DAPTOMYCIN FOR INJECTION POWDER FOR SOLUTION

Canada - English - Health Canada

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Active ingredient:
DAPTOMYCIN
Available from:
ACCORD HEALTHCARE INC
ATC code:
J01XX09
INN (International Name):
DAPTOMYCIN
Dosage:
500MG
Pharmaceutical form:
POWDER FOR SOLUTION
Composition:
DAPTOMYCIN 500MG
Administration route:
INTRAVENOUS
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
CYCLIC LIPOPEPTIDES
Product summary:
Active ingredient group (AIG) number: 0152298001; AHFS: 08:12.28.12
Authorization status:
APPROVED
Authorization number:
02494590
Authorization date:
2020-10-01

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PRODUCT MONOGRAPH

INCLUDING PATIENT MEDICATION INFORMATION

Pr

Daptomycin for Injection

Lyophilized Powder for Solution, For Intravenous Use Only

500 mg/vial

Antibacterial Agent

Accord Healthcare Inc.

3535 boul. St-Charles, Suite 704

Kirkland, Quebec

H9H 5B9

Date of Revision:

August 31, 2020

Submission Control Number:

242602

Page 2 of 60

Product Monograph of Daptomycin for Injection

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ......................................................... 3

SUMMARY PRODUCT INFORMATION ........................................................................ 3

INDICATIONS AND CLINICAL USE .............................................................................. 3

CONTRAINDICATIONS ................................................................................................... 4

WARNINGS AND PRECAUTIONS .................................................................................. 4

ADVERSE REACTIONS ................................................................................................. 11

DRUG INTERACTIONS ................................................................................................. 19

DOSAGE AND ADMINISTRATION ............................................................................. 22

ACTION AND CLINICAL PHARMACOLOGY ............................................................ 27

STORAGE AND STABILITY ......................................................................................... 32

SPECIAL HANDLING INSTRUCTIONS ....................................................................... 33

DOSAGE FORMS, COMPOSITION AND PACKAGING ............................................ 33

PART II: SCIENTIFIC INFORMATION .............................................................................. 34

PHARMACEUTICAL INFORMATION ......................................................................... 34

CLINICAL TRIALS ......................................................................................................... 35

DETAILED PHARMACOLOGY .................................................................................... 44

MICROBIOLOGY ............................................................................................................ 49

TOXICOLOGY ................................................................................................................ 52

SUPPORTING PRODUCT MONOGRAPHS .................................................................. 56

PATIENT MEDICATION INFORMATION .......................................................................... 57

Page 3 of 60

Product Monograph of Daptomycin for Injection

Pr

Daptomycin for Injection

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

All Nonmedicinal Ingredients

intravenous

Lyophilized Powder

for Solution /

500 mg/vial

Sodium hydroxide

INDICATIONS AND CLINICAL USE

Daptomycin for Injection is indicated for the following infections in adults:

Complicated skin and skin structure infections (cSSSI) caused by susceptible strains of

following Gram-positive microorganisms: Staphylococcus aureus (including

methicillin- resistant 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 co-

morbidity.

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 daptomycin 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.

Daptomycin for Injection is not indicated for the treatment of pneumonia.

Patients with persisting or relapsing Staphylococcus aureus infection or poor clinical response

Page 4 of 60

Product Monograph of Daptomycin for Injection

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.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of

Daptomycin for Injection and other antibacterial drugs, Daptomycin for Injection 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.

Pediatrics (<18 years of age): The safety and efficacy of daptomycin 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 Daptomycin for

Injection 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

Daptomycin for Injection is contraindicated in patients with

known hypersensitivity to

daptomycin.

WARNINGS AND PRECAUTIONS

General

Daptomycin for Injection

should be reconstituted with 0.9% sodium chloride for injection,

(see Reconstitution).

Daptomycin for Injection should not be used in conjunction with ReadyMED

®

elastomeric

infusion pumps. Stability studies of daptomycin solutions stored in ReadyMED

®

elastomeric

infusion pumps identified an impurity (2-mercaptobenzothiazole) leaching from this pump

system into the daptomycin solution (see Reconstitution).

Daptomycin for Injection is inactive against Gram-negative bacteria.

Because daptomycin activity is inhibited in the presence of pulmonary surfactant, Daptomycin for

Injection is not indicated for use in pneumonia.

The safety and efficacy of Daptomycin for Injection has not been established in patients

with

co-morbidities of meningitis, musculopathies, neuropathies or severe renal impairment.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Tubulointerstitial

Nephritis (TIN)

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Product Monograph of Daptomycin for Injection

DRESS and TIN have been reported in post-marketing experience with daptomycin. Patients

who develop fever, skin rash, peripheral eosinophilia and/or new or worsening renal impairment

or other organ impairment while receiving daptomycin should undergo medical evaluation. If

DRESS and/or TIN are suspected, Daptomycin for Injection should be discontinued promptly

and appropriate treatment instituted (see Renal).

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

daptomycin

use. If an allergic reaction occurs, administration of Daptomycin for Injection

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 aureu

s

infections was assessed in 19/120 (15.8%) daptomycin-treated patients [12 with methicillin-

resistant 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 daptomycin-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 Daptomycin for Injection, it is recommended that:

Patients should be monitored regularly for any signs and symptoms that might represent

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Product Monograph of Daptomycin for Injection

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 Daptomycin for Injection therapy in

patients with increased baseline CPK as these patients may be at increased risk of further

increases of CPK during Daptomycin for Injection therapy. If Daptomycin for Injection 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).

Daptomycin for Injection 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

Daptomycin for Injection.

In Phase 3 complicated skin and skin structure infection trials (cSSSI) of daptomycin, at a dose

of 4 mg/kg, elevations in serum CPK were reported as clinical adverse events in 15/534 (2.8%)

daptomycin -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 daptomycin - 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%) daptomycin -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 daptomycin for

14 days, no skeletal muscle effects or CPK elevations were observed.

Skeletal muscle effects associated with daptomycin

were observed in animals (see DETAILED

PHARMACOLOGY, Animal Pharmacology and TOXICOLOGY).

Neurologic

Neuropathy

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Product Monograph of Daptomycin for Injection

Cases of peripheral neuropathy have been reported during post-marketing therapy with daptomycin

(see ADVERSE REACTIONS).

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

Daptomycin for Injection.

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 daptomycin 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%) daptomycin-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 daptomycin

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 daptomycin

for 14 days, no evidence of peripheral nerve conduction deficits or symptoms of peripheral

neuropathy were observed.

In adult animals, effects of daptomycin

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 Daptomycin for Injection due

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 daptomycin in patients with severe renal impairment

(creatinine

clearance < 30 mL/min) have not been established. Daptomycin for Injection 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

Daptomycin

for Injection. Renal impairment has been reported during treatment with daptomycin although

the relationship to daptomycin remains unclear (see ADVERSE REACTIONS).

Page 8 of 60

Product Monograph of Daptomycin for Injection

Caution is advised prior to commencing therapy with Daptomycin for Injection in patients

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 daptomycin

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).

If DRESS and/or TIN are suspected, Daptomycin for Injection should be discontinued promptly

and appropriate treatment instituted.

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 daptomycin. 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

instituted as clinically indicated, as surgical intervention may be required in certain severe

cases (see ADVERSE REACTIONS).

Respiratory

Community-Acquired Pneumonia

Page 9 of 60

Product Monograph of Daptomycin for Injection

In Phase 3 studies of community-acquired pneumonia, the death rate and rates of serious

cardiorespiratory adverse events were higher in daptomycin-treated patients than in comparator-

treated patients. These differences were due to lack of therapeutic effectiveness of daptomycin

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 daptomycin. In reported cases

associated with daptomycin, patients developed fever, dyspnea with hypoxic respiratory

insufficiency, and diffuse pulmonary infiltrates or organizing pneumonia. In general, patients

developed eosinophilic pneumonia 2 to 4 weeks after starting daptomycin

and improved when

daptomycin was discontinued and steroid therapy was initiated. Recurrence of eosinophilic

pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms

while receiving Daptomycin for Injection should undergo prompt medical evaluation, and

Daptomycin for Injection should be discontinued immediately. Treatment with systemic

steroids

is recommended.

Susceptibility/Resistance

Development of Drug-Resistant Bacteria

The use of antibiotics may promote the overgrowth of non-susceptible organisms. Should

superinfection occur during therapy, appropriate measures should be taken.

Prescribing Daptomycin for Injection in the absence of a proven or strongly suspected bacterial

infection is unlikely to provide benefit to the patient and risks the development of drug- resistant

bacteria.

Special Populations

Pregnant Women: No clinical studies have been performed in pregnant women. Daptomycin

for Injection 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 Daptomycin for Injection.

Pediatrics (<18 years of age): The safety and efficacy of daptomycin 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 Daptomycin for

Injection in this age group is not recommended until further

data are available.

Pediatric patients younger than 12 months should not be given Daptomycin for Injection due

the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either

Page 10 of 60

Product Monograph of Daptomycin for Injection

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, treatment-

emergent adverse events were more common in patients ≥ 65 years old than in patients < 65

years of age. Of the 534 patients treated with daptomycin

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 daptomycin

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 Daptomycin

for Injection 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 Daptomycin for Injection therapy in patients with increased baseline CPK as these

patients may be at increased risk of further increases of CPK during

Daptomycin for Injection

therapy. If Daptomycin for Injection 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 Daptomycin for

Injection.

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 Daptomycin for Injection 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

Page 11 of 60

Product Monograph of Daptomycin for Injection

Daptomycin for Injection.

Warfarin

As experience with the concomitant administration of daptomycin and warfarin

is limited,

anticoagulant activity in patients receiving daptomycin and warfarin should be monitored for the

first several days after initiating therapy with Daptomycin for Injection.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Clinical studies enrolled 1,667 patients treated with daptomycin

and 1,319 treated with

comparator. Overall, at least one adverse event was reported by 51.3% of daptomycin-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 daptomycin 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, daptomycin 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,

daptomycin 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.

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Product Monograph of Daptomycin for Injection

Table 1. Incidence (%) of Treatment Emergent Adverse Events Irrespective of Causality

that Occurred in

2% of Patients in Either daptomycin or

Comparator

Treatment Groups in the Phase 3 cSSSI Studies

1

(Population: Safety

2

)

Adverse Event

Daptomycin

4 mg/kg

(N=534)

Comparator

3

(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%

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

Safety population includes all subjects who received at least one dose of daptomycin or comparator according to treatment actually received

during the trials

Comparators included vancomycin (1 g IV q12h), which was used in patients with known or suspected penicillin allergy or with methicillin-

resistant 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.

Page 13 of 60

Product Monograph of Daptomycin for Injection

Additional adverse events that occurred in < 1 to 2% of patients in either daptomycin (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 daptomycin-

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 daptomycin or

Comparator Treatment Groups in the Phase 3 cSSSI Studies

(Population: Safety)

Adverse Event

Daptomycin 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 daptomycin in the complicated skin and skin structure infection (cSSSI) trials

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 daptomycin and those treated

with comparator. CPK elevations in both groups were generally related to medical conditions,

Page 14 of 60

Product Monograph of Daptomycin for Injection

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 daptomycin or Comparator Treatment

Groups in Phase 3 cSSSI Studies

Change

All Patients

Patients with Normal CPK at Baseline

Daptomycin

(N=430)

Comparator

(N=459)

Daptomycin

(N=374)

Comparator

(N=392)

%

N

%

N

%

N

%

N

No Increase

90.7%

91.1%

91.2%

91.1%

Maximum Value

>1x ULN*

9.3%

8.9%

8.8%

8.9%

>2x ULN

4.9%

4.8%

3.7%

3.1%

>4x ULN

1.4%

1.5%

1.1%

1.0%

>5x ULN

1.4%

0.4%

1.1%

0.0%

>10x ULN

0.5%

0.2%

0.2%

0.0%

ULN (Upper Limit of Normal) is defined as 200 U/L.

In the cSSSI studies, 0.2% of patients treated with daptomycin 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.

Page 15 of 60

Product Monograph of Daptomycin for Injection

Table 4.

Incidence (%) of Treatment Emergent Adverse Events Irrespective of

Causality that Occurred in ≥ 5% of Patients in daptomycin or

Comparator

Treatment Groups in the SAB/SAIE Study (Population:

Safety

a

)

Adverse Events

Daptomycin

6 mg/kg

(N=120)

Comparator

b

(N=116)

Infections and Infestations

54.2%

48.3%

Urinary tract infection NOS

6.7%

9.5%

Osteomyelitis NOS

5.8%

6.0%

Sepsis NOS

5.0%

2.6%

Bacteremia

5.0%

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%

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%

Page 16 of 60

Product Monograph of Daptomycin for Injection

Adverse Events

Daptomycin 6 mg/kg

(N=120)

Comparator

b

(N=116)

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%

Safety population includes all subjects who received at least one dose of daptomycin or comparator according to treatment actually

received during the trials

Comparator: vancomycin (1 g IV q12h), which was used in patients with known or suspected penicillin allergy or with methicillin-

resistant 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.

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 daptomycin or

Comparator Treatment Groups in the Phase 3 SAB/SAIE Study

(Population: Safety)

Adverse Events

Daptomycin 6 mg/kg

(N=120)

Comparator

(N=116)

Investigations

Blood creatine phosphokinase (CPK) increased

5.0%

Blood phosphorus increased

2.5%

<1%

Blood alkaline phosphatase increased

1.7%

International normalized ratio increased

1.7%

Liver function test abnormal

1.7%

<1%

Blood creatinine increased

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

Page 17 of 60

Product Monograph of Daptomycin for Injection

Adverse Events

Daptomycin 6 mg/kg

(N=120)

Comparator

(N=116)

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

2.6%

Infections and Infestations

Candidal infection NOS

1.7%

Vaginal candidiasis

1.7%

General Disorders and Administration Site

Conditions

Chest pain

1.7%

Pyrexia

2.6%

Blood and Lymphatic System Disorders

Eosinophilia

1.7%

Nervous System Disorders

Dysgeusia

2.6%

Vascular Disorders

Hypotension NOS

2.6%

Musculoskeletal and Connective Tissue Disorders

Arthralgia

1.7%

Weakness in extremity

1.7%

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 drug-

related in the Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis

(SAB/SAIE) daptomycin-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

Page 18 of 60

Product Monograph of Daptomycin for Injection

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 daptomycin 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

daptomycin 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 daptomycin 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 daptomycin and comparator

in the SAB/SAIE trial.

Table 6.

Incidence (%) of Creatine Phosphokinase (CPK) Elevations from Baseline

through End of Treatment in either daptomycin or Comparator Treatment

Groups in the SAB/SAIE Study

Change

All Patients

Patients with Normal CPK at

Baseline

Daptomycin

(N=116)

%

N

Comparator

(N=111)

%

N

Daptomycin

(N=92)

%

N

Comparator

(N=96)

%

N

No Increase

75.9

87.4

75.0

87.5

Maximum Value > 1X ULN*

24.1

12.6

25.0

12.5

> 2X ULN

13.8

12.0

> 4X ULN

> 5X ULN

> 10X ULN

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 daptomycin-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

Daptomycin 6 mg/kg

(N=120)

n/N (%)

Comparator

a

(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%)

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.

Page 19 of 60

Product Monograph of Daptomycin for Injection

Post-Market Adverse Drug Reactions

The following adverse reactions have been reported with daptomycin in worldwide post- marketing

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

reaction 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.

Investigations: platelet count decreased.

Musculoskeletal Disorders: myoglobin increased; rhabdomyolysis (some reports involved

patients treated concurrently with daptomycin and HMG-CoA reductase inhibitors). Neurologic

Disorders: one case of coma post-anaesthesia/surgery; peripheral neuropathy. Renal and Urinary

Disorders: acute kidney injury; renal failure; renal insufficiency, tubulointerstitial nephritis (TIN).

Respiratory, Thoracic, and Mediastinal Disorders: cough; eosinophilic pneumonia (see

WARNINGS AND PRECAUTIONS Respiratory, Eosinophilic Pneumonia); organizing

pneumonia.

Skin and Subcutaneous Tissue Disorders: acute generalized exanthematous pustulosis; 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 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

Daptomycin for Injection. It is recommended that other medications associated with myopathy

should, if possible, be temporarily discontinued during treatment with Daptomycin for Injection

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

Daptomycin for Injection is co-administered with any other medicinal product known to reduce

renal filtration.

Drug-Drug Interactions

Drug-drug interaction studies were performed with daptomycin and other drugs that are likely to

either be co-administered or associated with overlapping toxicity as shown in Table 8.

Page 20 of 60

Product Monograph of Daptomycin for Injection

Table 8.

Established or Potential Drug-Drug Interactions with daptomycin

Drug Name

Ref

Effect

Clinical comment

Aztreonam

In a study in which 15 healthy adult subjects

received a single dose of

daptomycin

6 mg/kg

IV and a

combination dose of daptomycin

mg/kg IV and aztreonam 1 g IV, the C

0-∞

of daptomycin were not

significantly

altered by aztreonam.

No dosage adjustment of Daptomycin

for Injection is warranted when

Daptomycin for Injection is co-

administered with aztreonam.

HMG-CoA

Reductase

Inhibitors

In 20 healthy subjects on a stable daily

dose of oral simvastatin 40 mg,

administration of daptomycin

4 mg/kg

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

daptomycin

in patients is limited,

therefore, consideration should be

given to temporarily suspending use of

HMG-CoA reductase inhibitors in

patients receiving

Daptomycin for

Injection (see

WARNINGS AND

PRECAUTIONS, Musculoskeletal).

Probenecid

Concomitant administration of oral probenecid

(500 mg four times daily)

and a single dose of

daptomycin

4 mg/kg

IV did not significantly

alter the C

and AUC

0-∞

of daptomycin.

No dosage adjustment of Daptomycin

for Injection is warranted when

Daptomycin for Injection is co-

administered with probenecid.

Page 21 of 60

Product Monograph of Daptomycin for Injection

Drug Name

Ref

Effect

Clinical comment

Tobramycin

Non-

clinical

In a study in which 6 healthy adult males

received a single dose of daptomycin 2

mg/kg IV, tobramycin 1 mg/kg IV, and

both in combination, the mean C

0-∞

of daptomycin increased 12.7%

and 8.7%, respectively, when

administered with tobramycin. The mean

and AUC

0-∞

of tobramycin

decreased 10.7% and 6.6%, respectively,

when administered with daptomycin.

These differences were not statistically

significant.

In rats, mild skeletal muscle

degeneration and/or regeneration was

observed with 20 mg/kg IV daptomycin

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 daptomycin.

Tobramycin may have a weak

potentiating effect on muscle damage

caused by daptomycin.

The interaction between daptomycin and

tobramycin with a clinical dose of

daptomycin

is unknown. Caution is

warranted when Daptomycin for

Injection is co-administered with

tobramycin.

Warfarin

In 16 healthy subjects, concomitant

administration of daptomycin

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 daptomycin

warfarin is limited, anticoagulant

activity in patients receiving

Daptomycin for Injection and

warfarin should be monitored for

first several days after initiating

therapy with Daptomycin for

Injection.

Gentamicin

Non-

Clinical

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

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.

Page 22 of 60

Product Monograph of Daptomycin for Injection

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 Daptomycin for

Injection, it is recommended that clinicians:

Repeat the assessment of PT/INR, requesting that the specimen be drawn just prior to the

next

Daptomycin for Injection 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.

Evaluate for other causes of abnormally elevated PT/INR results.

DOSAGE AND ADMINISTRATION

Complicated Skin and Skin Structure Infections: Daptomycin

for Injection 4 mg/kg should be

administered intravenously 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): Daptomycin for Injection 6 mg/kg

should be administered intravenously 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 Daptomycin for Injection 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

Daptomycin for Injection should not be dosed more frequently than once a day. In Phase 1 and

2 clinical studies with daptomycin, creatine phosphokinase (CPK) elevations appeared to be

Page 23 of 60

Product Monograph of Daptomycin for Injection

more frequent when daptomycin

was dosed more frequently than once

daily.

Clinical studies with daptomycin 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).

Daptomycin for Injection should be reconstituted with a 21 gauge or smaller needle to

prevent

contamination of broken rubber in the reconstituted solution.

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 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

Patients with Creatinine Clearance < 30 mL/min

Daptomycin for Injection 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 daptomycin 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, Daptomycin for Injection 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.

Page 24 of 60

Product Monograph of Daptomycin for Injection

Table 10.

Dosage Adjustment of 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 48 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 48 hours

10 to 42 days with

an option for an

additional 14 days

*The dosage regimen for Daptomycin for Injection in paediatric patients with renal impairment has not been established

Patients with Hepatic Insufficiency

No dose adjustment is necessary when administering Daptomycin for Injection 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 daptomycin in patients under the age of 18 have not

been established. Use

of Daptomycin for Injection 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

Daptomycin for Injection should be reconstituted with 0.9% sodium chloride for injection, USP (see

Reconstitution).

Daptomycin for Injection is supplied in single-dose vials containing 500 mg daptomycin as a sterile,

lyophilized powder. The contents of a Daptomycin for Injection 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 Daptomycin for Injection

vials from refrigeration and allow

the product to sit at room temperature for a few minutes. Daptomycin for Injection vials do not

need to be warmed to room temperature prior to reconstitution.

Remove the polypropylene flip-off cap from the Daptomycin for Injection 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

Page 25 of 60

Product Monograph of Daptomycin for Injection

into the Daptomycin for Injection

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 Daptomycin for Injection

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 Daptomycin for Injection range in colour from pale yellow to light brown.

For IV injection over a period of 2 minutes:

Reconstitute Daptomycin for Injection, 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 Daptomycin for Injection, 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

Page 26 of 60

Product Monograph of Daptomycin for Injection

Because Daptomycin for Injection 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 Daptomycin for Injection 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).

Daptomycin for Injection should not be used in conjunction with ReadyMED

®

elastomeric

infusion pumps. Stability studies of daptomycin solutions stored in ReadyMED

®

elastomeric

infusion pumps

identified an impurity (2-mercaptobenzothiazole) leaching from this pump

system into the

daptomycin solution.

Daptomycin for Injection vials are for single-use only.

Compatible Intravenous Solutions

Daptomycin for Injection is compatible with 0.9% sodium chloride injection and lactated

Ringer’s injection. The following are compatible at room temperature when co-administered

with Daptomycin for Injection in

0.9% sodium chloride through the same IV line from separate

infusion bags: aztreonam,

ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin,

dopamine, heparin, and lidocaine.

Daptomycin for Injection 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

Daptomycin for Injection 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 Daptomycin for

Injection. No other product than the approved diluent should be added to the Daptomycin for

Injection vial or infusion bag.

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.

Daptomycin 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 daptomycin 3 g (43 mg/kg). Twenty-four hours later

symptoms of orofacial movements, lip smacking and shoulder shrugging were observed and

diagnosed as dyskinesia. Daptomycin was discontinued and the patient was treated with

benztropine and lorazepam. The events resolved and therapy was restarted without further

incident.

Page 27 of 60

Product Monograph of Daptomycin for Injection

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Daptomycin 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 daptomycin at steady-state following IV

administration of daptomycin over a 30-minute period at 4 to 12 mg/kg q24h to healthy young

adults are

summarized in Table 12.

Table 12.

Mean Daptomycin Pharmacokinetic Parameters in

Healthy Volunteers at Steady-State

Dose

b

(mg/kg)

N

Pharmacokinetic Parameters

a

Mean (Standard Deviation)

c

AUC

0-24

(µg*h/mL)

t

1/2

(h)

V

ss

(L/kg)

CL

T

(mL/h/kg)

c

C

(µg/mL)

c

C

(µg/mL)

4

494 (75)

8.1 (1.0)

0.096

(0.009)

8.3 (1.3)

57.8 (3.0)

5.9 (1.6)

6

632 (78)

7.9 (1.0)

0.101

(0.007)

9.1 (1.5)

93.9 (6.0)

6.7 (1.6)

8

858 (213)

8.3 (2.2)

0.101

(0.013)

9.0 (3.0)

123.3 (16.0)

10.3 (5.5)

10

1039 (178)

7.9 (0.6)

0.098

(0.017)

8.8 (2.2)

141.1 (24.0)

12.9 (2.9)

12

1277 (253)

7.7 (1.1)

0.097

(0.018)

9.0 (2.8)

183.7 (25.0)

13.7 (5.2)

0-24

: area under the concentration-time curve from 0 to 24 hours; t

: terminal elimination half-life ; V

: volume of distribution at steady-state;

: plasma clearance; C

: maximum plasma concentration (total drug)

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

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 C

(minimum plasma concentration)

of daptomycin during once-daily dosing with 6, 8, 10 and 12 mg/kg were dose proportional;

however, the mean C

(maximum plasma concentration) was slightly less than dose

proportional. Total clearance was unchanged across 4 to 12 mg/kg q24h.

Page 28 of 60

Product Monograph of Daptomycin for Injection

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 C

) 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 daptomycin to healthy volunteers over a 2-minute period at

doses of 4 and 6 mg/kg, the mean (SD) daptomycin steady-state AUC

0-tau

values were 475

(71) and 701 (82) µg

h/mL, respectively. The mean (SD) steady-state C

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 (V

) 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 C

of 27.6

g/mL (mean t

17.3

hrs).

In clinical studies, mean serum protein binding in subjects with creatinine clearance (CL

) ≥ 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 CL

< 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 (CL

< 80 mL/min) (see DOSAGE AND ADMINISTRATION).

Page 29 of 60

Product Monograph of Daptomycin for Injection

Special Populations and Conditions

Pediatrics: Currently, there are very limited data on the pharmacokinetics of daptomycin 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 daptomycin in

pediatric patients is not recommended until further data are

available.

Pediatric patients younger than 12 months should not be given daptomycin 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 daptomycin in pediatric patients were assessed in a Phase I single-dose

trial. A single 4 mg/kg dose of daptomycin 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,

) and elimination half-life (t

) 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 daptomycin 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 (AUC

0-∞

) 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 daptomycin 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 of daptomycin, the mean total clearance of

daptomycin was reduced approximately 35% and the mean AUC

0-∞

increased approximately

58% in elderly subjects compared to young healthy subjects. There were no differences in C

No dosage adjustment is warranted for elderly patients with normal renal function based on age

alone.

Page 30 of 60

Product Monograph of Daptomycin for Injection

Gender: No clinically significant gender-related differences in daptomycin pharmacokinetics

have been observed. No dosage adjustment is warranted based on gender when administering

Daptomycin for Injection.

Hepatic Insufficiency: The pharmacokinetics of daptomycin 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 daptomycin were not altered in

subjects with moderate hepatic impairment. No dosage adjustment is warranted when

administering Daptomycin for Injection to patients with mild to moderate hepatic

impairment

The pharmacokinetics of Daptomycin for Injection 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 non-

infected subjects with varying degrees of renal function (N=282). Following the administration

of a single 4 mg/kg IV dose of daptomycin, the plasma clearance (CL

) was reduced and the

systemic exposure (AUC

0-∞

) was increased with decreasing renal function (see Table 13). The

mean AUC

0-∞

was not markedly different for subjects and patients with creatinine clearance

) 30-80 mL/min as compared to those with normal renal function (CL

> 80 mL/min).

The mean AUC

0-∞

for subjects and patients with CL

< 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 AUC

0-∞

was 3-times higher than that observed in individuals with normal renal function. The mean C

ranged from 59.6 to 69.6 µg/mL in subjects with CL

≥ 30 mL/min, while those with CL

< 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. Daptomycin for injection should be administered following the completion of

hemodialysis on hemodialysis days (see DOSAGE AND ADMINISTRATION).

Page 31 of 60

Product Monograph of Daptomycin for Injection

Table 13.

Daptomycin Population Pharmacokinetic Parameters Following

a Single 30-Minute IV Infusion of 4 mg/kg of daptomycin 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)

AUC

0-

(µg*h/mL)

t

1/2

(h)

V

ss

(L/kg)

CL

T

(mL/h/kg)

Normal

>80 mL/min)

417 (155)

9.39 (4.74)

0.13

(0.05)

10.9 (4.0)

Mild Renal Impairment

50-80 mL/min)

466 (177)

10.75

(8.36)

0.12

(0.05)

9.9 (4.0)

Moderate Renal Impairment

30-<50 mL/min)

560 (258)

14.70

(10.50)

0.15

(0.06)

8.5 (3.4)

Severe Renal Impairment

<30 mL/min)

925 (467)

27.83

(14.85)

0.20

(0.15)

5.9 (3.9)

Hemodialysis and CAPD

1244 (374)

29.81

(6.13)

0.15

(0.04)

3.7 (1.9)

: creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; V

: 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 14). Patients (N=108)

received 6 mg/kg q24h of daptomycin and were stratified by varying degrees of renal function.

Plasma clearance (CL

) decreased with decreasing renal function, whereas AUC and C

increased with decreasing renal function. Mean AUC increased 1.6-fold while mean C

increased 2.8-fold in patients with moderate renal impairment compared to those with CL

> 80

mL/min. In the two patients with CL

< 30 mL/min, pharmacokinetic parameters were similar

to those with moderate renal impairment. Mean C

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 (V

) 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. Daptomycin for injection should be

administered following the completion of hemodialysis on hemodialysis days (see DOSAGE

AND ADMINISTRATION).

Page 32 of 60

Product Monograph of Daptomycin for Injection

Table 14.

Daptomycin Population Pharmacokinetic Parameters at Steady-

State in SAB/SAIE Patients Dosed with 6 mg/kg of daptomycin with Varying

Degrees of Renal Function

Renal Function

N

Pharmacokinetic Parameters

Mean (Standard Deviation)

1

AUC

0-24

[μg*h/mL]

t

1/2

[h]

V

ss

[L/kg]

CL

T

[mL/h/kg]

C

max

[μg/mL]

C

min

[μg/mL]

Normal

>80 L/min

545 (296)

9.0 (2.86)

0.15 (0.07)

13.2 (5.0)

108 (143)

6.9 (3.5)

Mild Impairment

50-80 mL/min

637 (215)

12.0 (2.26)

0.17 (0.04)

10.5 (3.5)

80 (41)

12.4 (5.6)

Moderate Impairment

30-<50 mL/min

868 (349)

16.1 (3.62)

0.17 (0.05)

8.2 (3.6)

114 (124)

19.0 (9.0)

Severe Impairment

<30 mL/min

1050, 892

25.8, 16.0

0.20, 0.15

5.7, 6.7

97, 83

25.4, 21.4

Mean (SD) values are presented except Severe Impairment where N=2;

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

A 41% reduction in daptomycin 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 daptomycin were evaluated in 6 moderately obese [Body

Mass Index (BMI) 25 to 39.9 kg/m

] and 6 extremely obese (BMI ≥ 40 kg/m

) subjects and

controls matched for age, sex, and renal function. Following administration of a single 4 mg/kg

IV dose of daptomycin based on total body weight, the plasma clearance of daptomycin

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 AUC

0-∞

daptomycin 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 daptomycin 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 daptomycin is warranted in obese patients

based solely on

weight.

STORAGE AND STABILITY

Store vials containing lyophilized powder at 2 to 8ºC.

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 Daptomycin for

Injection 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.

Page 33 of 60

Product Monograph of Daptomycin for Injection

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

Daptomycin for injection is supplied as a pale yellow to light brown lyophilized cake in a single-

use vial (500 mg/vial).

Available in package of 1 vial. Daptomycin for injection may also

contain sodium hydroxide used to adjust pH in trace amounts.

Page 34 of 60

Product Monograph of Daptomycin for Injection

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common name:

daptomycin

Chemical name:

N-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-

ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-

L-glutamyl-3- anthraniloyl-L-alanine

-lactone

Molecular formula:

Molecular mass:

1620.67 g/mol

Structural formula:

Table 15.

Physicochemical properties

Attribute

Description

Appearance

Clear, dark yellow to light brown solution (bulk drug substance; frozen

concentrate). Pale yellow to light brown lyophilized powder (lyophilized drug

product).

Solubility (at 25°C)

Water

> 1000 mg/mL

Acetonitrile

< 0.05 mg/mL

Methanol

34.9 mg/mL

Ethanol

1.20 mg/mL

Isopropyl alcohol

0.11 mg/mL

Partition Coefficient

1-octanol/water

-1.32

1-octanol/tris-buffer, pH 7.4

-3.26

pKa (aqueous)

2.9, 3.5, 4.3, 4.7, 10.5

Melting Point

215°C

Specific Rotation (at 25°C)

Water

+17.8°

Methanol

+11.2°

Page 35 of 60

Product Monograph of Daptomycin for Injection

CLINICAL TRIALS

Complicated Skin and Skin Structure Infections (cSSSI)

Study demographics and trial design

The patient demographics and basic trial design for the two pivotal cSSSI studies are

summarized in Table 16. Patients were included for skin and skin structure infections

complicated by factors implicating deeper soft tissue, significant surgical intervention, co-

morbidities, hospitalization and/or other factors. The main diagnoses were wound infections,

major abscesses and ulcer infections, 57% of which were considered severe in accordance with

the SIRS rating scale. Children, pregnant or lactating women and, among others, patients such

as those with bacteremia, pneumonia, osteomyelitis, primary muscle disorders or CPK > 50%

Upper Limit Normal, third degree burns, shock/hypotension, and severe renal impairment

(calculated creatinine clearance < 30 mL/min) were excluded. In the majority of patients with

Gram-positive cSSSI, the infections were polymicrobial either due to Gram-positive bacteria,

Gram-negative bacteria or anaerobes and 30% of patients received adjunctive surgery.

Microbiological analyses were restricted to Gram-positive organisms.

For purposes of the comparator arm, overall analyses, and the grouping of clinically similar

patients, all patients were pre-randomized to either vancomycin or anti-staphylococcal semi-

synthetic penicillins. Vancomycin was chosen in cases of known or suspected MRSA or patient

intolerance to penicillins. The anti-staphylococcal semi-synthetic penicillin chosen was

dependent upon availability and standard of care in the study country. All patients were then

randomized 1:1 to either daptomycin or the comparator arm. Patients could be switched to oral

therapies after a minimum of four days of IV treatment if clinical improvement was

demonstrated and if a switch was required for other relevant reasons. Patients initially treated

with penicillins could be switched to vancomycin if MRSA was cultured after randomization had

occurred. Aztreonam and metronidazole could be concurrently administered for the treatment of

Gram-negative and anaerobic bacteria respectively.

Overall, the daptomycin and comparator arms were comparable. In study 9801 the large

majority of patients were from the US whereas in study 9901 the majority was from South

Africa. In the former relative to the latter, study patients tended to be slightly older and included

slightly more Caucasians, diabetics, surgical interventions, and vancomycin usage.

Page 36 of 60

Product Monograph of Daptomycin for Injection

Table 16.

Summary of Trial Design and Demographics

Study

Number

(location)

Basic

Design

Primary

Efficacy

Parameter

Antibiotic

Treatments

Compared

(dose and

duration)

Number

of

Patients

Treated

(ITT)*

Mean Age

in Years

(range)

Gender

(%M/F)

Race

(% caucasian/

black/other)

DAP-SST-

9801

(US and

South

Africa)

Multicentre,

randomized,

parallel

group,

investigator

blinded

Clinical

outcome in

MITT* and

patient

populations

with cSSSI

7-12 days

after

treatment

cessation

Daptomycin

(4mg/kg/q24h IV

x 7-14 days)

versus

Comparator:

vancomycin

(1g q12h IV x 7-

14 days)

semi-

synthetic

penicillins**

(4-12 g/d IV in

divided doses x

7-14 days)

55.2

(18-91)

55.5

(19-94)

54.2/45.8

55.6/44.4

67.0/18.9/14.4

62.8/22.6/14.9

DAP-SST-

9901

(South

Africa,

Europe,

Australia

and Israel)

Multicentre,

randomized,

parallel

group,

investigator

blinded

Clinical

outcome in

MITT* and

patient

populations

with cSSSI

7-12 days

after

treatment

cessation

Daptomycin

(4mg/kg/q24h iv

x7-14days)

versus

Comparator:

vancomycin

(1g q12h iv x 7-

14days)

semi-

synthetic

penicillins***

(4-12 g/d iv in

divided doses x

7-14 days)

47.9

(18-87)

48.6

(17-85)

55.6/44.4

54.8/45.2

50.4/35.2/14.4

50.0/31.2/18.8

* analytical subpopulations included: ITT: intent to treat population (patients with cSSSI who received at least one dose); MITT: modified intent

to treat population (ITT patients with proved Gram-positive bacterial cSSSI at baseline); CE: clinically evaluable population (all ITT patients in

whom clinical outcome could be inferred to reflect the effect of the study drug, met clinical criteria for study infection, received correct study

drug as randomized for appropriate duration and intensity, had required clinical evaluations and did not receive confounding non-study

medications); ME: microbiologically evaluable population (CE patients with a Gram-positive bacterium at baseline); about 82% of ITT patients

met MITT criteria and 81% of ITT patients met CE criteria; 84% of CE patients met ME criteria for microbiological evaluability at Test of Cure

visit

** anti-staphylococcal semi-synthetic penicillin: nafcicillin, cloxacillin or oxacillin

*** anti-staphylococcal penicillin: flucloxacillin, cloxacillin or oxacillin

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Product Monograph of Daptomycin for Injection

Study results

Overall clinical efficacy results are provided in Tables 17 and 18 in terms of the sponsor-defined

primary clinical efficacy parameters at the Test Of Cure visit (7-12 days after cessation of

antibiotic treatment) for MITT and CE populations.

Table 17.

Clinical efficacy outcome (MITT population)

DAP-SST-9801

Daptomycin

Comparator

a

DAP-SST-9901

Daptomycin

Comparator

a

Pooled Results

Daptomycin

Comparator

a

(N=215)

(N=216)

(N=213)

(N=255)

(N=428)

(N=471)

Clinical Response

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

Clinical Success

140 (65.1)

140 (64.8)

179 (84.0)

212 (83.1)

319 (74.5)

352 (74.7)

Cure

90 (41.9)

84 (38.9)

82 (38.5)

109 (42.7)

172 (40.2)

193 (41.0)

Clinical

Improvement

50 (23.3)

56 (25.9)

97 (45.5)

103 (40.4)

147 (34.3)

159 (33.8)

Clinical Failure

75 (34.9)

76 (35.2)

34 (16.0)

43 (16.9)

109 (25.5)

119 (25.3)

Vancomycin or anti-staphylococcal semi-synthetic penicillins

Table 18.

Clinical efficacy outcome (CE population)

DAP-SST-9801

Daptomycin

Comparator

a

DAP-SST-9901

Daptomycin

Comparator

a

Pooled Results

Daptomycin

Comparator

a

(N=208)

(N=206)

(N=238)

(N=250)

(N=446)

(N=456)

Clinical Response

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

Clinical Success

158 (76.0)

158 (76.7)

214 (89.9)

226 (90.4)

372 (83.4)

384 (84.2)

Cure

105 (50.5)

96 (46.6)

103 (43.3)

117 (46.8)

208 (46.6)

213 (46.7)

Clinical

Improvement

53 (25.5)

62 (30.1)

111(46.6)

109 (43.6)

164(36.8)

171 (37.5)

Clinical Failure

50 (24.0)

48 (23.3)

24 (10.1)

24 (9.6)

74 (16.6)

72 (15.8)

Vancomycin or anti-staphylococcal semi-synthetic penicillins

The pooled clinical efficacy results, based on sponsor-defined clinical efficacy outcome

parameters for the MITT population in studies DAP-SST-9801 and DAP-SST 9901, are provided

in Table 19 in terms of infecting bacteria and patient pre-randomization to either anti-

staphylococcal semi-synthetic penicillins or vancomycin. These two clinical groupings were

based upon the likelihood of patients having MRSA or penicillin intolerance and the patients of

both groupings received either daptomycin or the appropriate comparator drug (vancomycin or

an anti-staphylococcal semi-synthetic penicillin).

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Product Monograph of Daptomycin for Injection

Table 19.

Pooled clinical success rates by infecting pathogen and patient pre-

randomization (MITT population)

Pre-randomized to

Semi-synthetic Penicillins

Drug Received

Pre-randomized to

Vancomycin

Drug Received

Daptomycin

Semi-synthetic

Penicillins

Daptomycin

Vancomycin

Pathogen

n/N(%)

n/N (%)

n/N (%)

n/N (%)

Staphylococcus aureus

(MSSA)

130/161 (80.7)

128/160 (80.0)

38/50 (76.0)

56/79 (70.9)

Staphylococcus aureus

(MRSA)

3/7 (42.9)

6/9 (66.7)

15/29 (51.7)

20/38 (52.6)

Streptococcus pyogenes

70/79 (88.6)

74/88 (84.1)

9/9 (100.0)

8/15 (53.3)

Streptococcus agalactiae

13/15 (86.7)

15/27 (55.6)

7/9 (77.8)

7/14 (50.0)

Similarly, the pooled microbiological efficacy results (eradication or presumed eradication in the

ME population) for studies DAP–SST-9801 and DAP-SST 9901, are provided in Table 20.

Table 20.

Pooled microbiological success rates (eradication or presumed eradication)

by infecting pathogen and patient pre-randomization (ME population)

Pre-randomization to

Semi-synthetic Penicillins

Drug Received

Semi-synthetic

Pre-randomization to

Vancomycin

Drug Received

Daptomycin

penicillins

Daptomycin

Vancomycin

Pathogen

n/N (%)

n/N (%)

n/N (%)

n/N (%)

Staphylococcus aureus

(MSSA)

108/144 (75.0)

108/139 (77.7)

31/41 (75.6)

49/68 (72.1)

Staphylococcus aureus

(MRSA)

2/4 (50.0)

3/6 (50.0)

12/21 (57.1)

18/30 (60.0)

Streptococcus pyogenes

66/72 (91.7)

65/79 (82.3)

9/9 (100.0)

7/9 (77.8)

Streptococcus agalactiae

12/14 (85.7)

12/18 (66.7)

6/7 (85.7)

7/11 (63.6)

Staphylococcus aureus Bacteremia/Staphylococcus aureus Infective Endocarditis

(SAB/SAIE) Trial

Study Demographics and Trial Design

The trial design and patient demographics for the Staphylococcus aureus bacteremia/

Staphylococcus aureus infective endocarditis (SAB/SAIE) trial are summarized in Table 21 and

Table 22.

Adult patients ≥ 18 years of age with clinically documented Staphylococcus aureus bacteremia

determined by at least one positive blood culture for Staphylococcus aureus obtained within 2

calendar days prior to the first dose of study drug and irrespective of source were enrolled. The

major exclusion criteria were patients with a prosthetic heart valve, cardiac decompensation

and/or valve damage, shock or hypotension, severe renal disease, increased AST or ALT, severe

neutropenia, or known osteomyelitis. Patients who developed osteomyelitis during treatment

were permitted to remain on study. In addition, patients with meningitis, pneumonia,

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Product Monograph of Daptomycin for Injection

polymicrobial bloodstream infections or with intravascular foreign material not planned for

removal within 4 days of dosing (except vascular stents in place > 6 months or permanent

pacemakers) were not to be enrolled.

Baseline characteristics in the Intent-to-Treat (ITT) population were well balanced between the

two treatment arms. Patients were generally seriously ill and included the elderly, those with

systemic inflammatory response syndrome (SIRS), diabetes mellitus, injection drug use,

extravascular foreign materials, intravascular foreign materials, percutaneous intravascular

devices, presence of a catheter at first positive culture, prior endocarditis, pre-existing valvular

heart disease, abnormal chest x-ray, HIV positive, prior endocarditis and surgery, infection

and/or trauma within 30 days of onset of the Staphylococcus aureus bacteremia. Eighty-nine

patients (38%) had bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA).

Vancomycin was used if the patient had methicillin-resistant Staphylococcus aureus.

Vancomycin was used unless or until susceptibility results proved to be methicillin-susceptible

whereupon therapy was changed to an anti-staphylococcal semi-synthetic penicillin (SSP) unless

contraindicated. The choice of anti-staphylococcal semi-synthetic penicillin was based on the

standard therapy in each country.

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Product Monograph of Daptomycin for Injection

Table 21.

Trial design in the pivotal SAB/SAIE Study

Study Number/

Country

Design

Primary Efficacy

Parameter

Treatment Regimen

Number of

Patients

Treated

DAP-IE-01-02

Multi-centre,

Co-primary

Dose

United States (40

randomized, open-

composite efficacy

Daptomycin

sites)

label, comparative

endpoint was

(6 mg/kg IV q24h)

Europe (8 sites)

(non-inferiority)

clinical and

microbiological

versus

success at test-of-

cure visit (6 weeks

vancomycin

after last treatment

(1 g IV q12h)

dose), based on an

Independent

semi-synthetic penicillin**

External

(2 g IV q4h)

Adjudication

Committee

Gentamicin

(1 mg/kg IV

outcome, in the

q8h): given to all patients in

ITT and PP

comparator group and those

populations*

with left-sided infective

endocarditis in daptomycin

group for the first 4 days (or

until blood cultures were

negative for 48 hours)

Duration

10-42 days

with an option to extend for

14 days.

The duration of treatment

was to be based on the

patient’s diagnosis as

determined by the

Investigator and the

susceptibility of the S. aureus

isolate.

ITT population included all patients who were randomized and received at least one dose of study medication; PP population included those in

the ITT population with documented adherence to the protocol

** Anti-staphylococcal semi-synthetic penicillins included nafcillin, oxacillin, cloxacillin or flucloxacillin based on standard therapy in each

country

Vancomycin and gentamicin were to be adjusted based on renal function and plasma level according to Investigator’s standard practice and

manufacturer’s guidelines

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Product Monograph of Daptomycin for Injection

Table 22.

Summary of Demographic Characteristics for the SAB/SAIE Study (ITT

Population)

Characteristic

Daptomycin

(N=120)

Comparator

(N=115)

Total

(N=235)

Median Age (years) (range)

50.5 (21, 87)

55.0 (25, 91)

53.0 (21, 91)

Age, years [N (%)]

30 (25.0%)

19 (15.8%)

37 (32.2%)

15 (13.0%)

67 (28.5%)

34 (14.5%)

Gender, N (%) Male

70 (58.3%)

71 (61.7%)

141 (60.0%)

Female

50 (41.7%)

44 (38.3%)

94 (40.0%)

Race, N (%) Caucasian

75 (62.5%)

81 (70.4%)

156 (66.4%)

BMI, kg/m

Median (range)

26.90 (17.6, 49.7)

25.67 (17.0, 44.0)

26.47 (17.0, 49.7)

CLcr, mL/min

, Median (range)

86.44 (28.0, 246.9)

83.61 (17.9, 277.0)

84.56 (17.9, 277.0)

CLcr, N (%) <50 mL/min

19 (15.8%)

22 (19.1%)

41 (17.4%)

Age category

75 years is a subset of the category

65 years.

Calculated by the Sponsor using the Cockcroft-Gault equation.

Upon entry, adult patients were classified for likelihood of endocarditis using the modified Duke

criteria (Possible, Definite, or Not Endocarditis). Echocardiography, including transesophageal

echocardiogram (TEE), was performed within 5 days following study enrollment. Final

diagnoses and outcome assessments at Test of Cure were made by a treatment-blinded

Independent External Adjudication Committee (IEAC), using protocol-specified clinical

definitions.

Of the 37 patients with an entry diagnosis of Definite Endocarditis, all (100%) had a final

diagnosis of infective endocarditis; of the 144 patients with an entry diagnosis of Possible

Endocarditis, 15 (10%) had a final diagnosis of infective endocarditis; and, of the 54 patients

with an entry diagnosis of Not Endocarditis, 1 (2%) had a final diagnosis of infective

endocarditis. There were 182 patients with bacteremia including 121 with complicated and 61

with uncomplicated Staphylococcus aureus bacteremia; and, there were 53 patients with

infective endocarditis, including 35 with right-sided and 18 with left-sided endocarditis.

A summary of the entry and final diagnostic subgroups (defined below) in the ITT population are

presented in Table 23.

Complicated bacteremia was defined as Staphylococcus aureus isolated from blood

cultures obtained on at least 2 different calendar days, and/or metastatic foci of infection

(deep tissue involvement), and classification of the patient as not having endocarditis

according to the modified Duke criteria.

Uncomplicated bacteremia was defined as Staphylococcus aureus isolated from blood

culture(s) obtained on a single calendar day, no metastatic foci of infection, no infection

of prosthetic material, and classification of the patient as not having endocarditis

according to the modified Duke criteria.

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Product Monograph of Daptomycin for Injection

Right-sided infective endocarditis (RIE) was definite or possible endocarditis according

to the modified Duke criteria and no echocardiographic evidence of predisposing

pathology or active involvement of either the mitral or aortic valve. Patients with a final

diagnosis of RIE based on these criteria were further classified as either complicated or

uncomplicated RIE as described below:

Complicated RIE included patients who met any of the following criteria: were

not intravenous drug users; had a positive blood culture for MRSA; had a serum

creatinine ≥2.5 mg/dL; or had evidence of extrapulmonary sites of infection.

Uncomplicated RIE included patients who met all of the following criteria: were

intravenous drug users; had a positive blood culture for MSSA; had a serum

creatinine <2.5 mg/dL; and were without evidence of extrapulmonary sites of

infection.

Left-sided infective endocarditis (LIE) was definite or possible endocarditis according to

modified Duke criteria and echocardiographic evidence of involvement or predisposing

pathology of the mitral or aortic valve.

Table 23.

Summary of Entry and Final Diagnostic Subgroups in the SAB/SAIE Trial

(ITT Population)

Diagnostic Subgroup

Daptomycin

(N=120)

Comparator

(N=115)

Total

(N=235)

IEAC Entry Diagnostic Subgroup [N (%)]

Definite IE

17 (14.2%)

20 (17.4%)

37 (15.7%)

Possible IE

73 (60.8%)

71 (61.7%)

144 (61.3%)

Not IE

30 (25.0%)

24 (20.9%)

54 (23.0%)

IEAC Final Diagnostic Subgroup [N (%)]

Complicated RIE

13 (10.8%)

12 (10.4%)

25 (10.6%)

Uncomplicated RIE

6 (5.0%)

4 (3.5%)

10 (4.3%)

Complicated bacteremia

60 (50.0%)

61 (53.0%)

121 (51.5%)

Uncomplicated bacteremia

32 (26.7%)

29 (25.2%)

61 (26.0%)

9 (7.5%)

9 (7.8%)

18 (7.7%)

Study Results

The overall success rates at Test of Cure in the ITT population were 44.2% (53/120) in patients

treated with daptomycin and 41.7% (48/115) in patients treated with comparator [95% CI 2.4% (-

10.2, 15.1)]. The success rates at Test of Cure in the Per Protocol Population were 54.4% (43/79)

in patients treated with daptomycin and 53.3% (32/60) with comparator [95% CI 1.1% (-15.6,

17.8)].

The success rates in the ITT population are shown in Table 24.

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Product Monograph of Daptomycin for Injection

Table 24.

Success Rates* at Test of Cure in the pivotal SAB/SAIE Trial (ITT

Population)

Population

Daptomycin

6 mg/kg n/N (%)

Comparator

a

n/N (%)

Difference:

Daptomycin−Comparator

(Confidence Interval)

Overall

53/120 (44.2%)

48/115 (41.7%)

2.4% (−10.2, 15.1)

Baseline Pathogen

MSSA

33/74 (44.6%)

34/70 (48.6%)

−4.0% (−22.6, 14.6)

MRSA

20/45 (44.4%)

14/44 (31.8%)

12.6% (−10.2, 35.5)

Entry Diagnosis

Definite or Possible Infective

Endocarditis

41/90 (45.6%)

37/91 (40.7%)

4.9% (−11.6, 21.4)

Not Infective Endocarditis

12/30 (40.0%)

11/24 (45.8%)

−5.8% (−36.2, 24.5)

Final Diagnosis

Complicated Bacteremia

26/60 (43.3%)

23/61 (37.7%)

5.6% (−17.3, 28.6)

Uncomplicated Bacteremia

18/32 (56.3%)

16/29 (55.2%)

1.1% (−31.7, 33.9)

Right-Sided Infective Endocarditis

(RIE)

8/19 (42.1%)

7/16 (43.8%)

−1.6% (−44.9, 41.6)

Complicated RIE

5/13 (38.5%)

6/12 (50.0%)

−11.5% (−62.4, 39.4)

Uncomplicated RIE

3/6 (50.0%)

1/4 (25.0%)

25.0% (−51.6, 100.0)

Left-Sided Infective Endocarditis

1/9 (11.1%)

2/9 (22.2%)

−11.1% (−55.9, 33.6)

Success: if patient was judged as cured or improved by IEAC, had a negative blood culture, did not receive potentially effective non-study

antibiotic that could have altered outcome, and received at least the minimum amount of study medication

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 According to the modified Duke criteria

According to the modified Duke criteria

95% Confidence Interval

97.5% Confidence Interval (adjusted for multiplicity)

99% Confidence Interval (adjusted for multiplicity)

See definitions above.

Table 25 presents a summary of success rates at Test of Cure by duration of study treatment in

the ITT population. Across all patients in the ITT population, success rates increased with

increasing duration of treatment in both the daptomycin and comparator groups.

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Product Monograph of Daptomycin for Injection

Table 25.

Summary of Success Rates at Test of Cure in the SAB/SAIE Trial by

Duration of Treatment and Final Diagnosis (ITT Population)

Group

Daptomycin

6 mg/kg q24h

n/N (%)

Comparator

n/N (%)

1-14

days

15-28

days

29-42

days

>42 days

1-14

days

15-28

days

29-42

days

>42 days

Overall ITT

29/77

15/29

7/11

14/52

21/41

11/18

(37.7%)

(51.7%)

(63.6%)

(66.7%)

(26.9%)

(51.2%)

(61.1%)

(50.0%)

Complicated

14/36

6/14

5/30

10/18

7/11

bacteremia

(38.9%)

(42.9%)

(57.1%)

(66.7%)

(16.7%)

(55.6%)

(63.6%)

(50.0%)

Uncomplicated

12/25

9/16

5/11

bacteremia

(48.0%)

(85.7%)

(0%)

(0%)

(56.2%)

(45.5%)

(100%)

(100%)

Right-sided

endocarditis

(33.3%)

(42.9%)

(66.7%)

(0%)

(0%)

(66.7%)

(60.0%)

(0%)

Left-sided

endocarditis

(0%)

(0%)

(100%)

(0%)

(0%)

(33.3%)

(0%)

(0%)

Note: anti-staphylococcal semi-synthetic penicillin (SSP) included nafcillin, oxacillin, cloxacillin, and flucloxacillin.

In the overall ITT population, there was no statistically significant difference in time to clearance

of Staphylococcus aureus bacteremia between daptomycin and comparator. The median time to

clearance in patients with MSSA was 4 days and in patients with MRSA was 8 days.

Failure of treatment due to persisting or relapsing Staphylococcus aureus infections was assessed

in 19/120 (15.8%) daptomycin-treated patients (12 with MRSA and 7 with 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 daptomycin-

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 (see WARNINGS AND PRECAUTIONS).

DETAILED PHARMACOLOGY

Animal Pharmacology

Adult Animals

In animals, daptomycin administration has been associated with effects on skeletal muscle with

no changes in cardiac or smooth muscle. Skeletal muscle effects were characterized by

degenerative/regenerative changes and variable elevations in creatine phosphokinase (CPK). No

fibrosis or rhabdomyolysis was evident in repeat dose studies up to the highest doses tested in

rats (150 mg/kg/day IV) and dogs (100 mg/kg/day IV). The degree of skeletal myopathy showed

no increase when treatment was extended from 1 month to up to 6 months. Severity was dose

dependent. All muscle effects, including microscopic changes, were fully reversible within 30

days following cessation of dosing.

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Product Monograph of Daptomycin for Injection

In adult animals, effects on peripheral nerve (characterized by axonal degeneration and

frequently accompanied by significant losses of patellar reflex, gag reflex and pain perception)

were observed at doses higher than those associated with skeletal myopathy. Deficits in the

dogs' patellar reflexes were seen within 2 weeks of the start of treatment at 40 mg/kg IV (9 times

the human C

at the 6 mg/kg IV q24h dose), with some clinical improvement noted within 2

weeks of the cessation of dosing. However, at 75 mg/kg/day IV for 1 month, 7/8 dogs failed to

regain full patellar reflex responses within the duration of a 3-month recovery period. In a

separate study in dogs receiving doses of 75 and 100 mg/kg/day IV for 2 weeks, minimal

residual histological changes were noted at 6 months after cessation of dosing. However,

recovery of peripheral nerve function was evident.

Acute IV administration of daptomycin to male mice was associated with dose-related effects on

the central nervous system that were minimal at dose levels below 100 mg/kg but significant at

200 mg/kg. These effects included decreased motor activity, leg weakness, tremors, grasping

loss, decreased abdominal tone, piloerection, decreased frequency of acetic acid-induced

writhing, and increased hexobarbital-induced sleep time. Animal model studies have

demonstrated that there is an increased penetration of daptomycin into the cerebrospinal fluid

through inflamed meninges.

Daptomycin has been shown to penetrate into rabbit meninges (non-inflamed, 2%; inflamed 6%).

In another study of general pharmacological properties at doses up to 150 mg/kg IV, daptomycin

caused no changes in gross behavior of rats at 15 mg/kg. Slight hypoactivity and abnormal

posture were observed at 50 mg/kg. At 150 mg/kg, changes included hypoactivity, abnormal

posture and gait, ptosis, decreased limb tone, increased defecation, and decreased food

consumption and body weight. Most effects were transient and reversed within 24 hours post-

dose. After pre-treatment at this dose, daptomycin also potentiated thiopental-Na anesthesia by 4

to 8-fold and inhibited motor coordination.

Tissue distribution studies in rats have shown that daptomycin is retained in the kidney.

The effect of concurrent administration of daptomycin and simvastatin on skeletal muscle was

studied in a repeat dose study in CD rats. A total of four groups of male rats (15 rats per group)

were treated as follows: Group 1: vehicle, days 0-27; Group 2: daptomycin 20 mg/kg/day IV,

days 14-27; Group 3: Simvastatin 10 mg/kg/day Oral, days 0-27; and Group 4: Simvastatin 10

mg/kg/day Oral, days 0-27 and daptomycin 20mg/kg/day IV, days 14-27. Blood for serum

chemistry was obtained on days 13 (prior to the initiation of daptomycin treatment) and 27.

Following 14 days of treatment with 10 mg/kg/day of simvastatin in combination with 20

mg/kg/day of daptomycin, a slight, statistically significant increase was detected in the levels of

aspartate aminotransferase but not creatine phosphokinase (Table 26). However, it is noteworthy

that following thirteen days of treatment with simvastatin alone (prior to the administration of

daptomycin), slight, statistically significant elevations in mean serum levels of creatine

phosphokinase and aspartate aminotransferase were detected in Group 4 animals as compared to

Group 3 animals (see Table 26). Because the magnitude of the difference in CPK and AST

between Group 4 and Group 3 (10/20 and 10/0 mg/kg/day simvastatin/daptomycin, respectively)

on day 27 (1.4 and 1.4-fold respectively) was comparable to that noted on day 13, the difference

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Product Monograph of Daptomycin for Injection

is most likely related to the pre-existing (day 13) elevation and not due to the addition of

daptomycin administration to simvastatin.

The microscopic examination of skeletal muscle at the end of study revealed minimal

degenerative and/or regenerative changes in animals from all groups. Although the incidence

was slightly higher for daptomycin (with or without simvastatin) as compared to vehicle or

simvastatin alone treated groups, there was no increase in the incidence or severity of muscle

effects in the daptomycin alone group as compared to daptomycin in combination with

simvastatin.

Together, these data support the conclusion that no effect of drug interaction on skeletal muscle

was observed upon co-administration of daptomycin and simvastatin to rats at clinically relevant

doses.

Table 26.

Summary of Creatine Phosphokinase (CPK) and Aspartate

Aminotransferase (AST) Levels in Rats Following Administration of Oral

Simvastatin With and Without Intravenous Daptomycin

Daily Dose

a

Control Vehicle

+ Vehicle

Group 1

Daptomycin

20mg/kg/day +

Vehicle

Group 2

Simvastatin

10 mg/kg/day

+Vehicle

Group 3

Simvastatin

10mg/kg/day +

Daptomycin

20 mg/kg/day

Group 4

CPK (IU/L)

331.4

435.7

352.5

590.2

Day 13

Day 27

509.1(54%)

568.5 (30%)

777.0 (121%)

1083 (84%)

AST (U/L)

99.2

99.3

97.7

121.7

Day 13

Day 27

104.5 (5%)

107.1 (8%)

121.3 (24%)

169.5

(39%)

Dose administration of simvastatin was initiated 14 days prior to addition of daptomycin treatment. Simvastatin was administered from

Treatment Days 0 to 27; Daptomycin was administered from Treatment Days 14-27.

Values for Day 13 preceded initiation of daptomycin treatment.

Significantly different from Groups 1 and 3 but not Group 2 by Duncan’s test (p<0.05)

Significantly different from Groups 1, 2 and 3 by Duncan’s test (p<0.05)

Numbers in parentheses represent the percentage increase in CPK or AST values from Day 13 to 27

The effect of concurrent administration of daptomycin and tobramycin with respect to

nephrotoxicity and neuromuscular toxicity was studied in rats. Daptomycin dose levels were 1,

5, and 20 mg/kg IV q24h. The tobramycin dose was 10 mg/kg SC b.i.d. Tobramycin treatment

alone was associated with mild nephropathy. In comparison to the control group, absolute and

relative kidney weights were increased in all groups receiving tobramycin. In addition, an

increased incidence and severity of cortical tubular regeneration was observed in all tobramycin-

treated groups. Concurrent administration of daptomycin had no effect on the tobramycin-

induced nephropathy. Mild skeletal muscle degeneration and/or regeneration were observed in

the high dose daptomycin group when given alone. When daptomycin was administered

concurrently with tobramycin, skeletal muscle degeneration and/or regeneration were observed

at dose levels of daptomycin ≥ 5 mg/kg. An increase in the incidence of the muscle damage in

relation to tobramycin dose suggests that daptomycin-induced myopathy may be potentiated by

co-administration of tobramycin. This increase is most likely related to the nephrotoxic effects

of tobramycin, which may have resulted in reduced renal clearance of daptomycin and higher

systemic exposure. No microscopic damage to the sciatic nerve was apparent.

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Product Monograph of Daptomycin for Injection

The effect of concurrent administration of daptomycin and gentamicin with respect to

nephrotoxicity was investigated in dogs. Gentamicin dose levels were 9 or 30 mg/kg/day IM (3

or 10 mg/kg q8h). The daptomycin dose was 30 mg/kg/day IV (10 mg/kg.q8h). When

daptomycin was administered with high dose gentamicin, blood urea nitrogen and creatinine

levels were 2-fold greater and potassium levels were slightly decreased (approximately 17%) as

compared to the values observed with gentamicin alone. High dose gentamicin alone produced

slight to minimal renal tubular necrosis and tubular epithelial regeneration. In animals receiving

high dose gentamicin in combination with daptomycin, the severity of these lesions was graded

as minimal to moderate. Thus, when a high dose of gentamicin was given in combination with

daptomycin, the severity of the nephrotoxic lesions was increased and changes in clinical

chemistry parameters indicative of renal effects were observed. In contrast, the administration of

daptomycin with a low dose of gentamicin did not produce a functionally meaningful difference

in the severity of nephrotoxicity. Daptomycin, given alone at 30 mg/kg/day did not induce

nephrotoxicity.

Juvenile Animals

Target organs of daptomycin-related effects in 7-week-old juvenile dogs were skeletal muscle

and nerve, the same target organs as in adult dogs. In juvenile dogs, nerve effects were noted at

lower daptomycin blood concentrations than in adult dogs following 28 days of dosing. In

contrast to adult dogs, juvenile dogs showed evidence of effects in nerves of the spinal cord as

well as peripheral nerves after 28 days of dosing. No nerve effects were noted in juvenile dogs

following 14 days of dosing at doses up to 75 mg/kg/day.

Administration of daptomycin to 7-week-old juvenile dogs for 28 days at doses of 50 mg/kg/day

produced minimal degenerative effects on the peripheral nerve and spinal cord in several

animals. A dose of 150 mg/kg/day for 28 days produced minimal degeneration in the peripheral

nerve and spinal cord as well as minimal to mild degeneration of the skeletal muscle in a

majority of animals, accompanied by slight to severe muscle weakness evident in most dogs.

Following a 28-day recovery phase, microscopic examination revealed apparent recovery of the

skeletal muscle and the ulnar nerve effects, but nerve degeneration in the sciatic nerve and spinal

cord was still observed in all 150 mg/kg/day dogs (see TOXICOLOGY).

Following once-daily administration of daptomycin to juvenile dogs for 28 days, microscopic

effects in nerve tissue were noted at a C

value of 417 µg/mL, which is approximately 3-fold

less than the C

value associated with nerve effects in adult dogs treated once daily with

daptomycin for 28 days (1308 µg/mL).

Neonatal Animals

Administration of daptomycin to postnatal day (PND) 4 neonatal dogs at 50 and 75 mg/kg/day

and AUC

values of ≥321 μg/mL and ≥1470 μgh/mL, respectively) produced marked

clinical signs of twitching, muscle rigidity in the limbs, impaired use of limbs, and a decrease in

body weights and overall body condition necessitating early discontinuation by PND 19. A dose

of 25 mg/kg/day from PND 4 to PND 31 (C

and AUC

values of 147 μg/mL and

717 μgh/mL, respectively) produced mild reversible clinical signs of twitching and one

incidence of muscle rigidity with no effects on body weight. No histopathological effect related

to daptomycin was observed (including peripheral and central nervous system and skeletal

Page 48 of 60

Product Monograph of Daptomycin for Injection

muscle) at any dose. No effects were observed in dogs administered daptomycin at 10

mg/kg/day, the NOAEL, following 28 days of treatment with associated C

and AUC

values

of 62 μg/mL and 247 μgh/mL, respectively.

Human Pharmacology

Pharmacodynamics

In a placebo-controlled study in healthy volunteers, there was no evidence that exposure to

daptomycin at 6 mg/kg IV q24h x 14d caused any meaningful changes in cardiac repolarization

as measured by QTcB. In nerve motor function studies, daptomycin administration did not

cause any significant changes in the set of objective measures indicative of neuropathy or

myopathy. Daptomycin administration was associated with a significant increase in the number

of affirmative responses to the neurological questionnaire designed to assess symptoms and

deficits associated with small fiber sensory function. During the 14-day follow-up period more

subjects in the daptomycin group (8) compared to the normal saline group (5) reported

symptoms of tingling, numbness and weakness.

In an ascending dose study, daptomycin was well-tolerated at doses up to 12 mg/kg for up to 14

days. No significant adverse effects, including effects on skeletal muscle and peripheral nerves,

were observed during the study period in any dose group.

Pharmacokinetics

The pharmacokinetic profile of daptomycin

in humans is highly predictable following

intravenous administration. Single and multiple doses of daptomycin, up to 12 mg/kg/day for up

to 14 consecutive days have been studied in healthy subjects (see Table 9, ACTION AND

CLINICAL PHARMACOLOGY).

The pharmacokinetics and concentrations of daptomycin in cantharides-induced skin blisters and

in plasma were determined over a 24-hour period following a single IV infusion of 4 mg/kg of

daptomycin

in healthy volunteers. Daptomycin penetrated the inflammatory exudate moderately

rapidly, with mean 1- and 2- hour concentrations of 9.4 µg/mL and 14.5 µg/mL, respectively.

in the inflammatory fluid occurred approximately 3 hours later than in plasma (3.7 hours vs.

1.5 hours) with a C

of 27.6 µg/mL. The mean C

in the plasma was 77.5 µg/mL. The

elimination half-life of daptomycin from the inflammatory exudate was highly variable, ranging

from 6.3 hours to 30.9 hours, with a mean of 17.3 hours. The mean AUC

0-24h

in the

inflammatory exudate was 318.2 µg

hr/mL. Mean plasma elimination half-life was 7.74 hours

with mean plasma AUC

0-24h

of 468.0 µg

hr/mL, representing approximately 88% of the mean

0-∞

(529.7 µg

hr/mL). The penetration of daptomycin into inflammatory exudate, calculated

as AUC

0-24h

exudate/AUC

0-24h

plasma, was 68.4%.

A study was conducted to evaluate the pharmacokinetics of daptomycin over a period of 3 weeks

in subjects with End Stage Renal Disease (ESRD) on hemodialysis three times weekly using

both high-flux (Baxter CT190G) and low-flux (Fresenius F8) dialysis membranes. Daptomycin

was administered as an 8 mg/kg loading dose followed by 6 mg/kg 3 times per week.

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Product Monograph of Daptomycin for Injection

The AUC values on Day 17 appear higher in the low-flux group at 2586

g x h/mL compared

with the high-flux group at 1716

g x h/mL (Table 27). However, examination of the individual

AUC’s of the 4 subjects in the low-flux group and 3 subjects in the high-flux group indicated

that the low flux cohort’s AUCs were consistently higher across all time points than those of the

subjects in the high-flux cohort. Thus, there was little evidence of excessive accumulation in the

low flux group compared with the high flux group.

Due to high variability in daptomycin pharmacokinetics between subjects under hemodialysis

using low-flux and high-flux membranes, no statistically significant differences were detectable.

However, the pre- to post-dialysis decrease in daptomycin levels was greater on the high-flux

membrane (41%) compared to the low-flux membrane (5 to 7%).

Table 27.

Pharmacokinetic Parameters of Daptomycin Following Single (Day 1) and

Repeat (3 times/week) Dosing of daptomycin in Subjects with ESRD

Mem-

brane

Type

Day

N

Pharmacokinetic Parameters

Mean (CV%)

C

max

(

g/mL)

C

min

(

g/mL)

AUC

a

(

g x h/mL)

T

1/2

(h)

CL

(mL/h/kg)

Vss

L/kg

Low-

Flux

91 (31)

1697 (33)

38.5 (21.3)

2.8 (40.7)

0.14 (17.8)

86 (33)

17 (9)

1916 (45)

42.3 (26.9)

3.5 (54.4)

0.18 (28.3)

103 (26)

29 (11)

2586 (35)

55.9 (36.1)

2.2 (35.4)

0.16 (21.0)

High -

Flux

107 (39)

1945 (34)

35.7 (11.3)

2.8 (51.6)

0.14 (54.2)

81 (38)

14 (6)

1672 (36)

38.1 (16.6)

3.7 (50.0)

0.19 (54.6)

94 (17)

22 (3)

1716 (27)

45.3 (37.8)

3.6 (44.1)

0.27 (85.1)

Subjects received 8 mg/kg on Day 1, followed by 6 mg/kg 3 times per week.

AUC (0-t): Area under the concentration versus time curve from 0 to end of dosing interval

MICROBIOLOGY

Daptomycin has clinical utility in the treatment of infections caused by aerobic Gram-positive

bacteria only. Daptomycin inserts directly into the cytoplasmic membrane of both growing and

stationary phase Gram-positive bacteria resulting in dissipation of the membrane potential and

efflux of potassium ions, which causes inhibition of protein, DNA and RNA synthesis and

bacterial cell death with negligible lysis. The antibacterial activity of daptomycin requires the

presence of free calcium, therefore, the determination of in vitro susceptibility of bacteria to

daptomycin requires that broth media be supplemented with physiological levels of free (ionized)

calcium at a concentration of 50 μg/mL. Daptomycin retains activity against Gram-positive

bacteria including methicillin-resistant Staphylococcus aureus (see INDICATIONS AND

CLINICAL USE). Daptomycin is not active against Gram-negative bacteria.

Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive

organisms in vitro. This has been demonstrated both by time-kill curves and by MBC/MIC

ratios (minimum bactericidal concentration/minimum inhibitory concentration) using broth

dilution methodology.

Daptomycin’s activity in vitro is inhibited in the presence of pulmonary surfactant. In mouse

and hamster models of broncho-alveolar pneumonia (BAP), daptomycin lacked efficacy.

Page 50 of 60

Product Monograph of Daptomycin for Injection

In vitro studies have investigated daptomycin interactions with other antibiotics. Antagonism, as

determined by kill curve studies, has not been observed. In vitro synergistic interactions of

daptomycin occurred with aminoglycosides, β-lactam antibiotics and rifampin against some

isolates of staphylococci including some methicillin-resistant isolates.

Daptomycin has been shown to be active against most isolates of the following bacteria both in

vitro and in clinical infections.

Table 28.

Daptomycin MIC

50

and MIC

90

for Susceptible Aerobic and Facultative

Gram- Positive Bacteria in vitro and in Clinical Infections

Microorganism

# of clinical isolates

MIC (μg/mL)

MIC

50

MIC

90

Range

Staphylococcus aureus (including

methicillin-resistant strains)

3848

0.25

<0.06 – 2

Streptococcus agalactiae

0.12

0.25

<0.06 - 0.5

Streptococcus pyogenes

<0.06

<0.06

<0.06 - 0.12

The following in vitro data are available (Table 29), but their clinical significance is unknown.

Greater than 90% of the following microorganisms demonstrate an in vitro MIC less than or

equal to the susceptible breakpoint for daptomycin versus the bacterial genus. The efficacy of

daptomycin in treating clinical infections due to these bacteria has not been established in

adequate and well-controlled clinical trials.

Table 29.

Daptomycin MIC

50

and MIC

90

for Susceptible Aerobic and Facultative

Gram- Positive Microorganisms in vitro

Microorganism

# of clinical isolates

MIC (μg/mL)

MIC

50

MIC

90

Range

Corynebacterium jeikeium

0.25

0.06 – 1

Enterococcus faecalis

(vancomycin-resistant strains)

0.25 – 2

Enterococcus faecalis

(vancomycin-susceptible strains)

<0.06 - 4

Enterococcus faecium

(including vancomycin-resistant

strains)

0.25 - 4

Staphylococcus epidermidis

(including methicillin-resistant

strains)

0.12 - 1

Staphylococcus haemolyticus

0.25

0.03 - 1

Streptococcus dysgalactiae subsp.

equisimilis

<0.03

0.06

<0.03 - 0.12

Resistance

At this time, no mechanism of resistance to daptomycin has been identified. There have been

reports of Staphylococcus aureus isolates exhibiting decreased or intermediate vancomycin

susceptibility demonstrating decreased daptomycin susceptibility.

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Product Monograph of Daptomycin for Injection

Non-susceptible isolates of Staphylococcus aureus have been recovered from patients in clinical

trials. These include one patient enrolled in a Phase 2 study, one who received daptomycin in a

compassionate use study, and seven from the SAB/SAIE trial.

Cases of daptomycin resistance have been reported in staphylococci during post-marketing.

Susceptibility Testing Methods

Susceptibility testing by dilution methods requires the use of daptomycin susceptibility powder.

The testing also requires the presence of physiological levels of free calcium ions (50 μg/mL of

calcium, using calcium chloride) in Mueller-Hinton broth.

Dilution Technique

Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates

of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined

using a standardized procedure based on a broth dilution method or equivalent using

standardized inoculum and concentrations of daptomycin. The use of the agar dilution method is

not recommended with daptomycin. The MICs should be interpreted according to the criteria in

Table 30.

Table 30.

Susceptibility Interpretive Criteria for Daptomycin

Pathogen

Broth Dilution MIC

(

g/mL)

a

S

I

R

Staphylococcus aureus

(methicillin-susceptible and methicillin-resistant)

Streptococcus pyogenes and Streptococcus agalactiae

The MIC interpretive criteria for S. aureus are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a

calcium content of 50 μg/mL; the MIC interpretive criteria for Streptococcus spp. other than S. pneumoniae are applicable only to tests performed

by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 μg/mL, supplemented with 2 to 5% lysed horse blood,

inoculated with a direct colony suspension and incubated in ambient air at 35ºC for 20 to 24 hours.

Limited data on daptomycin resistant strains precludes defining any categories other than “Susceptible”. Strains yielding test results suggestive

of a “Non-Susceptible” category should be retested, and if the result is confirmed, the isolate should be submitted to a reference laboratory for

confirmation of results using CLSI reference broth microdilution method.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial

compound in the blood reaches the concentrations usually achievable.

Diffusion Technique

Quantitative methods that require measurements of zone diameters have not been shown to

provide reproducible estimates of the susceptibility of bacteria to daptomycin. The use of a disk

diffusion method is not recommended with daptomycin.

Page 52 of 60

Product Monograph of Daptomycin for Injection

Quality Control

Standardized susceptibility test procedures require the use of quality control microorganisms to

control the technical aspects of the procedures. Standard daptomycin powder should provide the

range of values noted in Table 31. Quality control microorganisms are specific strains of

organisms with intrinsic biological properties relating to resistance mechanisms and their genetic

expression within bacteria; the specific strains used for microbiological quality control are not

clinically significant.

Table 31.

Acceptable Quality Control Ranges for Daptomycin to be used in Validation

of Susceptibility Test Results

QC Strain

Acceptable Quality Control Ranges

Broth Dilution MIC

(μg/mL)

a

Staphylococcus aureus ATCC 29213

0.12-1

Streptococcus pneumoniae ATCC 49619

0.06-0.5

The quality control ranges for S. aureus are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a

calcium content of 50 μg/mL; the quality control ranges for S. pneumoniae are applicable only to tests performed by broth dilution using Mueller-

Hinton broth adjusted to a calcium content of 50 μg/mL, supplemented with 2 to 5% lysed horse blood, inoculated with a direct colony

suspension and incubated in ambient air at 35ºC for 20 to 24 hours.

This organism may be used for validation of susceptibility test results when testing Streptococcus spp. other than S. pneumoniae.

TOXICOLOGY

Single-Dose Toxicity Studies

Acute toxicity testing identified the neuromuscular system (nervous system and/or skeletal

muscle) as the target organ of daptomycin toxicity, and uncovered potential differences in

sensitivity among the species tested (i.e., mouse, rat, dog, and monkey). Studies performed are

listed in Table 32 below.

Page 53 of 60

Product Monograph of Daptomycin for Injection

Table 32.

Results of Single-Dose Toxicity Studies

Species/

Strains

Route

Dose Levels

(mg/kg)

Max. Non-Lethal

Dose (mg/kg)

Noteworthy Findings

Mouse/ ICR

0, 700, 900,

1100, 1400

<700

0: Transient generalized leg weakness

700: 1M and 5F died

≥700: Generalized leg weakness,

hypoactivity, ataxia, tremors, ptosis, and

death

Rat/ Fischer

0, 110, 140,

180, 225

0: Transient generalized leg weakness

110: Transient generalized leg weakness,

hypoactivity

140: 4M and 1F died

≥140: Leg weakness, ataxia, hindlimb

paralysis, tremors, clonic convulsions,

and death

Dog/ Beagle

25, 200

≥25: Slight (2-3X) increases in serum

creatine phosphokinase (CPK) within 24

h post-dose and generally returned to

normal within 48 h after dosing

200: 10% decrease in body weight in 1 of

4 dogs, and slight reduction in appetite in

2 of 4 dogs

Monkey/

Rhesus

25, 200

25: Slight, transient lethargy and paleness

of the facial skin in 2 of 4 animals; CPK

increased >10-fold at 3 h post-dose and

returned to normal within 48 h

200: 1M and 2F died. Death preceded by

extreme lethargy, ataxia, and severe

muscle weakness; slight axonal

degeneration of the sciatic nerve in one of

the deaths; CPK increased >10-fold at 3 h

post-dose and did not return to normal

until Day 7 after dosing

Rat/ Fischer

0, 350, 700

0: Transient generalized leg weakness

≥ 350: Transient generalized leg

weakness; sores/scabs at injection sites

IV: intravenous; SC: subcutaneous; M: male; F: female; h: hour.

Repeat-Dose Toxicity Studies

The results of repeat-dose and investigative studies consistently demonstrated daptomycin’s

primary target organ to be skeletal muscle in adult rats and dogs, with effects observed in

peripheral nerve at higher dose levels in both species (Table 33). Skeletal myopathy was usually

accompanied by serum creatine phosphokinase (CPK) elevations in adult dogs, which preceded

clinical effects and correlated with the severity of microscopic lesions. Nephrotoxicity and

gastrointestinal effects observed in rats appear to be species-specific because these effects were

not evident in either dogs or monkeys up to the highest doses tested (75 mg/kg/day and 10

mg/kg/day in dogs and monkeys, respectively). Recovery from skeletal myopathy was more

rapid than recovery from daptomycin-related peripheral neuropathy. Recovery of peripheral

nerve function was evident within 3 to 6 months post-dosing, although very minimal histological

changes were observed 6 months after dosing cessation.

Page 54 of 60

Product Monograph of Daptomycin for Injection

In contrast to adult dogs, juvenile dogs showed evidence of effects in nerves of the spinal cord as

well as peripheral nerves after 28 days of dosing (Table 33 and see DETAILED

PHARMACOLOGY, Animal Pharmacology, Juvenile Animals). The effects were noted at

lower daptomycin doses and at lower daptomycin blood concentrations than in adult dogs. The

data suggests that as compared to adult populations, juvenile populations may be more sensitive

to daptomycin-related nerve effects.

Table 33.

Summary of Findings on Repeat-Dose Toxicity and Investigative Studies*

Species /

Strain

Study

Duration

Dose Range

(mg/kg/day)

Noteworthy Findings

(Dose levels affected)

Rat/ Fischer

2 weeks;

1, 3, and

6 months

1 to 150

Skeletal Muscle (≥ 5 mg/kg): Mild myofiber degeneration/regeneration (e.g.,

diaphragm, quadriceps, pectoral, biceps femoris); electron microscopy revealed

intracellular edema of endothelial cells and infiltration of macrophages and

monocytes. Both Type I and Type II fibers affected. Effects were reversible

within 30 days following cessation of dosing.

Nervous System (≥ 100 mg/kg): Peripheral neuropathy such as slight axonal

degeneration of the sciatic nerve.

Kidney (≥ 10 mg/kg): Increased kidney weight; vacuolar degeneration/

regeneration of renal cortical tubular epithelium; cytoplasmic bodies observed

upon electron microscopy. Effects were reversible.

GI Tract (≥ 20 mg/kg): Cecal changes (dilatation and increased weight)

attributable to changes in enterobacterial flora typical of prolonged antibiotic

treatment. Effects were reversible after an 8-week recovery phase.

Dog/ Beagle

2 weeks;

1, 3, and

6 months

1 to 100

Skeletal Muscle (≥ 10 mg/kg): Reversible myofiber degeneration/ regeneration

(degenerative effects limited to ≤ 0.1% of fibers). CPK/AST/ALT elevations.

Skeletal muscle effects are independent of C

and appear primarily related to

dosing frequency (time between doses) and/or AUC.

Nervous System (≥ 40 mg/kg; based upon 6 months of dosing): Abnormal

patellar reflex, decreased sensory and motor nerve conduction velocities,

minimal microscopic axonal degeneration observed following 6 months of

dosing (at 40 mg/kg/day). In shorter term studies (14 days to 3 months duration),

nerve effects were observed at doses ≥ 75 mg/kg. Moderate to severe clinical

signs (abnormal posture/gait, impaired coordination, inability to stand, sternal

recumbency) and functional (electrophysiology) deficits were evident.

Microscopic effects were detected in peripheral nerves, dorsal ganglia, nerve

roots (including left and right ventral and dorsal roots) and spinal nerves. C

appeared the key determinant for peripheral nerve effects. Recovery of

peripheral nerve function was evident within 3 to 6 months post-dosing

(consistent with the lack of effect upon the neuronal cell body), although

histological changes (dorsal roots, ventral roots and spinal nerves) were evident 6

months after dosing. In all but one case, the axonal degeneration observed in

these tissues was graded as very minimal and described as rare, scattered

vacuoles.

Juvenile

Dog/ Beagle

2 weeks

and 1

month

1 to 150

Skeletal Muscle (≥ 150 mg/kg): Reversible degeneration of skeletal muscle. In

contrast to adult dogs, CPK levels were not increased in juvenile dogs.

Nervous System (≥ 50 mg/kg): Minimal to slight axonal degeneration of

peripheral nerve fiber (sciatic, ulnar) and spinal cord (cervical, thoracic, lumbar,

dorsal nerve root) observed. Peripheral nerve (sciatic) and spinal cord (cervical,

thoracic, lumbar) effects were not reversed following a 4-week recovery phase.

Monkey/

Rhesus

1 month

1 to 10

No effects were observed up to 10 mg/kg, the highest dose tested.

* Daptomycin was administered by bolus IV injection in all studies; one study also investigated administration via 30-minute IV infusion. For

most studies, daptomycin was administered once daily (q24h), except for select investigative studies in which it was also administered on a three

times daily (q8h) regimen.

GI: gastrointestinal; CPK: creatine phosphokinase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; AUC: area under the curve;

: maximum serum concentration following dosing.

Page 55 of 60

Product Monograph of Daptomycin for Injection

Genotoxicity

Daptomycin was not mutagenic or clastogenic in a battery of genotoxicity tests, including the

Ames assay, a mammalian cell gene mutation assay, a test for chromosomal aberrations in

Chinese hamster ovary cells, an in vivo micronucleus assay, an in vitro DNA repair assay, and an

in vivo sister chromatid exchange assay in Chinese hamsters.

Carcinogenicity

Carcinogenicity studies have not been conducted.

Reproduction and Development Toxicity

Reproductive and developmental toxicity studies of daptomycin were conducted in rats (up to

150 mg/kg) and rabbits (up to 75 mg/kg) by once-daily bolus IV injection. Studies were

conducted at daptomycin dose levels up to and including those that caused parental toxicity (see

Repeat-Dose Toxicity Studies).

Daptomycin administration to the F

generation was not associated with any reproductive

toxicity, such as adverse effects on mating, fertility, parturition, and lactation. Further, there

were no findings to suggest that daptomycin treatment of the F

generation resulted in any

developmental toxicities in the F

generation. No test article-related mortality, teratogenic

potential, alterations in growth, or functional toxicities was noted in any of the studies. Effects

on progeny were limited to a slight (~10%), transient decrease in body weight at a dose level of

150 mg/kg in rats; this effect was reversible within 14 days postpartum. No other effects on the

growth, behavior, or reproductive performance of the offspring were noted.

Page 56 of 60

Product Monograph of Daptomycin for Injection

SUPPORTING PRODUCT MONOGRAPHS

CUBICIN

/CUBICIN

RF (Daptomycin for Injection) 500mg/vial Lyophilized Powder

for Solution, Control no #235553, Product Monograph, Sunovion Pharmaceuticals Canada

Inc. (May 15, 2020).

Page 57 of 60

Product Monograph of Daptomycin for Injection

READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE

PATIENT MEDICATION INFORMATION

Pr

Daptomycin for Injection

500 mg/vial

Read this carefully before you start taking Daptomycin for Injection and each time you get a refill. This

leaflet is a summary and will not tell you everything about this drug. Talk to your healthcare

professional about your medical condition and treatment and ask if there is any new information about

Daptomycin for Injection.

What is Daptomycin for Injection used for?

Daptomycin for Injection is used in adults (18 years and older) to treat bacterial infections:

of the skin and soft tissues (e.g. fascia or muscle layers)

in the blood, including certain heart valve infections (native valve, right-sided infective

endocarditis)

Antibacterial drugs like Daptomycin for Injection treat only infections caused by bacteria. They do not

treat viral infections. Although you may feel better early in treatment,

Daptomycin for Injection should be used exactly as directed. Misuse or overuse of

Daptomycin for Injection could lead to growth of bacteria that will not be killed by

Daptomycin for Injection (resistance). This means that Daptomycin for Injection may not work for you

in the future.

How does Daptomycin for Injection work?

Daptomycin for Injection are antibiotics. They work by killing certain bacteria that cause your infection.

What are the ingredients in Daptomycin for Injection?

Medicinal ingredients: Daptomycin

Non-medicinal ingredients: Sodium hydroxide

Daptomycin for Injection comes in the following dosage forms:

Lyophilized powder for solution available as 500 mg/20 mL

Do not use Daptomycin for Injection if:

you are allergic to daptomycin.

To help avoid side effects and ensure proper use, talk to your healthcare professional before you

take Daptomycin for Injection. Talk about any health conditions or problems you may have,

including if you:

have kidney or severe liver problems.

have high blood levels of creatine phosphokinase (CPK).

are pregnant, or planning on becoming pregnant.

are breastfeeding or plan to breastfeed. Breastfeeding should be stopped during treatment with

Daptomycin for Injection.

are allergic to any antibiotics or other drugs.

are taking other medications (see The following may interact with Daptomycin for Injection).

have any questions about your treatment, both before and during treatment.

Page 58 of 60

Product Monograph of Daptomycin for Injection

Other warnings you should know about:

Stop taking Daptomycin for Injection and contact your doctor right away if you:

have severe or lasting diarrhea (bloody or watery) with or without

fever.

stomach pain or tenderness.

You may have Clostridium difficile colitis (bowel inflammation).

Tell your healthcare professional about all the medicines you take, including any drugs, vitamins,

minerals, natural supplements or alternative medicines.

The following may interact with Daptomycin for Injection:

Drugs that lower cholesterol (HMG-CoA reductase inhibitors also known as “statins” such as

atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin)

Tobramycin (another antibiotic)

Blood thinners (warfarin)

How to take Daptomycin for Injection:

Daptomycin for Injection will be given intravenously (injected into a vein) by a doctor or nurse in a

hospital or clinical setting.

Usual dose:

Serious skin infections: The usual adult dose is 4 mg for every kg of body weight. Your dose will be given

either as an injection over a 2-minute period or by infusion over a 30-minute period every 24 hours for 7 to

14 days.

Bacterial infections in the blood, including certain heart valve infections: The usual adult dose is 6 mg for

every kg of body weight. Your dose will be given either as an injection over a 2-minute period or by

infusion over a 30-minute period every 24 hours for 10 to 56 days.

Use in children: Daptomycin for Injection is not recommended for use in patients under the age of 18

years.

Overdose:

If you think you have taken too much Daptomycin for Injection, contact your

healthcare professional, hospital emergency department or regional poison control centre

immediately, even if there are no symptoms.

What are possible side effects from using Daptomycin for Injection?

These are not all the possible side effects you may feel when taking Daptomycin for Injection. If you

experience any side effects not listed here, contact your healthcare professional.

Common side effects may include:

headache or dizziness.

diarrhea or constipation.

nausea or vomiting.

rash or itching.

difficulty sleeping.

Page 59 of 60

Product Monograph of Daptomycin for Injection

Serious side effects and what to do about them

Symptom / effect

Talk to your healthcare professional

Stop taking drug

and get immediate

medical help

Only if severe

In all cases

UNCOMMON

A serious allergic reaction with

symptoms such as:

shortness of breath,

difficulty swallowing.

hives, itching, drug rash,

blister-like sores.

swelling of the mouth,

throat, lips and limbs

(angioedema).

Pain in the hands and feet with

symptoms such as:

burning, "pins and

needles", numbness.

muscle pain, weakness or

tiredness (myopathy).

Irregular heartbeat

Kidney problems with symptoms

such as:

reduced kidney function,

kidney failure.

increased urination,

bloody urine.

lower back pain, pressure

in the bladder.

fatigue and nausea.

Fever or rash

VERY RARE

Respiratory problems with

symptoms such as:

fever, cough, shortness of

breath or difficulty

breathing (eosinophilic

pneumonia).

Inflammation of the

lungs (organizing

pneumonia)

Page 60 of 60

Product Monograph of Daptomycin for Injection

If you have a troublesome symptom or side effect that is not listed here or becomes bad enough to

interfere with your daily activities, talk to your healthcare professional.

Reporting Side Effects

You can report any suspected side effects associated with the use of health products

to Health Canada by:

Visiting the Web page on Adverse Reaction Reporting:

https://www.canada.ca/en/health-canada/services/drugs-health-

products/medeffect-canada/adverse-reaction-reporting.html

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need information about how to manage

your side effects. The Canada Vigilance Program does not provide medical advice.

Storage:

Daptomycin for Injection vials containing lyophilized powder should be stored at 2ºC to 8ºC.

Reconstituted solutions are to be used immediately or refrigerated (2ºC to 8ºC) and used within

72 hours, then discarded. Health Care professionals should refer to the Product Monograph for

more details.

Keep out of reach and sight of children.

If you want more information about Daptomycin for Injection:

Talk to your healthcare professional

Find this document plus the full product monograph, prepared for health professionals by visiting

the Health Canada website at: https://health-products.canada.ca/dpd-bdpp/index-eng.jsp or by

calling the sponsor Accord Healthcare Inc. at 1-866-296-0354.

This leaflet was prepared by:

Accord Healthcare Inc.

3535 boul. St. Charles Suite 704

Kirkland, QC, H9H 5B9

Canada

Last Revised: August 31, 2020

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