Imported and Distributed by:

Oryx Pharmaceuticals Inc., a subsidiary of Arrow Pharmaceuticals Inc. 6500 Kitimat Road Mississauga, Ontario Canada, L5N 2B8

Date of Preparation:

September 20, 2007

Submission Control Nos: 102320 & 104227

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 10 DRUG INTERACTIONS 19 DOSAGE AND ADMINISTRATION 22 OVERDOSAGE 25 ACTION AND CLINICAL PHARMACOLOGY 26 STORAGE AND STABILITY 30 SPECIAL HANDLING INSTRUCTIONS 30 DOSAGE FORMS, COMPOSITION AND PACKAGING 30

PART II: SCIENTIFIC INFORMATION 31

PHARMACEUTICAL INFORMATION 31 CLINICAL TRIALS 32 DETAILED PHARMACOLOGY 42 MICROBIOLOGY 47 TOXICOLOGY 50 REFERENCES 54

PART III: CONSUMER INFORMATION. 55

CUBICIN(r)

(Daptomycin for Injection)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

CUBICIN(r)

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

WARNINGS AND PRECAUTIONS

General

The use of antibiotics may promote the overgrowth of non-susceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken. Prescribing CUBICIN(r) (daptomycin for injection) in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

CUBICIN(r)

is inactive against Gram-negative bacteria.

Because daptomycin activity is inhibited in the presence of pulmonary surfactant, CUBICIN(r) is not indicated for use in pneumonia. The safety and efficacy of CUBICIN(r) has not been established in patients with co-morbidities of meningitis, musculopathies, neuropathies or severe renal impairment.

Immune System

Hypersensitivity

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

Persisting or Relapsing Staphylococcus aureus Infection

Patients with persisting or relapsing Staphylococcus aureus infection or poor clinical response should have repeat blood cultures. If a culture is positive for Staphylococcus aureus, MIC susceptibility testing of the isolate should be performed using a standardized procedure, as well as diagnostic evaluation to rule out sequestered foci of infection. Appropriate surgical intervention (e.g., debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of a change in antibiotic regimen may be required. In the Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) trial, failure of treatment due to persisting or relapsing Staphylococcus aureus infections was assessed in 19/120 (15.8%) CUBICIN(r)-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 CUBICIN(r)-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) 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). Therefore, in patients receiving CUBICIN(r) it is recommended that:

• Patients should be monitored regularly for any signs and symptoms that might represent myopathy including muscle pain or weakness, particularly in the distal extremities.

• Any patient who develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days.

• Plasma CPK levels should be measured at baseline and at least once weekly during therapy in all patients.

• Patients who develop unexplained elevations in CPK should be monitored more frequently than once weekly.

• Consideration should be given prior to initiation of CUBICIN(r) therapy in patients with increased baseline CPK as these patients may be at increased risk of further increases of CPK

during CUBICIN(r) therapy. If CUBICIN(r) 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 insufficiency, and those who recently received or are currently taking other medications known to be associated with myopathy (e.g., HMG-CoA reductase inhibitors).

CUBICIN(r) CUBICIN(r)

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

.

CUBICIN(r), CUBICIN(r)

In Phase 3 complicated skin and skin structure infection trials (cSSSI) of

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

-treated patients, compared to 10/558 (1.8%) comparator-treated patients.

In the Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) trial, at a dose of 6 mg/kg, elevations in CPK were reported as clinical adverse events in 8/120 (6.7%) of CUBICIN(r)- treated patients, compared to 1/116 (< 1%) of the comparator-treated patients. There were a total of 11 patients who experienced CPK elevations to above 500 U/L (2.5 times ULN). Of these 11 patients, 5 had recent prior or concomitant treatment with an HMG-CoA reductase inhibitor. Three (2.6%) CUBICIN(r)-treated patients, including 1 with trauma associated with heroin overdose, 1 with spinal cord compression and 1 with concomitant HMG-CoA reductase inhibitor, had an elevation in CPK > 500 U/L with associated musculoskeletal symptoms. None of the patients in the comparator group had an elevation of CPK > 500 U/L with associated musculoskeletal symptoms. In a Phase 1 study in healthy volunteers examining doses up to 12 mg/kg q24h of CUBICIN(r) for 14 days, no skeletal muscle effects or CPK elevations were observed.

CUBICIN(r) Part II, DETAILED PHARMACOLOGY, Animal Pharmacology and TOXICOLOGY

Skeletal muscle effects associated with

were observed in animals (see

).

Neurologic

Neuropathy

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

CUBICIN(r)

.

Direct effects on the central nervous system have not been investigated. In a small number of patients in Phase 1 and Phase 2 studies at doses up to 6 mg/kg, administration of CUBICIN(r) was associated with decreases in nerve conduction velocity and with adverse events (e.g., paresthesias, Bell's palsy) possibly reflective of peripheral or cranial neuropathy. In the Staphylococcus aureus bacteremia/ Staphylococcus aureus infective endocarditis (SAB/SAIE) trial, a total of 11/120 (9.2%) CUBICIN(r)-treated patients had treatment-emergent adverse events related to the peripheral nervous system. All of the events were classified as mild to moderate in severity, most were of short duration and resolved during continued treatment with CUBICIN(r) or were likely due to an alternative etiology. In a Phase 1 study in healthy volunteers examining doses up to 12 mg/kg q24h of CUBICIN(r) for 14 days, no evidence of peripheral nerve conduction deficits or symptoms of peripheral neuropathy were observed.

CUBICIN(r) Part II, DETAILED PHARMACOLOGY, Animal Pharmacology and TOXICOLOGY

In animals, effects of

on peripheral nerve were observed (see

).

Renal

CUBICIN(r) CUBICIN(r) 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. DOSAGE AND ADMINISTRATION, Patients with Renal Impairment

The safety and efficacy of

in patients with severe renal insufficiency (creatinine clearance < 30 mL/min) have not been established.

In these patients, a dose adjustment is required (see

). 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 insufficiency (creatinine clearance < 80 mL/min). Consideration should be given to monitoring renal function in patients treated with CUBICIN(r). Renal insufficiency has been reported during treatment with CUBICIN(r) although the relationship to daptomycin remains unclear (see ADVERSE REACTIONS). Caution is advised prior to commencing therapy with CUBICIN(r) in patients who already have some degree of renal insufficiency (creatinine clearance < 80 mL/min). Regular monitoring of renal function is advised during the concomitant administration of potentially nephrotoxic agents, regardless of the patient's underlying renal function. In the Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) trial, at a dose of CUBICIN(r) 6 mg/kg/day, a lower clinical success rate and an increase in serious adverse events were seen in patients with moderately impaired renal function (creatinine clearance 30 to < 50 mL/min).

Carcinogenesis and Mutagenesis

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

Gastrointestinal

Pseudomembranous Colitis

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including CUBICIN(r), and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of any antibacterial agent. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies have indicated that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis." If a diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. 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.

Respiratory

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

Special Populations

Pregnant Women: CUBICIN(r)

No clinical studies have been performed in pregnant women.

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: CUBICIN(r)

It is not known if daptomycin is excreted in human milk. Breastfeeding should be discontinued during treatment with

.

Pediatrics (<18 years of age)CUBICIN(r)

: The safety and efficacy of

in patients under the age of 18 have not been established.

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 CUBICIN(r) in Phase 3 controlled clinical trials of complicated skin and skin structure infection (cSSSI), 27.0% were 65 years of age or older and 12.4% were 75 years or older. Of the 120 patients treated with CUBICIN(r) in the Phase 3 Staphylococcus aureus bacteremia/Staphylococccus aureus infective endocarditis (SAB/SAIE) controlled clinical trial, 25.0% were 65 years of age or older and 15.8% were 75 years or older.

Monitoring and Laboratory Tests

Creatine Phosphokinase (CPK)

Patients should be monitored regularly for any signs and symptoms that might represent myopathy including muscle pain or weakness, particularly in the distal extremities. Any patient who develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days. Plasma CPK levels should be measured at baseline and at least once weekly during CUBICIN(r) therapy in all patients. Patients who develop unexplained elevations in CPK should be monitored more frequently than once weekly. Consideration should be given prior to initiation of CUBICIN(r) therapy in patients with increased baseline CPK as these patients may be at increased risk of further increases of CPK during CUBICIN(r) therapy. If CUBICIN(r) is given, these patients should be monitored more frequently than once weekly.

WARNINGS AND PRECAUTIONS, Musculoskeletal, Myopathy and Creatine Phosphokinase (CPK)

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 insufficiency, and those who recently received or are currently taking other medications known to be associated with myopathy (e.g., HMG-CoA reductase inhibitors) [see

].

Renal

Consideration should be given to monitoring renal function in patients treated with CUBICIN(r). In patients with renal insufficiency (creatinine clearance < 80 mL/min) response to treatment, renal function and creatine phosphokinase (CPK) should be closely monitored. The safety and efficacy of CUBICIN(r) in patients with severe renal insufficiency (creatinine clearance < 30 mL/min) have not been established.

Neuropathy

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

CUBICIN(r)

.

Warfarin

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

DRUG INTERACTIONS

Overview

There is limited experience regarding concomitant administration of CUBICIN(r) (daptomycin for injection) with other medicinal products that may trigger myopathy. However, some cases of marked rises in creatine phosphokinase (CPK) levels and cases of rhabdomyolysis occurred in patients taking one of these medications at the same time as CUBICIN(r). It is recommended that other medications associated with myopathy should, if possible, be temporarily discontinued during treatment with CUBICIN(r) unless the benefits of concomitant administration outweigh the risk. If co-administration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients should be closely monitored for any signs or symptoms that might represent myopathy. Daptomycin is primarily cleared by renal filtration and, therefore, plasma levels may be increased during co-administration with medicinal products that reduce renal filtration (e.g., NSAIDs and COX-2 inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-administration due to additive renal effects. Therefore, caution is advised when CUBICIN(r) is co-administered with any other medicinal product known to reduce renal filtration.

Drug-Drug Interactions

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

Table 8. Established or Potential Drug-Drug Interactions with CUBICIN(r)

CT: Clinical Trial

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Clinically relevant plasma levels of daptomycin have been observed to cause a significant concentration-dependent false prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay. The possibility of an erroneously elevated PT/INR result due to interaction with a recombinant thromboplastin reagent may be minimized by drawing specimens for PT or INR testing near the time of trough plasma concentrations of daptomycin. If confronted with an abnormally high PT/INR result in a patient being treated with CUBICIN(r), consideration should be given for evaluating PT/INR utilizing alternative methods.

DOSAGE AND ADMINISTRATION

Complicated Skin and Skin Structure Infections: (r)

CUBICIN

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

Staphylococcus aureus Bloodstream Infections (Bacteremia) including those with Right- Sided Staphylococcus aureus Infective Endocarditis (Native Valve): CUBICIN(r) 6 mg/kg should be administered over a 30-minute period by IV infusion in 0.9% sodium chloride injection, USP once every 24 hours. Duration of treatment should be based on the treating physician's working diagnosis. In the clinical trial, duration ranged from 10 days to 42 days with an option for an additional 14 days. There are limited safety data for the use of CUBICIN(r) for more than 28 days.

Dosing and Administration Considerations

General

CUBICIN(r) CUBICIN(r)

should not be dosed more frequently than once a day. In Phase 1 and 2 clinical studies, creatine phosphokinase (CPK) elevations appeared to be more frequent when

was dosed more frequently than once daily.

ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions

Clinical studies have shown that dosing adjustments based on age alone, gender, race or obesity are not required (see

).

Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to daptomycin. Empiric therapy may be initiated while awaiting test results. Antimicrobial therapy should be adjusted as needed based upon test results. To reduce the development of drug-resistant bacteria and maintain the effectiveness of CUBICIN(r) and other antibacterial drugs, CUBICIN(r) should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. The recommended dosing schedule for adult patients including those with creatinine clearance

>=

30 mL/min is presented in Table 9.

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

Patients with Renal Impairment

Daptomycin is eliminated primarily by the kidney. No dose adjustment is required in patients whose creatinine clearance is >=30 mL/min (see Table 9).

Patients with Creatinine Clearance < 30 mL/min

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

Clinical efficacy and safety of CUBICIN(r) have not been established in patients with severe renal impairment (creatinine clearance < 30 mL/min). The dose interval adjustment guidance presented below in Table 10 is based on pharmacokinetic modeling data. Response to treatment, renal function and creatine phosphokinase (CPK) should be closely monitored in these patients. Whenever possible, CUBICIN(r) should be administered following the completion of dialysis on dialysis days. The use of high-flux dialysis membranes during 4 hours of hemodialysis may increase the percentage of dose removed compared with low-flux membranes.

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

Patients with Hepatic Insufficiency

No dose adjustment is necessary when administering CUBICIN(r) 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).

Reconstitution

CUBICIN(r) CUBICIN(r)

is supplied in single-use vials containing 500 mg daptomycin as a sterile, lyophilized powder. The contents of a

500 mg vial should be reconstituted with 10 mL of 0.9% sodium chloride for injection. Since no preservative or bacteriostatic agent is present in the product, aseptic technique must be used in preparation of the product.

Procedure

• Prior to reconstitution, remove the CUBICIN(r) vials from refrigeration and allow the product to sit at room temperature for a few minutes. CUBICIN(r) vials do not need to be warmed to room temperature prior to reconstitution.

• Remove the polypropylene flip-off cap from the CUBICIN(r) vial to expose the central portions of the rubber stoppers. Gently tap vial twice on counter to settle/loosen the lyophilized powder cake.

• Using a syringe, slowly transfer the diluent through the center of the rubber stopper into the CUBICIN(r) vial, pointing the transfer needle toward the wall of the vial to prevent excessive foaming. Ensure that the complete daptomycin product is wetted by gently rotating the vial.

• Allow the product to sit undisturbed for approximately 10 minutes at room temperature.

• Gently swirl the CUBICIN(r) 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. Reconstituted CUBICIN(r) should then be further diluted with 0.9% sodium chloride IV infusion (typical volume 50 mL) and infused over 30 minutes. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Freshly reconstituted solutions of CUBICIN(r) range in colour from pale yellow to light brown. Chemical and physical in-use stability on the reconstituted solution in the vial has been demonstrated for 12 hours at 25degC and up to 48 hours if stored under refrigeration (2 to 8degC). Store reconstituted solution for up to 12 hrs at room temperature (15 to 25oC) or up to 48 hrs at 2 to 8oC under normal lighting conditions. Avoid excessive heat. The combined time (vial and infusion bag) at 25degC should not exceed 12 hours (48 hours if refrigerated).

CUBICIN(r)

vials are for single-use only.

Compatible Intravenous Solutions

CUBICIN(r) CUBICIN(r) CUBICIN(r) CUBICIN(r) CUBICIN(r)

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

is not compatible with glucose (dextrose) containing diluents. Because only limited data are available on the compatibility of

with other IV substances, additives or other medications should not be added to

single-use vials or infused simultaneously through the same IV line. 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

.

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

OVERDOSAGE

In the event of overdosage, supportive care is advised with maintenance of glomerular filtration. CUBICIN(r) is slowly cleared from the body by hemodialysis (approximately 15% recovered over 4 hours) or peritoneal dialysis (approximately 11% recovered over 48 hours). The use of high-flux membranes during 4 hours of hemodialysis may increase the percentage of dose removed, as evidenced by the larger decrease in the pre- to post-dose concentrations (41%) compared with low-flux membranes (5 to 7%). A 58-year old male with a history of multiple sclerosis, diabetes and hypertension was administered an accidental single dose of CUBICIN(r) 3 g (43 mg/kg). Twenty-four hours later symptoms of orofacial movements, lip smacking and shoulder shrugging were observed and diagnosed as dyskinesia. CUBICIN(r) was discontinued and the patient was treated with benztropine and lorazepam. The events resolved and therapy was restarted without further incident.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

CUBICIN(r) Part II, MICROBIOLOGY

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

).

Resistance

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

Pharmacokinetics

The mean pharmacokinetic parameters of CUBICIN(r) at steady-state following IV administration of 4 to 12 mg/kg q24h to healthy young adults are summarized in Table 11.

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

min

a

AUC

: area under the concentration-time curve from 0 to 24 hours; t : terminal elimination half-life ,V : volume of distribution at steady-

1/2 ss

state; CLT: plasma clearance; Cmax: maximum plasma concentration (total drug)

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

c

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

Absorption: Daptomycin pharmacokinetics were generally linear and time-independent at doses of 4 to 12 mg/kg q24h. Steady-state trough concentrations were achieved by the third daily dose. The mean (standard deviation) steady-state trough concentrations attained following administration of 4, 6, 8, 10 and 12 mg/kg q24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9) and 13.7 (5.2) mg/mL, respectively. The mean AUC and Cmin (minimum plasma concentration) of daptomycin during once-daily dosing with 6, 8, 10 and 12 mg/kg were dose proportional; however, the mean Cmax (maximum plasma concentration) was slightly less than dose proportional. Total clearance was unchanged across 4 to 12 mg/kg q24h. Distribution: Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The overall mean binding at doses from 4 to 12 mg/kg ranged from 90 to 93%. The apparent volume of distribution (Vd) of daptomycin at steady-state in healthy adult subjects was low, approximately 0.1 L/kg at doses of 4 to 12 mg/kg, consistent with distribution primarily within the extracellular space. Daptomycin penetrates into skin blister fluid and reaches a mean Cmax of 27.6 mg/mL (mean t1/2= hrs). In clinical studies, mean serum protein binding in subjects with creatinine clearance (CLCR) >= 30 mL/min was comparable to that observed in healthy subjects with normal renal function. However, there was a trend toward decreasing serum protein binding among subjects with CLCR < 30 mL/min (87.6%), including hemodialysis patients (85.9%) and continuous ambulatory peritoneal dialysis patients (83.5%). The protein binding of daptomycin in subjects with moderate hepatic impairment (Child-Pugh B) was similar to healthy adult subjects.

Metabolism: In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 (CYP) isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. In in vitro studies, daptomycin was not detectably metabolized by human liver microsomes. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the CYP system. In a separate study, no metabolites were observed in plasma on Day 1 following administration of daptomycin at 6 mg/kg to healthy subjects. Inactive metabolites have been detected in urine, as determined by the difference in total radioactivity concentrations and microbiologically active concentrations. Minor amounts of 3 oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.

Excretion:

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

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

Special Populations and Conditions

PediatricsCUBICIN(r)

: The pharmacokinetics of

in pediatric populations (< 18 years of age) have not been established.

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

Gender: CUBICIN(r) CUBICIN(r)

No clinically significant gender-related differences in

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

.

Hepatic Insufficiency: CUBICIN(r) CUBICIN(r) CUBICIN(r) CUBICIN(r)

The pharmacokinetics of

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

were not altered in subjects with moderate hepatic impairment. No dosage adjustment is warranted when administering

to patients with mild to moderate hepatic impairment. The pharmacokinetics of

in patients with severe hepatic insufficiency have not been evaluated.

Renal Insufficiency 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 CUBICIN(r), the plasma clearance (CLT) was reduced and the systemic exposure (AUC0-[?]) was increased with decreasing renal function (see Table 12). The mean AUC0-[?] was not markedly different for subjects and patients with creatinine clearance (CLCR) 30-80 mL/min as compared to those with normal renal function (CLCR > 80 mL/min). The mean AUC0-[?] for subjects and patients with CLCR < 30 mL/min was approximately 2-times higher than that observed in individuals with normal renal function. For subjects on hemodialysis (dosed post-dialysis)/continuous ambulatory peritoneal dialysis, the mean AUC0-[?] was 3-times higher than that observed in individuals with normal renal function. The mean Cmax ranged from 59.6 to 69.6 ug/mL in subjects with CLCR >= 30 mL/min while those with CLCR < 30 mL/min ranged from 41.1 to 57.7 ug/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 insufficiency, both renal function and creatine phosphokinase (CPK) should be monitored more frequently. CUBICIN(r) should be administered following the completion of hemodialysis on hemodialysis days (see DOSAGE AND ADMINISTRATION).

Table 12. CUBICIN(r) Population Pharmacokinetic Parameters Following a

Single 30-Minute IV Infusion of 4 mg/kg to Patients with Complicated Skin and Skin Structure Infections (cSSSI) and Healthy Volunteers with Varying Degrees of Renal Function

CLCR: creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; Vss: volume of distribution at steady-state;

CAPD: continuous ambulatory peritoneal dialysis

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

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

1/2 ss

T max

min

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

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

A 41% reduction in CUBICIN(r) plasma concentration was achieved using high-flux dialysis membranes, and a 5 to 7% reduction was achieved using low-flux dialysis membranes. Obesity: The pharmacokinetics of CUBICIN(r) were evaluated in 6 moderately obese [Body Mass Index (BMI) 25 to 39.9 kg/m2] and 6 extremely obese (BMI >= 40 kg/m2) subjects and controls matched for age, sex, and renal function. Following administration of a single 4 mg/kg IV dose based on total body weight, the plasma clearance of CUBICIN(r) normalized to total body weight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects compared with non-obese controls. The AUC0-[?] of CUBICIN(r) increased approximately 30% in moderately obese and 31% in extremely obese subjects compared with non-obese controls. In the complicated skin and skin structure infection trials (cSSSI), 8 patients > 150 kg received CUBICIN(r) 4 mg/kg. The highest total dose exposure occurred in one patient weighing 238.6 kg (total exposure 20 900 mg daptomycin over 21 days). No dosage adjustment of CUBICIN(r) is warranted in obese patients based solely on weight.

STORAGE AND STABILITY

Store at 2 to 8oC. Store reconstituted solution for up to 12 hrs at room temperature (15 to 25oC) or up to 48 hrs at 2 to 8oC under normal lighting conditions. Avoid excessive heat.

SPECIAL HANDLING INSTRUCTIONS

For information on reconstitution, see DOSAGE AND ADMINISTRATION above.

DOSAGE FORMS, COMPOSITION AND PACKAGING

CUBICIN(r)

(daptomycin for injection) is supplied as a pale yellow to light brown lyophilized cake in a single-use vial (500 mg/10 mL vial). Available in packages of 10 vials.

CUBICIN(r)

may also contain sodium hydroxide used to adjust pH in trace amounts.

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 e1-lactone Molecular formula: C72H101N17O26 Molecular mass: 1620.67 Structural formula:

HO 2C

NH HN

HO O O

NH

O NH 2

O O

O

O

CONH2 O

H N

O

O H

N (C H2)8CH3

HO 2C O HN O

CO 2H

N H

NH2

HO 2C

Table 14. Physicochemical properties

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 15. 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 clearnace < 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.

Table 15. Summary of Trial Design and Demographics

* 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

Study results

Overall clinical efficacy results are provided in Tables 16 and 17 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 16 Clinical efficacy outcome (MITT population)

a

Vancomycin or anti-staphylococcal semi-synthetic penicillins

Table 17. Clinical efficacy outcome (CE population)

a

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 18 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 CUBICIN(r) or the appropriate comparator drug (vancomycin or an anti-staphylococcal semi-synthetic penicillin).

Table 18. Pooled clinical success rates by infecting pathogen and patient pre- randomization (MITT population)

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 19.

Table 19. Pooled microbiological success rates (eradication or presumed eradication) by infecting pathogen and patient pre-randomization (ME population)

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 20 and Table 21. 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, 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.

Table 20. Trial design in the pivotal SAB/SAIE Study

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

Table 21. Summary of Demographic Characteristics for the SAB/SAIE Study (ITT Population)

a Age category >=75 years is a subset of the category >=65 years.

b

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 22. 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.

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 22. Summary of Entry and Final Diagnostic Subgroups in the SAB/SAIE Trial (ITT Population)

Study Results

The overall success rates at Test of Cure in the ITT population were 44.2% (53/120) in patients treated with CUBICIN(r) 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 CUBICIN(r) 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 23.

Table 23. Success Rates * at Test of Cure in the pivotal SAB/SAIE Trial (ITT Population)

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

a

Comparator: vancomycin (1 g IV q12h) or anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, flucloxacillin; 2 g

IV q4h), each with initial low-dose gentamicin According to the modified Duke criteria

b

According to the modified Duke criteria

c

95% Confidence Interval

d

97.5% Confidence Interval (adjusted for multiplicity)

e

99% Confidence Interval (adjusted for multiplicity)

f

See definitions above.

Table 24 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 CUBICIN(r) and comparator groups.

Table 24. Summary of Success Rates at Test of Cure in the SAB/SAIE Trial by Duration of Treatment and Final Diagnosis (ITT Population)

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 CUBICIN(r) 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%) CUBICIN(r)-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 CUBICIN(r)- 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

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. 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 Cmax 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 25). However, it is noteworthy that following thirteen days of treatment with simvistatin 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 25). 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 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 25. Summary of Creatine Phosphokinase (CPK) and Aspartate Aminotransferase (AST) Levels in Rats Following Administration of Oral Simvastatin With and Without Intravenous Daptomycin

a

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.

b

Values for Day 13 preceded initiation of daptomycin treatment.

c

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

d

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

e

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. 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.

Human Pharmacology

Pharmacodynamics

In a placebo-controlled study in healthy volunteers, there was no evidence that exposure to CUBICIN(r) (daptomycin for injection) at 6 mg/kg IV q24h x 14d caused any meaningful changes in cardiac repolarization as measured by QTcB. In nerve motor function studies, CUBICIN(r) administration did not cause any significant changes in the set of objective measures indicative of neuropathy or myopathy. CUBICIN(r) 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 CUBICIN(r) group (8) compared to the normal saline group (5) reported symptoms of tingling, numbness and weakness. In an ascending dose study, CUBICIN(r) 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 CUBICIN(r) in humans is highly predictable following intravenous administration. Single and multiple doses of CUBICIN(r), 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 CUBICIN(r) in cantharides-induced skin blisters and in plasma were determined over a 24-hour period following a single IV infusion of 4 mg/kg in healthy volunteers. CUBICIN(r) penetrated the inflammatory exudate moderately rapidly, with mean 1- and 2- hour concentrations of 9.4 ug/mL and 14.5 ug/mL, respectively. Tmax in the inflammatory fluid occurred approximately 3 hours later than in plasma (3.7 hours vs. 0.5 hours) with a Cmax of 27.6 ug/mL. The mean Cmax in the plasma was 77.5 ug/mL. The elimination half-life of CUBICIN(r) 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 AUC0-24h in the inflammatory exudate was 318.2 ug *hr/mL. Mean plasma elimination half-life was 7.74 hours with mean plasma AUC0-24h of 468.0 ug *hr/mL, representing approximately 88% of the mean AUC0-[?] (529.7 ug *hr/mL). The penetration of CUBICIN(r) into inflammatory exudate, calculated as AUC0-24h exudate/AUC0-24h plasma, was 68.4%. A study was conducted to evaluate the pharmacokinetics of CUBICIN(r) 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. CUBICIN(r) was administered as an 8 mg/kg loading dose followed by 6 mg/kg 3 times per week. The AUC values on Day 17 appear higher in the low-flux group at 2586 mg x h/mL compared with the high-flux group at 1716 mg x h/mL (Table 26). 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 CUBICIN(r) 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 26: Pharmacokinetic Parameters of CUBICIN(r) Following Single (Day 1) and Repeat (3 times/week) Dosing in Subjects with ESRD

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

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 mg/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.

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, b-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 27. Daptomycin MIC50 and MIC90 for Susceptible Aerobic and Facultative Gram- Positive Bacteria in vitro and in Clinical Infections

The following in vitro data are available (Table 28), 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 28. Daptomycin MIC50 and MIC90 for Susceptible Aerobic and Facultative Gram- Positive Microorganisms in vitro

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. 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 CUBICIN(r) 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 mg/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 29.

Table 29. Susceptibility Interpretive Criteria for Daptomycin

a 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 mg/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 mg/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.

b

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.

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 30. 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 30. Acceptable Quality Control Ranges for Daptomycin to be used in Validation of Susceptibility Test Results

a 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 mg/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 mg/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.

b 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 31 below.

Table 31. Results of Single-Dose Toxicity Studies

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 rats and dogs, with effects observed in peripheral nerve at higher dose levels in both species (Table 32). 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.

Table 32. Summary of Findings on Repeat-Dose Toxicity and Investigative Studies *

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

• Nervous System (>= 100 mg/kg): Peripheral neuropathy such as slight axonal

• Kidney (>= 10 mg/kg): Increased kidney weight; vacuolar degeneration/

• GI Tract (>= 20 mg/kg): Cecal changes (dilatation and increased weight)

• Skeletal Muscle (>= 10 mg/kg): Reversible myofiber degeneration/

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

• Skeletal Muscle (>= 150 mg/kg): Reversible degeneration of skeletal muscle.

• Nervous System (>= 50 mg/kg): Minimal to slight axonal degeneration of

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; Cmax: maximum serum concentration following dosing.

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 F0 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 F0 generation resulted in any developmental toxicities in the F1 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.

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing; sixteenth informational supplement. CLSI Document M100-S16; Wayne, PA. 2006 January.

2. Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial disk susceptibility tests; approved standard--ninth edition. CLSI Document M2-A9; Wayne, PA. 2006 January.

3. Arbeit RD, Maki D, Tally FP, et al. The safey and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. CID 2004; 38:1673-81.

4. Fowler, Jr. VG, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355:653-65.

5. Li JS, Sexton DJ, Mick N et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000; 30:633-38.

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