized powder cake.
  • Using a syringe, slowly transfer the diluent through the center of the rubber stopper into the CUBICIN vial, pointing the transfer needle toward the wall of the vial to prevent excessive foaming. Ensure that the complete daptomycin product is wetted by gently rotating the vial.
  • Allow the product to sit undisturbed for approximately 10 minutes at room temperature.
  • Gently swirl the CUBICIN vial until a clear, fully reconstituted solution is obtained. This typically takes from 5 to 15 minutes.
  • AVOID VIGOROUS SHAKING TO PREVENT FOAMING OF THE PRODUCT DURING RECONSTITUTION.

The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Freshly reconstituted solutions of CUBICIN range in colour from pale yellow to light brown.

For IV injection over a period of 2 minutes

Reconstitute CUBICIN, as directed above, to a concentration of 50 mg/mL with 0.9% sodium chloride for injection.

For IV infusion over a period of 30 minutes

Reconstitute CUBICIN, as directed above, to a concentration of 50 mg/mL with 0.9% sodium chloride for injection. Further dilute using aseptic technique with additional 0.9% sodium chloride for injection to a final concentration in the range of 2.5 to 20 mg/mL (typically 10 mg/mL).

Vial Size Nominal
Concentration of
Reconstituted
Solution
Approximate
Available
Volume of
Reconstituted
Solution
Volume of
Additional
Diluent
Total Volume
of Solution for
Infusion
Nominal
Concentration of
Solution for
Infusion
500 mg 50 mg/mL 10 mL 15 mL 25 mL 20 mg/mL
500 mg 50 mg/mL 10 mL 40 mL 50 mL 10 mg/mL
500 mg 50 mg/mL 10 mL 190 mL 200 mL 2.5 mg/mL

Because CUBICIN does not contain any preservative or bacteriostatic agent, aseptic technique must be used during preparation for administration and the product should be used promptly. If reconstituted CUBICIN® within the vial or infusion bag is not used immediately, it must be refrigerated at 2 to 8°C. It is recommended that the solution be used within 72 hours due to the possibility of microbial contamination during reconstitution (see also STORAGE AND STABILITY).

CUBICIN should not be used in conjunction with ReadyMED® elastomeric infusion pumps. Stability studies of CUBICIN solutions stored in ReadyMED elastomeric infusion pumps identified an impurity (2-mercaptobenzothiazole) leaching from this pump system into the CUBICIN solution.

CUBICIN vials are for single-use only.

Compatible Intravenous Solutions

CUBICIN is compatible with 0.9% sodium chloride injection and lactated Ringer’s injection.

The following are compatible at room temperature when co-administered with CUBICIN in 0.9% sodium chloride through the same IV line from separate infusion bags: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin, and lidocaine.

CUBICIN is not compatible with glucose (dextrose) containing diluents. Other than the nine drugs listed above, additives and other medications should not be infused simultaneously with CUBICIN through the same IV line because only limited data are available on compatibility. If the same IV line is used for sequential infusion of several different drugs, the line should be flushed with a compatible infusion solution before and after infusion with CUBICIN. No other product than the approved diluent should be added to the CUBICIN® vial or infusion bag.

As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used. Discard unused portion.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

In the event of overdosage, supportive care is advised with maintenance of glomerular filtration. CUBICIN is slowly cleared from the body by hemodialysis (approximately 15% recovered over 4 hours) or peritoneal dialysis (approximately 11% recovered over 48 hours). The use of high-flux membranes during 4 hours of hemodialysis may increase the percentage of dose removed, as evidenced by the larger decrease in the pre- to post-dose concentrations (41%) compared with low-flux membranes (5 to 7%).

A 58-year old male with a history of multiple sclerosis, diabetes and hypertension was administered an accidental single dose of CUBICIN 3 g (43 mg/kg). Twenty-four hours later symptoms of orofacial movements, lip smacking and shoulder shrugging were observed and diagnosed as dyskinesia. CUBICIN® was discontinued and the patient was treated with benztropine and lorazepam. The events resolved and therapy was restarted without further incident.

Action And Clinical Pharmacology

Mechanism of Action

CUBICIN (daptomycin for injection) is a cyclic lipopeptide antibacterial agent. Daptomycin binds to Gram-positive bacterial membranes in a calcium-dependant manner and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of protein, DNA, and RNA synthesis, which results in bacterial cell death. Activity of daptomycin is dependant on the presence of physiological levels of free calcium ions (50 μg/mL) (see MICROBIOLOGY).

Resistance

Cases of daptomycin resistance have been reported in staphylococci in clinical trials and during post-marketing use.

Pharmacokinetics

The mean pharmacokinetic parameters of CUBICIN at steady-state following IV administration of CUBICIN over a 30-minute period at 4 to 12 mg/kg q24h to healthy young adults are summarized in Table 11.


Table 11. Mean CUBICIN Pharmacokinetic Parameters in Healthy Volunteers at Steady-State

Doseb
(mg/kg)
N Pharmacokinetic Parametersa Mean (Standard Deviation)
cAUC0-24
(μg*h/mL)
t1/2 (h) Vss (L/kg) CLT
(mL/h/kg)
cCmax
(μg/mL)
cCmin
(μg/mL)
4 6 494 (75) 8.1 (1.0) 0.096
(0.009)
8.3 (1.3) 57.8 (3.0) 5.9 (1.6)
6 6 632 (78) 7.9 (1.0) 0.101
(0.007)
9.1 (1.5) 93.9 (6.0) 6.7 (1.6)
8 6 858 (213) 8.3 (2.2) 0.101
(0.013)
9.0 (3.0) 123.3 (16.0) 10.3 (5.5)
10 9 1039 (178) 7.9 (0.6) 0.098
(0.017)
8.8 (2.2) 141.1 (24.0) 12.9 (2.9)
12 9 1277 (253) 7.7 (1.1) 0.097
(0.018)
9.0 (2.8) 183.7 (25.0) 13.7 (5.2)
a AUC0-24: area under the concentration-time curve from 0 to 24 hours; t½: terminal elimination half-life ; Vss: volume of distribution at steadystate; CLT: plasma clearance; Cmax: maximum plasma concentration (total drug)

b Doses of CUBICIN in excess of 6 mg/kg have not been approved

c Values relate to total drug in plasma (free + protein bound)


Absorption

Daptomycin pharmacokinetics were generally linear and time-independent at doses of 4 to 12 mg/kg q24h. Steady-state trough concentrations were achieved by the third daily dose. The mean (standard deviation) steady-state trough concentrations attained following administration of 4, 6, 8, 10 and 12 mg/kg q24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9) and 13.7 (5.2) μg/mL, respectively. The mean AUC and Cmin (minimum plasma concentration) of daptomycin during once-daily dosing with 6, 8, 10 and 12 mg/kg were dose proportional; however, the mean Cmax (maximum plasma concentration) was slightly less than dose proportional. Total clearance was unchanged across 4 to 12 mg/kg q24h.

Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional pharmacokinetics in the approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure (AUC and Cmax) was demonstrated in healthy subjects following administration of daptomycin as a 30-minute intravenous infusion or as a 2-minute intravenous injection.

Following IV administration of CUBICIN to healthy volunteers over a 2-minute period at doses of 4 and 6 mg/kg, the mean (SD) steady-state AUC0-tau values were 475 (71) and 701 (82) μg*h/mL, respectively. The mean (SD) steady-state Cmax values were 63 (11) and 92 (18) μg/mL, respectively.

Distribution

Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The overall mean binding at doses from 4 to 12 mg/kg ranged from 90 to 93%. The apparent volume of distribution (Vd) of daptomycin at steady-state in healthy adult subjects was low, approximately 0.1 L/kg at doses of 4 to 12 mg/kg, consistent with distribution primarily within the extracellular space.

Daptomycin penetrates into skin blister fluid and reaches a mean Cmax of 27.6 μg/mL (mean t½=17.3 hrs).

In clinical studies, mean serum protein binding in subjects with creatinine clearance (CLCR) ≥ 30 mL/min was comparable to that observed in healthy subjects with normal renal function. However, there was a trend toward decreasing serum protein binding among subjects with CLCR < 30 mL/min (87.6%), including hemodialysis patients (85.9%) and continuous ambulatory peritoneal dialysis patients (83.5%). The protein binding of daptomycin in subjects with moderate hepatic impairment (Child-Pugh B) was similar to healthy adult subjects.

Metabolism

In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 (CYP) isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. In in vitro studies, daptomycin was not detectably metabolized by human liver microsomes. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the CYP system.

In a separate study, no metabolites were observed in plasma on Day 1 following administration of daptomycin at 6 mg/kg to healthy subjects. Inactive metabolites have been detected in urine, as determined by the difference in total radioactivity concentrations and microbiologically active concentrations. Minor amounts of 3 oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.

Excretion

Daptomycin is excreted primarily by the kidney. In a mass balance study of 5 healthy subjects using radiolabelled daptomycin, approximately 78% of the administered dose was recovered from urine based on total radioactivity (approximately 52% of the dose based on microbiologically active concentrations) and 5.7% of the dose was recovered from feces (collected for up to nine days) based on total radioactivity.

Due to limited clinical experience, response to treatment, renal function and creatine phosphokinase (CPK) should be closely monitored in all patients with some degree of renal impairment (CLCR < 80 mL/min) (see DOSAGE AND ADMINISTRATION).

Special Populations and Conditions

Pediatrics

Currently, there are very limited data on the pharmacokinetics of CUBICIN in pediatric patients. Multiple-dose pharmacokinetic studies have not been conducted. The safety and efficacy in pediatric patients has not been established. Therefore, use of CUBICIN in pediatric patients is not recommended until further data are available.

Pediatric patients younger than 12 months should not be given CUBICIN due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs (see INDICATIONS AND CLINICAL USE, Pediatrics, DETAILED PHARMACOLOGY, Animal Pharmacology, and TOXICOLOGY).

The pharmacokinetics of CUBICIN in pediatric patients were assessed in a Phase I single-dose trial. A single 4 mg/kg dose of CUBICIN as a 30-minute infusion was evaluated in three groups of pediatric patients with proven or suspected Gram-positive infections who were receiving standard antibacterial therapy (2-6 years, 7-11 years and 12-17 years). Results from this trial indicated that in the younger age groups (2-6 years and 7-11 years), exposure (AUC, Cmax) and elimination half-life (t½) were reduced compared to adolescents (12-17 years) while clearance was increased in the younger age groups. Therefore, the single-dose data demonstrated differences in the kinetics of daptomycin that are a function of age (e.g., increased clearance with decreasing age).

Another Phase I single-dose trial was conducted to evaluate the pharmacokinetics of daptomycin after a single 8 mg/kg or 10 mg/kg dose of CUBICIN® administered as a 1-hour infusion in pediatric subjects aged 2 to 6 years, inclusive, with proven or suspected Gram-positive infections who were receiving standard antibacterial therapy. The mean exposure (AUC0-∞) was 429 and 550 μg*hr/ml after the administration of 8 and 10 mg/kg single intravenous doses, respectively. The pharmacokinetics of daptomycin appears to be linear in the age group and dose range studied. The half-life, clearance and volume of distribution were generally similar at both dose levels tested.

Geriatrics

The pharmacokinetics of CUBICIN were evaluated in 12 healthy elderly subjects (≥ 75 years of age) and 11 healthy young matched controls (18 to 30 years of age). Following administration of a single 4 mg/kg IV dose, the mean total clearance of daptomycin was reduced approximately 35% and the mean AUC0-∞ increased approximately 58% in elderly subjects compared to young healthy subjects. There were no differences in Cmax. No dosage adjustment is warranted for elderly patients with normal renal function based on age alone.

Gender

No clinically significant gender-related differences in CUBICIN pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when administering CUBICIN.

Hepatic Insufficiency

The pharmacokinetics of CUBICIN were evaluated in 10 subjects with moderate hepatic impairment (Child-Pugh Class B) and compared with healthy volunteers (N=9) matched for gender, age, and weight. The pharmacokinetics of CUBICIN were not altered in subjects with moderate hepatic impairment. No dosage adjustment is warranted when administering CUBICIN to patients with mild to moderate hepatic impairment. The pharmacokinetics of CUBICIN in patients with severe hepatic insufficiency have not been evaluated.

Renal Impairment in Complicated Skin and Skin Structure Infections (cSSSI)

Population derived pharmacokinetic parameters were determined for patients with cSSSI and healthy noninfected subjects with varying degrees of renal function (N=282). Following the administration of a single 4 mg/kg IV dose of CUBICIN, the plasma clearance (CLT) was reduced and the systemic exposure (AUC0-∞) was increased with decreasing renal function (see Table 12). The mean AUC0-∞ was not markedly different for subjects and patients with creatinine clearance (CLCR) 30-80 mL/min as compared to those with normal renal function (CLCR > 80 mL/min). The mean AUC0-∞ for subjects and patients with CLCR < 30 mL/min was approximately 2-times higher than that observed in individuals with normal renal function. For subjects on hemodialysis (dosed post-dialysis)/continuous ambulatory peritoneal dialysis, the mean AUC0-∞ was 3-times higher than that observed in individuals with normal renal function. The mean Cmax ranged from 59.6 to 69.6 μg/mL in subjects with CLCR ≥ 30 mL/min, while those with CLCR < 30 mL/min ranged from 41.1 to 57.7 μg/mL. In non-infected adult subjects undergoing dialysis, approximately 15% and 11% of the administered dose was removed by 4 hours of hemodialysis and 48 hours of continuous ambulatory peritoneal dialysis, respectively. In patients with renal impairment, both renal function and creatine phosphokinase (CPK) should be monitored more frequently. CUBICIN should be administered following the completion of hemodialysis on hemodialysis days (see DOSAGE AND ADMINISTRATION).


Table 12. CUBICIN Population Pharmacokinetic Parameters Following a Single 30-Minute IV Infusion of 4 mg/kg to Patients with Complicated Skin and Skin Structure Infections (cSSSI) and Healthy Volunteers with Varying Degrees of Renal Function

>
Renal Function N Pharmacokinetic Parameters
Mean (Standard Deviation)
AUC0-∞
(μg*h/mL)
t½
(h)
Vss
(L/kg)
CLT
(mL/h/kg)
Normal
(CLCR>80 mL/min)
165 417 (155) 9.39 (4.74) 0.13
(0.05)
10.9 (4.0)
Mild Renal Impairment
(CLCR 50-80 mL/min)
64 466 (177) 10.75
(8.36)
0.12
(0.05)
9.9 (4.0)
Moderate Renal Impairment
(CLCR 30-<50 mL/min)
24 560 (258) 14.70
(10.50)
0.15
(0.06)
8.5 (3.4)
Severe Renal Impairment
(CLCR <30 mL/min)
8 925 (467) 27.83
(14.85)
0.20
(0.15)
5.9 (3.9)
Hemodialysis and CAPD 21 1244 (374) 29.81
(6.13)
0.15
(0.04)
3.7 (1.9)
CLCR: creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; Vss: volume of distribution at steady-state; CAPD: continuous ambulatory peritoneal dialysis

Renal Impairment in the Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) Trial

A second population analysis was conducted to determine pharmacokinetic parameters at steady-state in SAB/SAIE patients (Table 13). Patients (N=108) received 6 mg/kg q24h and were stratified by varying degrees of renal function. Plasma clearance (CLT) decreased with decreasing renal function, whereas AUC and Cmin increased with decreasing renal function. Mean AUC increased 1.6-fold while mean Cmin increased 2.8-fold in patients with moderate renal impairment compared to those with CLCR > 80 mL/min. In the two patients with CLCR < 30 mL/min, pharmacokinetic parameters were similar to those with moderate renal impairment. Mean Cmax values ranged from 80 to 114 μg/mL in patients with moderate to mild renal impairment and were similar to those of normal subjects. In SAB/SAIE patients, the overall mean volume of distribution at steady-state (Vss) was 0.16 L/kg and was greater than that in non-infected subjects (0.1 L/kg), but similar to cSSSI patients. In non-infected adult subjects undergoing dialysis, approximately 15% and 11% of the administered dose was removed by 4 hours of hemodialysis (N=6) and 48 hours of continuous ambulatory peritoneal dialysis [CAPD (N=5)], respectively. In patients with renal impairment, both renal function and CPK should be monitored more frequently. CUBICIN should be administered following the completion of hemodialysis on hemodialysis days (see DOSAGE AND ADMINISTRATION).


Table 13. CUBICIN Population Pharmacokinetic Parameters at Steady-State in SAB/SAIE Patients Dosed with 6 mg/kg with Varying Degrees of Renal Function

Renal Function N Pharmacokinetic Parameters Mean (Standard Deviation)1
AUC0-24
(μg*h/mL)
t½
(h)
Vss
(L/kg)
CLT
(mL/h/kg)
Cmax
[μg/mL]
Cmin
[μg/mL]
Normal
(CLCR2>80 mL/min)
62 545 (296) 9.0 (2.86) 0.15 (0.07) 13.2 (5.0) 108 (143) 6.9 (3.5)
Mild Renal Impairment
(CLCR 50-80 mL/min)
29 637 (215) 12.0 (2.26) 0.17 (0.04) 10.5 (3.5) 80 (41) 12.4 (5.6)
Moderate Renal Impairment
(CLCR 30-<50 mL/min)
15 868 (349) 16.1 (3.62) 0.17 (0.05) 8.2 (3.6) 114 (124) 19.0 (9.0)
Severe Renal Impairment
(CLCR <30 mL/min)
2 1050, 892 25.8, 16.0 0.20, 0.15 5.7, 6.7 97, 83 25.4, 21.4
1 Mean (SD) values are presented except Severe Impairment where N=2;

2 Creatinine clearance was estimated using the Cockcroft-Gault equation with actual body weight.


A 41% reduction in CUBICIN plasma concentration was achieved using high-flux dialysis membranes, and a 5 to 7% reduction was achieved using low-flux dialysis membranes.

Obesity

The pharmacokinetics of CUBICIN were evaluated in 6 moderately obese [Body Mass Index (BMI) 25 to 39.9 kg/m2] and 6 extremely obese (BMI ≥ 40 kg/m2) subjects and controls matched for age, sex, and renal function. Following administration of a single 4 mg/kg IV dose based on total body weight, the plasma clearance of CUBICIN normalized to total body weight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects compared with non-obese controls. The AUC0-∞ of CUBICIN increased approximately 30% in moderately obese and 31% in extremely obese subjects compared with non-obese controls. In the complicated skin and skin structure infection trials (cSSSI), 8 patients > 150 kg received CUBICIN 4 mg/kg. The highest total dose exposure occurred in one patient weighing 238.6 kg (total exposure 20 900 mg daptomycin over 21 days). No dosage adjustment of CUBICIN is warranted in obese patients based solely on weight.

Storage And Stability

Store vials containing lyophillized powder at 2 to 8°C.

Chemical and physical in-use stability of the reconstituted solution in the vial, or infusion solutions, has been demonstrated for 12 hours at 25°C and up to 10 days if stored under refrigeration (2 to 8°C), under normal lighting conditions. However, because CUBICIN does not contain any preservative or bacteriostatic agent, aseptic technique must be used during preparation for administration and the product should be used promptly. If the reconstituted product is not used immediately, it must be refrigerated at 2 to 8°C. It is recommended that the solution be used within 72 hours due to the possibility of microbial contamination during reconstitution. Avoid excessive heat.

The combined time (vial and infusion bag) at room temperature, up to 25°C, should not exceed 12 hours. The combined time (vial and infusion bag) at 2-8°C should not exceed 10 days.

Special Handling Instructions

For information on reconstitution, see DOSAGE AND ADMINISTRATION above.

Dosage Forms, Composition And Packaging

CUBICIN (daptomycin for injection) is supplied as a pale yellow to light brown lyophilized cake in a single-use vial (500 mg/10 mL vial). Available in packages of 10 vials. CUBICIN may also contain sodium hydroxide used to adjust pH in trace amounts.