Daptomycin for Injection Rf (Eugia Pharma) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Daptomycin for Injection RF (daptomycin for injection) is indicated for the following infections in adults:

Complicated skin and skin structure infections (cSSSI) caused by susceptible strains of the following Gram-positive microorganisms: Staphylococcus aureus (including 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 RF is not indicated for the treatment of pneumonia.

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

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Daptomycin for Injection RF and other antibacterial drugs, Daptomycin for Injection RF 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):

Daptomycin for Injection RF is indicated for the following infections in pediatric patients (aged 1 to 17 years):

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

Staphylococcus aureus bloodstream infections (bacteremia) caused by methicillin-susceptible and methicillin-resistant strains.

The safety and effectiveness of daptomycin in the treatment of cSSSI and S. aureus bloodstream infections (bacteremia) have been established in the age groups 1 to 17 years of age. Use of daptomycin in these age groups is supported by evidence from adequate and well-controlled studies in adults, with additional data from pharmacokinetic (PK) studies in pediatric patients, and from safety, efficacy and PK studies in pediatric patients with cSSSI and S. aureus bloodstream infections.

Safety and effectiveness in pediatric patients below the age of one year have not been established. Daptomycin for Injection RF is not recommended in pediatric patients younger than one year of age due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs.

The dosage regimen for daptomycin in pediatric patients with renal impairment has not been established.

Daptomycin has not been studied in pediatric patients with other bacterial infections.

CONTRAINDICATIONS

Daptomycin for Injection RF is contraindicated in patients with known hypersensitivity to

daptomycin.

WARNINGS AND PRECAUTIONS

General

Daptomycin for Injection RF must be reconstituted only with either Sterile Water for Injection or Bacteriostatic Water for Injection. (see Reconstitution)

Daptomycin for Injection RF should not be used in conjunction with ReadyMED® elastomeric infusion pumps. Stability studies of daptomycin solutions stored in ReadyMed elastometric infusion pumps identified an impurity (2 mercaptobenzothiazole) leaching from this pump into daptomycin solutions (see reconstitution).

Daptomycin for Injection RF is inactive against Gram-negative bacteria.

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

The safety and efficacy of daptomycin 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)

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 for Injection RF should undergo medical evaluation. If DRESS and/or TIN are suspected, Daptomycin for Injection RF 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 RF 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 adult 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%) 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 RF 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 Daptomycin for Injection RF therapy in patients with increased baseline CPK as these patients may be at increased risk of further increases of CPK during Daptomycin for Injection RF therapy. If Daptomycin for Injection RF 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 RF 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 adult 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 adult 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 adult 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

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 adult 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 adult 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 RF due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs (see INDICATIONS AND CLINICAL USE, Pediatrics, DETAILED PHARMACOLOGY, Animal Pharmacology and TOXICOLOGY).

Renal

The safety and efficacy of daptomycin in patients with severe renal impairment (creatinine clearance < 30 mL/min) have not been established. Daptomycin for Injection RF 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 adult 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 adult 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).

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

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

In the adult 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).

The dosage regimen for daptomycin in pediatric patients with renal impairment has not been established.

If DRESS and/or TIN are suspected, Daptomycin for Injection RF 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 be instituted as clinically indicated, as surgical intervention may be required in certain severe cases (see ADVERSE REACTIONS).

Respiratory

Community-Acquired Pneumonia

In adult 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 in the treatment of community-acquired pneumonia in patients experiencing these adverse events (see INDICATIONS AND CLINICAL USE). Daptomycin’s activity in vitro is inhibited by the presence of pulmonary surfactant.

Eosinophilic Pneumonia

Eosinophilic pneumonia has been reported in patients receiving 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 RF should undergo prompt medical evaluation, and Daptomycin for Injection RF 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 RF 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 RF 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 effectiveness of daptomycin in the treatment of cSSSI and S. aureus bloodstream infections (bacteremia) have been established in the age groups 1 to 17 years of age. Use of daptomycin in these age groups is supported by evidence from adequate and well-controlled studies in adults, with additional data from pharmacokinetic (PK) studies in pediatric patients, and from safety, efficacy and PK studies in pediatric patients with cSSSI and S. aureus bloodstream infections.

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

Geriatrics (≥ 65 years of age): In the adult 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 RF 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 RF therapy in patients with increased baseline CPK as these patients may be at increased risk of further increases of CPK during Daptomycin for Injection RF therapy. If Daptomycin for Injection RF 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 in patients with severe renal impairment (creatinine clearance <30 mL/min) have not been established.

The dosage regimen for daptomycin in pediatric patients with renal impairment has not been established.

Neuropathy

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

Warfarin

As experience with the concomitant administration of daptomycin and warfarin is limited, anticoagulant activity in patients receiving Daptomycin for Injection RF and warfarin should be

monitored for the first several days after initiating therapy with Daptomycin for Injection.

ADVERSE REACTIONS

Daptomycin for injection containing arginine hydrochloride has not been studied in clinical trials. The treatment-emergent adverse reaction profile of Daptomycin for Injection containing arginine hydrochloride is expected to be similar to that of Daptomycin for Injection arginine hydrochloride-free formulation. The active ingredient in Daptomycin for Injection containing arginine hydrochloride is the same as that in Daptomycin for Injection arginine hydrochloride-free.

Adverse Drug Reaction Overview

Adults

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 adult Phase 3, double-blind, controlled complicated skin and skin structure infection (cSSSI) trials. In the randomized, comparative, open-label adult 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 adult Phase 1, 2 and 3 clinical studies were described as mild or moderate in intensity.

In the adult 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 adult 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 adult 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 adult 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 in Adults

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

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

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

¹ This table includes Adverse Events from both cSSSI Phase 3 trials. The first trial was conducted in the U.S. and South Africa, the second in Europe, South Africa, Australia and Israel

² Safety population includes all subjects who received at least one dose of daptomycin or comparator according to treatment actually received during the trials ³ Comparators included vancomycin (1 g IV q12h), which was used in patients with known or suspected penicillin allergy or with 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.

Additional adverse events that occurred in < 1 to 2% of patients in either daptomycin (4 mg/kg) or comparator treatment groups in the adult 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 adult 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 Adult Phase 3 cSSSI Studies (Population: Safety)

Less Common Clinical Trial Adverse Drug Reactions (<1%) in Two Adult 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 are as follows:

Body as a Whole: fatigue, weakness, rigors, discomfort, tremor, flushing, hypersensitivity Blood/Lymphatic System: leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased international normalized ratio (INR)

Cardiovascular System: supraventricular arrhythmia

Dermatologic System: eczema

Digestive System: abdominal distension, flatulence, stomatitis, jaundice, increased serum lactate dehydrogenase

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

Musculoskeletal System: myalgia, muscle cramps, muscle weakness, osteomyelitis Nervous System: vertigo, mental status change, paraesthesia Special Senses: taste disturbance, eye irritation Reproductive System and Breast Disorders: vaginitis

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

In the two adult 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, 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 adult cSSSI trials.

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

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

In the adult 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 in Adults

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

The rates of the most common treatment emergent adverse events irrespective of causality and organized by body system observed in the adult Staphylococcus aureus

bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) trial are displayed in Table 4.

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

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

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

c NOS: Not Otherwise Specified

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

The most common possibly or probably drug-related treatment emergent adverse events, organized by body system, observed in the adult 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 Adult Phase 3 SAB/SAIE Study (Population: Safety)

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

The following events, not included above in Table 5, were reported as possibly or probably drug- related in the adult 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

Abnormal Hematologic and Clinical Chemistry Findings in the Adult SAB/SAIE Trial In the adult 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 adult 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 Adult SAB/SAIE Study

* 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

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.

Complicated Skin and Skin Structure Infection (cSSSI) Trial in Pediatric Patients

The safety of daptomycin was evaluated in one cSSSI clinical trial which included 256 pediatric patients (1 to 17 years of age) treated with intravenous daptomycin and 133 patients treated with comparator agents. Patients were given age-dependent doses once daily for a treatment period of up to 14 days (median treatment period was 3 days). The doses given by age group were as follows: 10 mg/kg for 1 to <2 years, 9 mg/kg for 2 to 6 years, 7 mg/kg for 7 to 11 years and 5

mg/kg for 12 to 17 years of age. Patients treated with daptomycin were 51% male, 49% female and 46% Caucasian and 32% Asian.

In the pediatric cSSSI study, daptomycin was discontinued in 7/256 (2.7%) patients due to an adverse reaction, while comparator was discontinued in 7/133 (5.3%) patients.

Most Common Clinical Trial Adverse Drug Reactions in the Pediatric cSSSI Trial

The rates of the most common adverse events, organized by body system, observed in pediatric patients with cSSSI are displayed in Table 8.

Table 8. Incidence (%) of Adverse Events that Occurred in ≥2% of Pediatric Patients in the daptomycin Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the Pediatric cSSSI Trial

*Comparators included intravenous therapy with either vancomycin, clindamycin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin, or cloxacillin)

The safety profile in the clinical trial of cSSSI pediatric patients was similar to that observed in the cSSSI adult trials.

Staphylococcus aureus Bacteremia Trial in Pediatric Patients

The safety of daptomycin was evaluated in one S. aureus bacteremia clinical trial which treated 55 pediatric patients with intravenous daptomycin and 26 patients with comparator agents. Patients were given age-dependent doses once daily for a treatment period of up to 42 days (mean duration of IV treatment was 12 days). The doses by age group were as follows: 12 mg/kg for 1 to <6 years, 9 mg/kg for 7 to 11 years and 7 mg/kg for 12 to 17 years of age. Patients treated with daptomycin were 69% male and 31% female. No patients 1 to <2 years of age were enrolled.

In the bacteremia study, daptomycin was discontinued in 3/55 (5.5%) patients due to an adverse reaction, while comparator was discontinued in 2/26 (7.7%) patients.

Most Common Clinical Trial Adverse Drug Reactions in the Pediatric Bacteremia Trial

The rates of the most common adverse events, organized by body system, observed in pediatric patients with bacteremia are displayed in Table 9.

Table 9. Incidence (%) of Adverse Events that Occurred in ≥5% of Pediatric Patients in the daptomycin Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the Pediatric Bacteremia Trial

*Comparators included intravenous therapy with either vancomycin, cefazolin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin, or cloxacillin)

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 (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 adult patients taking one of these medications at the same time as daptomycin. It is recommended that other medications associated with myopathy should, if possible, be temporarily discontinued during treatment with Daptomycin for Injection RF 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 RF is co-administered with any other medicinal product known to reduce renal filtration.

Drug-Drug Interactions

Daptomycin for injection containing arginine hydrochloride has not been studied in drug-drug interaction studies. The active ingredient in Daptomycin for Injection containing arginine hydrochloride is the same as that in Daptomycin for Injection arginine hydrochloride-free formulation. Therefore, differences in drug-drug interactions between Daptomycin for Injection containing arginine hydrochloride and Daptomycin for Injection arginine hydrochloride-free are not expected.

Drug-drug interaction studies were performed in adults with Daptomycin and other drugs that are likely to either be co-administered or associated with overlapping toxicity as shown in Table 10.

Table 10. Established or Potential Drug-Drug Interactions with Daptomycin for Injection

CT: Clinical Trial

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Clinically relevant plasma levels of daptomycin have been observed to cause a significant concentration-dependent false prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay. The possibility of an erroneously elevated PT/INR result due to interaction with a recombinant thromboplastin reagent may be minimized by drawing specimens for PT or INR testing near the time of trough plasma concentrations of daptomycin. However, sufficient daptomycin levels may be present at trough to cause interaction.

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

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

DOSAGE AND ADMINISTRATION

Adults

Complicated Skin and Skin Structure Infections: Daptomycin for Injection RF (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 RF 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 RF for more than 28 days.

Clinical studies in adult 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).

Clinical studies have not been conducted with Daptomycin for Injection containing arginine hydrochloride.

Dosing and Administration Considerations

General

• Daptomycin for Injection RF 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 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 RF 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 11.

Table 11. Recommended Dosage of Daptomycin for Injection RF 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 11).

Patients with Creatinine Clearance < 30 mL/min

Daptomycin for Injection RF 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 for Injection RF have not been established in patients with severe renal impairment (creatinine clearance < 30 mL/min).

The dose interval adjustment guidance presented below in Table 12 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 RF 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 12. Dosage Adjustment of Daptomycin for Injection RF in Adult* Patients with Severe Renal Impairment (creatinine clearance < 30 mL/min)

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

Patients with Hepatic Insufficiency

No dose adjustment is necessary when administering Daptomycin for Injection RF 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

Complicated Skin and Skin Structure Infections:

Table 13. Recommended Dosage of Daptomycin for Injection RF in Pediatric Patients (aged 1 to 17 years) with cSSSI, based on Age

*Recommended dosage is for pediatric patients (1 to 17 years of age) with normal renal function. Dosage adjustment for pediatric patients with renal impairment has not been established.

Staphylococcus aureus Bloodstream Infections (Bacteremia):

Table 14. Recommended Dosage of Daptomycin for Injection RF in Pediatric Patients (aged 1 to 17 years) with S. aureus Bacteremia based on Age

*Recommended dosage is for pediatric patients (1 to 17 years of age) with normal renal function. Dosage adjustment for pediatric patients with renal impairment has not been established.

Dosing and Administration Considerations

• Unlike in adults, do NOT administer Daptomycin for Injection RF by injection over a two (2) minute period to pediatric patients.
• Administer Daptomycin for Injection RF to pediatric patients intravenously by infusion over a 30-or 60-minute period, based on age:
• Pediatric Patients 7 to 17 years of age: Administer Daptomycin for Injection RF intravenously by infusion over a 30-min period. The appropriate volume of reconstituted Daptomycin for Injection RF (concentration of 50 mg/mL) should be further diluted into a 50 mL intravenous infusion bag containing 0.9% sodium chloride injection. The infusion rate should be maintained at 1.67 mL/minute over the 30-minute period.
• Pediatric Patients 1 to 6 years of age: Administer Daptomycin for Injection RF intravenously by infusion over a 60-minute period. The appropriate volume of reconstituted Daptomycin for Injection RF (concentration of 50 mg/mL) should be further diluted into an intravenous infusion bag containing 25 mL of 0.9% sodium chloride injection. The infusion rate should be maintained at 0.42 mL/minute over the 60-minute period.

Reconstitution

Daptomycin for Injection RF must be reconstituted ONLY with either Sterile Water for Injection or Bacteriostatic Water for Injection (see Reconstitution).

Daptomycin for Injection RF must be reconstituted within the vial only with either Sterile Water for Injection or Bacteriostatic Water for Injection.

Do NOT use saline based diluents for the reconstitution in the vial because this will result in a hyperosmotic solution that may result in infusion site reactions if the reconstituted product is

administered as an intravenous injection over a period of 2 minutes.

Daptomycin for Injection RF is supplied in single-dose vials containing 500 mg daptomycin as a sterile, lyophilized powder. The contents of a Daptomycin for Injection RF 500 mg vial should be reconstituted with 10 mL of either Sterile Water for Injection or Bacteriostatic Water 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

Remove the polypropylene flip-off cap from the Daptomycin for Injection RF vial to expose the central portion of the rubber stopper.

1. 1. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow it to dry. After cleaning, the rubber stopper should not be touched or allowed to touch any other surface.
2. 2. Transfer 10 mL of Sterile Water for Injection or Bacteriostatic Water for Injection through the center of the rubber stopper into the Daptomycin for Injection RF vial. Use a beveled sterile transfer needle that is 21 gauge or smaller in diameter, pointing the transfer needle toward the wall of the vial.
3. 3. Rotate or swirl the vial to dissolve the contents for a few minutes, as needed, to obtain a completely reconstituted solution.
4. 4. Slowly remove the reconstituted liquid containing daptomycin (50 mg/mL) from the vial using a beveled sterile needle that is 21 gauge or smaller in diameter.

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 RF range in colour from pale yellow to light brown.

Daptomycin for Injection RF 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 RF vials are for single-use only.

For IV injection over a period of 2 minutes:

Reconstitute Daptomycin for Injection, as directed above, to a concentration of 50 mg/mL with 10 mL of either Sterile Water for Injection or Bacteriostatic Water for Injection.

For IV infusion over a period of 30 minutes:

Reconstitute Daptomycin for Injection, as directed above, with 10 mL of either Sterile Water for Injection or Bacteriostatic Water for Injection to a concentration of 50 mg/mL. Further dilute into a 50 mL IV infusion bag containing 0.9% sodium chloride for injection to a final concentration in the range of 1 to 14 mg/mL (typically 10 mg/mL). Refer to Table 15 for allowable in-use storage following reconstitution.

Examples of Daptomycin for Injection RF Concentrations for Sample Dose to be Delivered

*Typical IV bag volume.

†Daptomycin is dosed by mg/kg

Because Daptomycin for Injection RF does not contain any preservative or bacteriostatic agent, aseptic technique must be used during preparation for administration. Table 15 below provides in-use storage conditions for Daptomycin for Injection RF in acceptable IV diluents. The listed shelf-life of reconstituted and diluted solutions of Daptomycin for Injection RF should not be exceeded. Unused portions of Daptomycin for Injection RF should be discarded.

Table 15 In-Use Storage Conditions for Daptomycin for Injection RF Once Reconstituted in Acceptable IV Diluents

¹It is recommended that the solution be used within 1 day due to the possibility of microbial contamination during reconstitution.

²It is recommended that the solution be used within 3 days due to the possibility of microbial contamination during reconstitution.

³In-use periods are not cumulative, reconstituted solution may be stored for the given time period in the vial or for the given time period in the syringe or for the given time period in the IV bag.

Compatible Intravenous Solutions

Daptomycin for Injection RF is chemically and physically compatible with Sterile Water for Injection, Bacteriostatic Water for Injection and 0.9% sodium chloride injection for injection. See DOSAGE AND ADMINISTRATION, Reconstitution section above for information on solutions recommended for use in the reconstitution or dilution of Daptomycin for Injection.

Daptomycin for Injection RF is NOT compatible with glucose (dextrose) containing diluents.

Because only limited data are available on the compatibility of Daptomycin for Injection RF with other IV substances, additives and other medications should not be added to Daptomycin for Injection RF single-dose vials or infusion bags, or infused simultaneously with Daptomycin for Injection RF through the same IV line. If the same IV line is used for sequential infusion of different drugs, the line should be flushed with a compatible intravenous solution before and after infusion with Daptomycin for Injection RF. No other product than the approved diluent should be added to the Daptomycin for Injection RF vial or infusion bag.

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

OVERDOSAGE

For management of a suspected drug overdose, contact your regional poison control centre.

In the event of overdosage, supportive care is advised with maintenance of glomerular filtration. 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.

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 16.

Table 16. Mean Daptomycin Pharmacokinetic Parameters in Healthy Adult Volunteers at Steady-State

^a AUC_0-24: area under the concentration-time curve from 0 to 24 hours; t½: terminal elimination half-life ; Vss: volume of distribution at steady- state; CLT: plasma clearance; Cmax: maximum plasma concentration (total drug) ^b Doses of daptomycin in excess of 6 mg/kg have not been approved

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

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

Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional pharmacokinetics in the approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure (AUC and Cmax) was demonstrated in healthy adult 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 adult volunteers over a 2-minute period at doses of 4 and 6 mg/kg, the mean (SD) daptomycin steady-state AUC0-tau values were 475 (71) and 701 (82) µg^*h/mL, respectively. The mean (SD) steady-state Cmax values were 63 (11) and 92 (18) µg/mL, respectively.

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

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

In clinical studies, mean serum protein binding in adult subjects with creatinine clearance (CLCR) ≥ 30 mL/min was comparable to that observed in healthy adult 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 adult 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 adult subjects using radio labelled daptomycin, approximately 78% of the administered dose was recovered from urine based on total radioactivity (approximately 52% of the dose based on microbiologically active concentrations) and 5.7% of the dose was recovered from feces (collected for up to nine days) based on total radioactivity.

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

Pharmacokinetic studies with Daptomycin for Injection containing arginine hydrochloride have not been conducted. The active ingredient in Daptomycin for Injection containing arginine hydochloirde is the same as that in Daptomycin for Injection arginine hydrochloride-free formulation. Pharmacokinetic parameters of Daptomycin for Injection containing arginine hydrochloride are expected to be similar to those of Daptomycin for Injection arginine hydrochloride-free.

Special Populations and Conditions

Pediatrics: The pharmacokinetics of daptomycin in pediatric subjects was evaluated in 3 single- dose pharmacokinetic studies. In general, body weight-normalized total body clearance in pediatric patients was higher than in adults and increased with a decrease of age, whereas elimination half-life tends to decrease with a decrease of age. Body weight-normalized total body clearance and elimination half-life of daptomycin in children 2 to 6 years of age were similar at different doses.

A study was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in pediatric patients (1 to 17 years old, inclusive) with cSSSI caused by Gram-positive pathogens. Patients were enrolled into 4 age groups and intravenous daptomycin doses of 5 to 10 mg/kg once daily were administered. Following administration of multiple doses, daptomycin exposure (AUCss and Cmax,ss) was similar across different age groups after dose adjustment based on body weight and age (Table 17).

Table 17. Mean (SD) Daptomycin Population Pharmacokinetic Parameters in cSSSI Pediatric Populations

AUCss: area under the concentration-time curve at steady-state; t½: terminal elimination half-life; Vss: volume of distribution at steady-state; CLT: plasma clearance; Cmax: maximum plasma concentration at steady-state (total drug).

*Mean is calculated from N=2

A study was conducted to assess the safety, efficacy and pharmacokinetics of daptomycin in pediatric patients with S. aureus bacteremia. Patients were enrolled into 3 age groups and intravenous doses of 7 to 12 mg/kg once daily were administered. Following administration of multiple doses, daptomycin exposure (AUCss and Cmax,ss) was similar across different age groups after dose adjustment based on body weight and age (Table 18).

Table 18. Mean (SD) of Daptomycin Pharmacokinetics in Bacteremia Pediatric Patients

AUCss: area under the concentration-time curve at steady-state; t½: terminal elimination half-life; Vss: volume of distribution at steady-state; CLT: plasma clearance; Cmax: maximum plasma concentration at steady-state (total drug).

No patients 1 to <2 years of age were enrolled in the study. Simulation using a population pharmacokinetic model demonstrated that the AUCss of daptomycin in pediatric patients 1 to <2 years of age receiving daptomycin 12 mg/kg once daily would be comparable to adult patients receiving 6 mg/kg once daily.

Pharmacokinetic studies with Daptomycin for Injection containing arginine hydrochloride have not been conducted. The active ingredient in Daptomycin for Injection containing arginine hydochloirde is the same as that in Daptomycin for Injection arginine hydrochloride-free formulation. Pharmacokinetic parameters of Daptomycin for Injection containing arginine hydrochloride are expected to be similar to those of Daptomycin for Injection arginine hydrochloride-free.

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

Gender: No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when administering Daptomycin for Injection RF.

Hepatic Insufficiency: The pharmacokinetics of daptomycin were evaluated in 10 adult subjects with moderate hepatic impairment (Child-Pugh Class B) and compared with healthy adult 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 RF to patients with mild to moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic insufficiency have not been evaluated.

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

Population derived pharmacokinetic parameters were determined for adult patients with cSSSI and healthy non-infected adult 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 (CLT) was reduced and the systemic exposure (AUC_0-∞) was increased with decreasing renal function (see Table 19). The mean AUC_0-∞ was not markedly different for subjects and patients with creatinine clearance (CL_CR) 30-80 mL/min as compared to those with normal renal function (CL_CR > 80 mL/min). The mean AUC_0-∞ 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 AUC_0-∞ was 3-times higher than that observed in individuals with normal renal function.

The mean C_max ranged from 59.6 to 69.6 µg/mL in subjects with CL_CR ≥ 30 mL/min, while those with CL_CR < 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 RF should be administered following the completion of hemodialysis on hemodialysis days (see DOSAGE AND ADMINISTRATION).

Table 19. Daptomycin Population Pharmacokinetic Parameters Following a Single 30- Minute IV Infusion of 4 mg/kg of daptomycin to Adult Patients with Complicated Skin and Skin Structure Infections (cSSSI) and Healthy Volunteers with Varying Degrees of Renal Function

CL_CR: creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; Vss: volume of distribution at steady-state; CAPD: continuous ambulatory peritoneal dialysis

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

A second population analysis was conducted to determine pharmacokinetic parameters at steady-state in adult SAB/SAIE patients (Table 20). Patients (N=108) received 6 mg/kg q24h of daptomycin 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 CL_CR > 80 mL/min. In the two patients with CL_CR < 30 mL/min, pharmacokinetic parameters were similar to those with moderate renal impairment. Mean Cmax values ranged from 80 to 114 μg/mL in patients with moderate to mild renal impairment and were similar to those of normal subjects. In SAB/SAIE patients, the overall mean volume of distribution at steady-state (V_ss) 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 RF should be administered following the completion of hemodialysis on hemodialysis days (see DOSAGE AND ADMINISTRATION).

Table 20. Daptomycin Population Pharmacokinetic Parameters at Steady-State in Adult SAB/SAIE Patients Dosed with 6 mg/kg of daptomycin with Varying Degrees of Renal Function

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 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/m²] and 6 extremely obese (BMI ≥ 40 kg/m²) adult 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 adult subjects and 23% lower in extremely obese adult subjects compared with non-obese controls. The AUC0-∞ of daptomycin increased approximately 30% in moderately obese and 31% in extremely obese adult subjects compared with non-obese controls. In the adult complicated skin and skin structure infection trials (cSSSI), 8 adult 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 for Injection RF is warranted in obese patients based solely on weight.

STORAGE AND STABILITY

Store vials containing lyophilized powder at 15°C to 30°C.

For the in-use shelf life of reconstituted and diluted solutions of Daptomycin for Injection, see DOSAGE AND ADMINISTRATION, Reconstitution above.

SPECIAL HANDLING INSTRUCTIONS

For information on reconstitution, see DOSAGE AND ADMINISTRATION above.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Daptomycin for Injection RF is a preservative free, sterile, 500 mg/mL vial, single use vial and approximate pH of solution upon reconstitution and supplied as a pale yellow to light brown lyophilized cake or powder in a clear glass vial (Type-I) and stoppered with grey igloo rubber stopper and sealed with aluminium seal having gray color PP disc.

Daptomycin for Injection RF also contains Arginine Hydrochloride, sodium hydroxide.

Daptomycin for Injection RF available in Pack of 1 vial and 10 Vials in a Carton.

Rubber stopper is not made with natural rubber latex.

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 ε1-lactone

Molecular formula: C₇₂H₁₀₁N₁₇O₂₆ Molecular mass: 1619.7 g/mol Structural formula:

Table 21. Physicochemical properties

CLINICAL TRIALS

Complicated Skin and Skin Structure Infections (cSSSI) in Adults

Study demographics and trial design

The patient demographics and basic trial design for the two pivotal adult cSSSI studies are summarized in Table 22. Adult 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.

Table 22. 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 23 and 24 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 23. Clinical efficacy outcome (MITT population)

a Vancomycin or anti-staphylococcal semi-synthetic penicillins

Table 24. 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 25 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).

Table 25. 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 26.

Table 26. Pooled microbiological success rates (eradication or presumed eradication) by infecting pathogen and patient pre-randomization (ME population)

Complicated Skin and Skin Structure Infections (cSSSI) in Pediatric Patients (1 to 17 years of Age)

The cSSSI pediatric trial was a single prospective multi-center, randomized, comparative trial. A total of 396 pediatric patients aged 1 to 17 years with cSSSI caused by Gram-positive pathogens were enrolled into the study. Patients known to have bacteremia, osteomyelitis, endocarditis, and pneumonia at baseline were excluded. Patients were enrolled in a stepwise approach into four age groups and given age-dependent doses of daptomycin once daily for up to 14 days. The different age groups and doses evaluated were as follows: Adolescents (12 to 17 years) treated with 5 mg/kg of daptomycin (n=113), Children (7 to 11 years) treated with 7 mg/kg of daptomycin (n=113), Children (2 to 6 years) treated with 9 mg/kg of daptomycin (n=125) and Infants (1 to <2) treated with 10 mg/kg of daptomycin (n=45).

Patients were randomized 2:1 to receive daptomycin or a standard of care (SOC) comparator, which included intravenous therapy with either vancomycin, clindamycin, or an anti- staphylococcal semi-synthetic penicillin (nafcillin, oxacillin, or cloxacillin). Patients could switch to oral therapy after clinical improvement was demonstrated (no minimum IV dosing was required).

The primary objective of this study was to evaluate the safety of daptomycin. The clinical outcome was determined by resolution or improvement of symptoms at the End-of-Treatment (EOT), 3 days after the last dose, and at Test-of-Cure (TOC), 7 – 14 days after the last dose. Investigator observed outcomes were verified in blinded fashion. Of the 396 subjects randomized in the study, 389 subjects were treated with daptomycin or comparator and included in the ITT population. Of these, 257 subjects were randomized to the daptomycin group and 132 subjects were randomized to the comparator group. Approximately 95% of subjects switched to oral therapy. The mean day of switch was day 4, and ranged from day 1 to day 14. The clinical success rates determined at 7 – 14 days after last dose of therapy (IV and oral) (TOC visit) were 88% (227/257) for daptomycin and 86% (114/132) for comparator.

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

Study Demographics and Trial Design

The trial design and patient demographics for the adult Staphylococcus aureus bacteremia/ Staphylococcus aureus infective endocarditis (SAB/SAIE) trial are summarized in Table 27 and Table 28.

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 27. 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 28. 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 29.

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 29. 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 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 30.

Table 30. 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 31 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.

Table 31. 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 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%) adult 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).

Staphylococcus aureus Bacteremia (SAB) Trial in Pediatric Patients (1 to 17 years of Age)

The pediatric S. aureus bacteremia study was designed as a prospective multi-center, randomized comparative trial to treat pediatric patients aged 1 to 17 years with bacteremia. Patients known to have endocarditis or pneumonia at baseline were excluded. Patients were enrolled in a stepwise approach into three age groups and given age-dependent doses of daptomycin once daily for up to 42 days. The different age groups and doses evaluated were as follows: Adolescents (12 to 17 years) treated with daptomycin dosed at 7 mg/kg (n=14) once daily, Children (7 to 11 years) treated with daptomycin dosed at 9 mg/kg once daily (n=19) and Children (2 to 6 years) treated with daptomycin dosed at 12 mg/kg once daily (n=22). No patients 1 to <2 years were enrolled.

Patients were randomized 2:1 to receive daptomycin or a standard of care comparator, which included intravenous therapy with vancomycin, semi-synthetic penicillin, first generation cephalosporin or clindamycin. Patients could switch to oral therapy after clinical improvement was demonstrated (no minimum IV dosing was required).

The primary objective of this study was to assess the safety of daptomycin. The clinical outcome was determined by resolution or improvement of symptoms at the Test-of-Cure (TOC) visit, 7 to 14 days after the last dose, which was assessed by the site level Blinded Evaluator.

Of the 82 subjects randomized in the study, 81 subjects were treated with daptomycin or comparator and included in the safety population, and 73 had a proven S. aureus bacteremia at Baseline. Of these, 51 subjects were randomized to the daptomycin group and 22 subjects were

randomized to the comparator group. The mean duration of IV therapy was 12 days, with a range of 1 to 44 days. Forty-eight subjects switched to oral therapy, and the mean duration of oral therapy was 21 days. The clinical success rates determined at 7 to 14 days after last dose of therapy (IV and oral) (TOC visit) were 88% (45/51) for daptomycin and 77% (17/22) for comparator.

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.

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 32). 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 32). 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 32. Summary of Creatine Phosphokinase (CPK) and Aspartate Aminotransferase (AST) Levels in Rats Following Administration of Oral Simvastatin With and Without Intravenous Daptomycin

AST (U/L) Day 13 ^b 99.2 99.3 97.7 121.7^d

Day 27 104.5 (5%)^e 107.1 (8%)^e 121.3 (24%)^e 169.5^d (39%)^{e 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.

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 Cmax value of 417 µg/mL, which is approximately 3-fold less than the Cmax 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 (Cmax and AUCinf values of ≥321 μg/mL and ≥1470 μg•h/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 (Cmax and AUCinf values of 147 μg/mL and 717 μg•h/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 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 Cmax and AUCinf values of 62 μg/mL and 247 μg•h/mL, respectively.

Human Pharmacology

Pharmacodynamics

In a placebo-controlled study in healthy adult 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 in adults, 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 in adults, 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 adult subjects (see Table 16, 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 adult 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. 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 µg/mL. The mean Cmax 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 AUC0-24h in the inflammatory exudate was 318.2 µg⋅hr/mL. Mean plasma elimination half-life was 7.74 hours with mean plasma AUC0-24h of 468.0 µg⋅hr/mL, representing approximately 88% of the mean AUC0-∞ (529.7 µg⋅hr/mL). The penetration of daptomycin into inflammatory exudate, calculated as AUC0-24h exudate/AUC0-24h plasma, was 68.4%.

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

The AUC values on Day 17 appear higher in the low-flux group at 2586 μg x h/mL compared with the high-flux group at 1716 μg x h/mL (Table 33). However, examination of the individual AUC’s of the 4 adult subjects in the low-flux group and 3 adult 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 adult 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 33. Pharmacokinetic Parameters of Daptomycin Following Single (Day 1) and Repeat (3 times/week) Dosing of daptomycin in Adult 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 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. 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 34. 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 35), 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 35. 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 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 36.

Table 36. 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 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.

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 37. 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 37. 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 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.

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 38 below.

Table 38. 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 adult rats and dogs, with effects observed in peripheral nerve at higher dose levels in both species (Table 39). 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.

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

* 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. 1.

   Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial

   Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

2. 2.

   Clinical and Laboratory Standards Institute (CLSI). Performance Standards for

   Antimicrobial Susceptibility Testing; Twenty-seventh Informational Supplement, CLSI document M100-S27, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2017.

3. 3.

   Clinical and Laboratory Standards Institute (CLSI). Performance Standards for

   Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

4. 4.

   CUBICIN® RF (Daptomycin for Injection) Product Monograph, Cubist

   Pharmaceuticals LLC, Last Revised: May 15, 2020. Control No. 235553.