Cubicin™
`(daptomycin for injection)
`Rx only
`To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cubicin
`and other antibacterial drugs, Cubicin should be used only to treat or prevent infections caused
`by bacteria.
`
`DESCRIPTION
`
`Cubicin contains daptomycin, a cyclic lipopeptide antibacterial agent derived from the
`fermentation of Streptomyces roseosporus. The chemical name is N-decanoyl-L-tryptophyl-L-
`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. The chemical structure is:
`
`(CH 2 )8 CH 3
`
`O
`
`HN
`
`CONH 2
`O
`
`NH
`
`NH
`
`HN
`
`O
`CO 2 H
`
`NH 2
`
`O
`
`NH 2
`
`O
`
`NH
`
`O
`
`HN
`
`NH
`
`O
`
`O
`
`O
`
`HN
`
`HO 2 C
`
`HN
`
`NH
`
`HO
`
`O
`
`O
`
`O
`
`NH
`
`O
`
`HN
`
`O
`
`NH
`
`HO 2 C
`
`HN
`
`O
`
`O
`
`HO 2 C
`
`The empirical formula is C72H101N17O26; the molecular weight is 1620.67. Cubicin is supplied as
`a sterile, preservative-free, pale yellow to light brown, lyophilized cake containing
`approximately 900 mg/g of daptomycin for intravenous use following reconstitution with 0.9%
`sodium chloride injection. The only inactive ingredient is sodium hydroxide which is used in
`minimal quantities for pH adjustment. Freshly reconstituted solutions of Cubicin range in color
`from pale yellow to light brown.
`
`CLINICAL PHARMACOLOGY
`
`Pharmacokinetics
`
`The mean (SD) pharmacokinetic parameters of daptomycin on Day 7 following the intravenous
`administration of 4 mg/kg, 6 mg/kg, and 8 mg/kg q24h to healthy young adults (mean age 35.8
`years) are summarized in Table 1.
`
`1
`2
`3
`4
`5
`6
`7
`
`8
`
`9
`10
`11
`12
`
`13
`14
`15
`16
`17
`18
`19
`
`20
`
`21
`
`22
`23
`24
`
`1
`
`AMNEAL EX. 1004
`
`

`

`9/12/03
`
`25
`
`Table 1. Mean (SD) Daptomycin Pharmacokinetic Parameters in Healthy Volunteers on Day 7
`
`Dose
`mg/kg
`
`Cmax
`(µg/mL)
`57.8
`(3.0)
`
`98.6
`(12)
`
`133
`(13.5)
`
`*
`
`Tmax
`(h)
`0.8
`(0.5, 1.0)
`
`0.5
`(0.5,1.0)
`
`0.5
`(0.5,1.0)
`
`AUC0-24
`(µg*h/mL)
`494
`(75)
`
`747
`(91)
`
`1130
`(117)
`
`t1/2
`(h)
`8.1
`(1.0)
`
`8.9
`(1.3)
`
`9.0
`(1.2)
`
`4
`(n=6)
`6
`(n=6)
`8
`(n=6)
`*Median (minimum, maximum)
`Cmax = Maximum plasma concentration; Tmax = Time to Cmax; AUC0-24 = Area under concentration-time curve from 0
`to 24 hours; t½ = Terminal elimination half-life; Vd = Apparent volume of distribution; CLT = Systemic clearance;
`CLR = renal clearance; Ae24 = Percent of dose recovered in urine over 24 hours as unchanged daptomycin following
`the first dose.
`Daptomycin pharmacokinetics are nearly linear and time-independent at doses up to 6 mg/kg
`administered once daily for 7 days. Steady-state concentrations are achieved by the third daily
`dose. The mean (SD) steady-state trough concentrations (Days 4 to 8) attained following
`administration of 4, 6, and 8 mg/kg q24h are 5.9 (1.6), 9.4 (2.5) and 14.9 (2.9) µg/mL,
`respectively.
`
`Vd
`(L/kg)
`0.096
`(0.009)
`
`0.104
`(0.013)
`
`0.092
`(0.012)
`
`CLT
`(mL/h/kg)
`8.3
`(1.3)
`
`CLR
`(mL/h/kg)
`4.8 (1.3)
`
`8.1
`(1.0)
`
`7.2
`(0.8)
`
`4.4
`(0.3)
`
`3.7 (0.5)
`
`Ae24
`%
`53.0
`(10.8)
`
`47.4
`(11.5)
`
`52.1
`(5.19)
`
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`
`36
`
`37
`38
`39
`40
`41
`
`42
`43
`44
`45
`46
`47
`
`48
`49
`
`50
`
`51
`52
`53
`
`Distribution
`
`Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a
`concentration-independent manner. The mean serum protein binding of daptomycin was
`approximately 92% in healthy adults after the administration of 4 mg/kg or 6 mg/kg. Serum
`protein binding was not altered as a function of daptomycin concentration, dose, or number of
`doses received.
`
`In clinical studies, mean serum protein binding in subjects with CLCR ≥30 mL/min was
`comparable to that observed in healthy subjects with normal renal function. However, there was
`a trend toward decreasing serum protein binding among subjects with CLCR <30 mL/min
`(87.6%) including hemodialysis patients (85.9%) and CAPD patients (83.5%). The protein
`binding of daptomycin in subjects with hepatic impairment (Child-Pugh B) was similar to
`healthy adult subjects.
`
`The apparent volume of distribution of daptomycin at steady-state in healthy adult subjects was
`approximately 0.09 L/kg.
`
`Metabolism
`
`In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the
`activities of the following human cytochrome (CYP) P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6,
`2E1, and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs
`
`2
`
`AMNEAL EX. 1004
`
`

`

`9/12/03
`
`metabolized by the CYP P450 system. It is unknown whether daptomycin is a substrate of the
`CYP P450 system.
`
`In five healthy young adults after infusion of radiolabeled 14C-daptomycin, the plasma total
`radioactivity was similar to the concentration determined by microbiological assay. Inactive
`metabolites of daptomycin have been detected in the urine, as determined by the difference in
`total radiolabeled concentrations and microbiologically active concentrations. The site of
`metabolism has not been identified.
`
`Excretion
`
`Daptomycin is excreted primarily by the kidney. In a mass balance study of five healthy subjects
`using radiolabeled 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.
`
`Because renal excretion is the primary route of elimination, dosage adjustment is necessary in
`patients with severe renal insufficiency (CLCR < 30 mL/min) (see DOSAGE AND
`ADMINISTRATION).
`
`Special Populations
`
`Renal Insufficiency
`
`Population derived pharmacokinetic parameters were determined for patients with skin and skin
`structure infections and healthy non-infected subjects with varying degrees of renal function
`(n=282). Following the administration of a single 4 mg/kg IV dose of daptomycin, the plasma
`clearance (CLT) was reduced and the systemic exposure (AUC0-∞) was increased with decreasing
`renal function (see Table 2). The mean AUC0-∞ was not markedly different for subjects and
`patients with CLCR 30-80 mL/min as compared to those with normal renal function (CLCR
`>80mL/min). The mean AUC0-∞ values for subjects and patients with CLCR <30 mL/min and
`hemodialysis (dosed post dialysis)/CAPD subjects were approximately 2- and 3-times higher,
`respectively, than the values in individuals with normal renal function. The mean Cmax ranged
`from 59.6 µg/mL to 69.6 µg/mL in subjects with CLCR ≥ 30 mL/min while those with CLCR <30
`mL/min ranged from 41.1 µg/mL to 57.7 µg/mL. In 11 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 CAPD, respectively. The recommended dosing regimen is 4 mg/kg
`once every 24 hours for patients with CLCR ≥ 30 mL/min and 4 mg/kg once every 48 hours for
`CLCR <30 mL/min, including those on hemodialysis and CAPD. Daptomycin should be
`administered following the completion of hemodialysis on hemodialysis days (see DOSAGE
`AND ADMINISTRATION).
`
`54
`55
`
`56
`57
`58
`59
`60
`
`61
`
`62
`63
`64
`65
`66
`
`67
`68
`69
`
`70
`
`71
`
`72
`73
`74
`75
`76
`77
`78
`79
`80
`81
`82
`83
`84
`85
`86
`87
`88
`
`3
`
`AMNEAL EX. 1004
`
`

`

`9/12/03
`
`89
`90
`91
`
`Table 2. Mean (SD) Daptomycin Population Pharmacokinetic Parameters Following a Single 30-Minute
`Intravenous Infusion of 4 mg/kg to Infected Patients and Non-Infected Subjects with Varying Degrees of
`Renal Function
`
`Renal Function
`
`AUC0-∞
`(µg*h/mL)
`417 (155)
`
`t1/2
`(h)
`9.39 (4.74)
`
`Vss
`(L/kg)
`0.13 (0.05)
`
`CLT
`(mL/h/kg)
`10.9 (4.0)
`
`466 (177)
`
`10.75 (8.36)
`
`0.12 (0.05)
`
`9.9 (4.0)
`
`Normal
`(CLCR >80 mL/min) (N=165)
`Mild Renal Impairment
`(CLCR 50-80 mL/min) (N=64)
`Moderate Renal Impairment
`(CLCR 30-<50 mL/min) (N=24)
`Severe Renal Impairment
`(CLCR <30 mL/min) (N=8)
`3.7 (1.9)
`0.15 (0.04)
`29.81 (6.13)
`1244 (374)
` Hemodialysis and CAPD (N=21)
`Note: CLCR = Creatinine clearance estimated using the Cockroft-Gault equation with actual body weight.
`Hepatic Insufficiency
`
`560 (258)
`
`925 (467)
`
`14.70
`(10.50)
`
`27.83
`(14.85)
`
`0.15 (0.06)
`
`8.5 (3.4)
`
`0.20 (0.15)
`
`5.9 (3.9)
`
`The pharmacokinetics of daptomycin were evaluated in 10 subjects with moderate hepatic
`impairment (Child-Pugh Class B) and compared with healthy volunteers (n=9) matched for
`gender, age and weight. The pharmacokinetics of daptomycin were not altered in subjects with
`moderate hepatic impairment. No dosage adjustment is warranted when administering
`daptomycin to patients with mild to moderate hepatic impairment. The pharmacokinetics of
`daptomycin in patients with severe hepatic insufficiency have not been evaluated.
`
`Gender
`
`No clinically significant gender-related differences in daptomycin pharmacokinetics have been
`observed between healthy male and female subjects. No dosage adjustment is warranted based
`on gender when administering daptomycin.
`
`Geriatric
`
`The pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects (≥ 75 years of
`age) and 11 healthy young matched controls (18-30 years of age). Following administration of a
`single intravenous 4 mg/kg dose, the mean total clearance of daptomycin was reduced
`approximately 35% and the mean AUC0-∞ increased approximately 58% in elderly subjects
`compared to young healthy subjects. There were no differences in Cmax. No dosage adjustment is
`warranted for elderly patients with normal (for age) renal function.
`
` Obesity
`
`The pharmacokinetics of daptomycin were evaluated in six moderately obese (Body Mass Index
`[BMI] 25-39.9 kg/m2) and six extremely obese (BMI ≥40 kg/m2) subjects and controls matched
`for age, sex, and renal function. Following administration of a single intravenous 4 mg/kg dose
`
`4
`
`92
`93
`
`94
`95
`96
`97
`98
`99
`
`100
`
`101
`102
`103
`
`104
`
`105
`106
`107
`108
`109
`110
`
`111
`
`112
`113
`114
`
`AMNEAL EX. 1004
`
`

`

`9/12/03
`
`115
`116
`117
`118
`119
`120
`
`121
`
`122
`123
`
`124
`
`125
`126
`
`127
`
`128
`129
`130
`131
`132
`
`133
`
`134
`135
`136
`137
`138
`139
`140
`
`141
`
`142
`143
`144
`145
`
`146
`
`147
`148
`149
`150
`
`based on total body weight, the plasma clearance of daptomycin increased approximately 18% in
`moderately obese subjects and 46% in extremely obese subjects compared with non-obese
`controls. The AUC0-∞ of daptomycin increased approximately 30% in moderately obese and 31%
`in extremely obese subjects compared with non-obese controls. The differences were most likely
`due to differences in the renal clearance of daptomycin. No dosage adjustment of daptomycin is
`warranted in obese subjects.
`
`Pediatric
`
`The pharmacokinetics of daptomycin in pediatric populations (<18 years of age) have not been
`established.
`
`Drug-Drug Interactions
`
`Drug-drug interaction studies were performed with daptomycin and other drugs that are likely to
`either be co-administered or associated with overlapping toxicity.
`
`Aztreonam
`
`In a study in which 15 healthy adult subjects received a single dose of daptomycin IV 6 mg/kg,
`aztreonam 1,000 mg IV, and both in combination, the Cmax and AUC0-∞ of daptomycin were not
`significantly altered by aztreonam; the Cmax and AUC0-∞ of aztreonam were also not significantly
`altered by daptomycin. No dosage adjustment of either antibiotic is warranted when co-
`administered.
`
`Tobramycin
`
`In a study in which 6 healthy adult males received a single dose of daptomycin IV 2 mg/kg,
`tobramycin IV 1 mg/kg, and both in combination, the mean Cmax and AUC0-∞ of daptomycin
`increased 12.7% and 8.7%, respectively, when administered with tobramycin. The mean Cmax
`and AUC0-∞ of tobramycin decreased 10.7% and 6.6%, respectively, when administered with
`daptomycin. None of these differences was statistically significant. The interaction between
`daptomycin and tobramycin with a clinical dose of daptomycin (4 mg/kg) is unknown. Caution is
`warranted when daptomycin is co-administered with tobramycin.
`
`Warfarin
`
`In 16 healthy subjects, concomitant administration of daptomycin 6 mg/kg once daily for 5 days
`followed by a single oral dose of warfarin (25 mg) had no significant effect on the
`pharmacokinetics of either drug and did not significantly alter the INR (International Normalized
`Ratio). (see PRECAUTIONS, Drug Interactions)
`
`Simvastatin
`
`In 20 healthy subjects on a stable daily dose of simvastatin 40 mg, administration of daptomycin
`IV 4 mg/kg once daily for 14 days (n=10) was not associated with a higher incidence of adverse
`events than subjects receiving placebo once daily (n=10) (see PRECAUTIONS, Drug
`Interactions).
`
`5
`
`AMNEAL EX. 1004
`
`

`

`151
`
`152
`153
`154
`155
`
`156
`
`157
`158
`159
`160
`161
`162
`
`163
`164
`165
`
`166
`167
`168
`169
`
`170
`
`171
`172
`173
`174
`
`175
`
`176
`177
`178
`179
`180
`181
`182
`183
`184
`185
`
`9/12/03
`
`Probenecid
`
`Concomitant administration of probenecid (500 mg four times daily) and a single dose of
`daptomycin IV 4 mg/kg did not significantly alter the Cmax and AUC0-∞ of daptomycin. No
`dosage adjustment of daptomycin is warranted when daptomycin is co-administered with
`probenecid.
`
`MICROBIOLOGY
`
`Daptomycin is an antibacterial agent of a new class of antibiotics, the cyclic lipopeptides.
`Daptomycin is a natural product which has clinical utility in the treatment of infections caused
`by aerobic Gram-positive bacteria. The in vitro spectrum of activity of daptomycin encompasses
`most clinically relevant Gram-positive pathogenic bacteria. Daptomycin retains potency against
`antibiotic resistant Gram-positive bacteria including isolates resistant to methicillin, vancomycin,
`and linezolid.
`
`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 using broth dilution methodology.
`
`In vitro studies have demonstrated additive or indifferent interactions of daptomycin with other
`antibiotics. Antagonism, as determined by kill curve studies, has not been observed. In vitro
`synergistic interactions occurred with aminoglycosides and β-lactam antibiotics against some
`isolates of staphylococci and enterococci, including some MRSA isolates.
`
`Mechanism of Action
`
`The mechanism of action of daptomycin is distinct from any other antibiotic. Daptomycin binds
`to bacterial membranes and causes a rapid depolarization of membrane potential. The loss of
`membrane potential leads to inhibition of protein, DNA, and RNA synthesis, which results in
`bacterial cell death.
`
`Resistance
`
`Mechanisms of Resistance
`At this time, no mechanism of resistance to daptomycin has been identified.
`Currently, there are no known transferable elements that confer resistance to
`daptomycin.
`Cross Resistance
`Cross-resistance has not been observed with any other class of antibiotic.
`
`Other
`
`The emergence of resistance to daptomycin occurred in 2 of more than 1000
`(<0.2%) infected subjects across the entire set of Phase 2 and 3 clinical trials. In
`one case, a resistant S. aureus was isolated from a patient in a Phase 2 study who
`
`6
`
`AMNEAL EX. 1004
`
`

`

`186
`187
`188
`189
`190
`191
`
`192
`193
`194
`195
`196
`197
`198
`199
`200
`201
`202
`
`203
`204
`205
`206
`207
`208
`209
`
`210
`211
`212
`213
`
`214
`
`215
`216
`217
`218
`219
`220
`
`221
`
`222
`223
`
`9/12/03
`
`received daptomycin at less than the protocol-specified dose for the initial 5 days
`of therapy. In the second case, a resistant E. faecalis was isolated from a patient
`with an infected chronic decubitus ulcer enrolled in a salvage trial.
`Daptomycin has been shown to be active against most isolates of the following microorganisms
`both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE
`section.
`
`Aerobic and facultative Gram-positive microorganisms:
`Enterococcus faecalis (vancomycin-susceptible strains only)
`Staphylococcus aureus (including methicillin-resistant strains)
`Streptococcus agalactiae
`Streptococcus dysgalactiae subsp. equisimilis
`Streptococcus pyogenes
`The following in vitro data are available, 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 microorganisms has not been established in adequate and
`well-controlled clinical trials.
`
`Aerobic and facultative Gram-positive microorganisms:
`Corynebacterium jeikeium
`Enterococcus faecalis (vancomycin-resistant strains)
`Enterococcus faecium (including vancomycin-resistant strains)
`Staphylococcus epidermidis (including methicillin-resistant strains)
`Staphylococcus haemolyticus
`Susceptibility Testing Methods
`
`Susceptibility testing by dilution methods requires the use of daptomycin susceptibility powder.
`The testing also requires presence of physiological levels of free calcium ions (50 mg/L calcium
`chloride) in Mueller-Hinton broth medium and a minimum of 28 mg/L calcium chloride in
`Mueller-Hinton agar medium.
`
`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 procedure2, 3. Standardized procedures are based on a dilution method
`(broth or agar) or equivalent with standardized inoculum concentrations and standardized
`concentrations of daptomycin powder. The MIC values should be interpreted according to the
`criteria in Table 3.
`
`Diffusion technique
`
`Quantitative methods that require measurement of zone diameters also provide reproducible
`estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized
`
`7
`
`AMNEAL EX. 1004
`
`

`

`224
`225
`226
`
`227
`
`228
`229
`230
`231
`232
`233
`234
`235
`236
`237
`238
`239
`240
`241
`242
`
`243
`
`244
`245
`246
`247
`248
`249
`
`9/12/03
`
`procedure requires the use of standardized inoculum concentrations1, 3. This procedure uses
`paper disks impregnated with 30 µg of daptomycin to test the susceptibility of microorganisms to
`daptomycin. The disk diffusion interpretive criteria are provided in Table 3.
`
`Table 3. Susceptibility Interpretive Criteria for Daptomycin
`
`Pathogen
`
`Minimal inhibitory
`concentration (µg/mL)a
`
`Staphylococcus aureus
`(methicillin-susceptible and
`methicillin-resistant)
`Streptococcus pyogenes,
`Streptococcus agalactiae, and
`Streptococcus dysgalactiae
`subsp. equisimilis
`Enterococcus faecalis
`(vancomycin–susceptible
`only)
`
`S
`≤1
`
`≤1
`
`≤4
`
`Disk diffusion zone
`Diameter (mm)b
`S
`I
`(c)
`≥16
`
`≥16
`
`(c)
`
`R
`(c)
`
`(c)
`
`I
`(c)
`
`(c)
`
`R
`(c)
`
`(c)
`
`(c)
`
`(c)
`
`≥11
`
`(c)
`
`(c)
`
`a. The MIC interpretive criteria for S. aureus and E. faecalis are applicable only to tests performed by broth
`microdilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L; the MIC interpretive
`criteria for Streptococcus spp. other than S. pneumoniae are applicable only to tests performed by broth
`microdilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L, 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. The zone diameter interpretive criteria for Streptococcus spp. other than S. pneumoniae are applicable only to
`tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood and incubated in
`5% CO2 at 35ºC for 20 to 24 hours.
`c. The current absence of 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 further testing.
`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.
`
`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 4. 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.
`
`8
`
`AMNEAL EX. 1004
`
`

`

`9/12/03
`
`250
`251
`
`Table 4. Acceptable Quality Control Ranges for Daptomycin to be Used in Validation of Susceptibility Test
`Results
`
`QC Strain
`
`Enterococcus faecalis
`ATCC 29212
`Staphylococcus aureus
`ATCC 29213
`Staphylococcus aureus
`ATCC 25923
`Streptococcus pneumoniae
`ATCC 49619 c
`
`Acceptable Quality Control Ranges
`Minimum Inhibitory
`Disk Diffusion
`Concentration
`(Zone Diameters in mm) b
`(MIC in µg/mL)a
`1-8
`
`Not applicable
`
`0.25-1
`
`Not applicable
`
`Not applicable
`
`0.06-0.5 d
`
`18-23
`
`19-26 e
`
`252
`253
`254
`255
`256
`257
`258
`259
`260
`261
`262
`263
`264
`
`265
`266
`267
`268
`269
`270
`271
`
`272
`
`273
`274
`275
`276
`
`277
`278
`
`a. Quality control ranges reflect MICs obtained when Mueller-Hinton broth is supplemented with calcium to a
`final concentration of 50 mg/L.
`b. Some lots of Mueller-Hinton agar are deficient in calcium and give small zone diameters.
`c. This organism may be used for validation of susceptibility test results when testing Streptococcus spp. other
`than S. pneumoniae.
`d. This quality control range for S. pneumoniae is applicable only to tests performed by broth microdilution using
`cation adjusted Mueller-Hinton broth with 2-5% lysed horse blood inoculated with a direct colony suspension
`and incubated in ambient air at 35ºC for 20 to 24 hours.
`e. This quality control zone diameter range is applicable only to tests performed using Mueller-Hinton agar
`supplemented with 5% defibrinated sheep blood inoculated with a direct colony suspension and incubated in
`5% CO2 at 35ºC for 20 to 24 hours.
`INDICATIONS AND USAGE
`
`Cubicin (daptomycin for injection) is indicated for the treatment of complicated skin and skin
`structure infections caused by susceptible strains of the following Gram-positive microorganisms
`(see also DOSAGE AND ADMINISTRATION): Staphylococcus aureus (including
`methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus
`dysgalactiae subsp. equisimilis and Enterococcus faecalis (vancomycin-susceptible strains only).
`Combination therapy may be clinically indicated if the documented or presumed pathogens
`include Gram-negative or anaerobic organisms. (see CLINICAL STUDIES).
`
`Daptomycin is not indicated for the treatment of pneumonia.
`
`Appropriate specimens for microbiological examination should be obtained in order to isolate
`and identify the causative pathogens and to determine their susceptibility to daptomycin.
`Empiric therapy may be initiated while awaiting test results. Antimicrobial therapy should be
`adjusted as needed based upon test results.
`
`To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cubicin
`and other antibacterial drugs, Cubicin should be used only to treat or prevent infections that are
`
`9
`
`AMNEAL EX. 1004
`
`

`

`279
`280
`281
`282
`
`283
`
`284
`
`285
`
`286
`287
`288
`289
`
`290
`291
`292
`
`293
`294
`295
`296
`297
`
`298
`
`299
`
`300
`301
`
`302
`303
`304
`
`305
`
`306
`307
`308
`309
`310
`
`311
`312
`313
`
`9/12/03
`
`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.
`
`CONTRAINDICATIONS
`
`Cubicin is contraindicated in patients with known hypersensitivity to daptomycin.
`
`WARNINGS
`
`Pseudomembranous colitis has been reported with nearly all antibacterial agents, including
`daptomycin, and may range in severity from mild to life-threatening. Therefore it is important to
`consider this diagnosis in patients who present with diarrhea subsequent to the administration of
`any antibacterial agent.
`
`Treatment with antibacterial agents alters the normal flora of the colon and may permit
`overgrowth of clostridia. Studies indicated that a toxin produced by Clostridium difficile is a
`primary cause of “antibiotic-associated colitis.”
`
`If a diagnosis of pseudomembranous colitis has been established, appropriate therapeutic
`measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug
`discontinuation alone. In moderate to severe cases, consideration should be given to
`management with fluids and electrolytes, protein supplementation, and treatment with an
`antibacterial agent clinically effective against C. difficile.
`
`PRECAUTIONS
`
`General
`
`The use of antibiotics may promote the overgrowth of nonsusceptible organisms. Should
`superinfection occur during therapy, appropriate measures should be taken.
`
`Prescribing Cubicin in the absence of a proven or strongly suspected bacterial infection or a
`prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
`development of drug-resistant bacteria.
`
`Skeletal Muscle
`
`In Phase 3 complicated skin and skin structure infection (cSSSI) trials, elevations in serum
`creatine phosphokinase (CPK) were reported as clinical adverse events in 15/534 (2.8%)
`daptomycin-treated patients, compared to 10/558 (1.8%) comparator-treated patients. Skeletal
`muscle effects associated with daptomycin were observed in animals (see ANIMAL
`PHARMACOLOGY).
`
`Patients receiving Cubicin should be monitored for the development of muscle pain or weakness,
`particularly of the distal extremities. CPK levels should be monitored weekly in patients who
`receive Cubicin. Patients who develop unexplained elevations in CPK while receiving
`
`10
`
`AMNEAL EX. 1004
`
`

`

`9/12/03
`
`314
`315
`316
`317
`318
`319
`
`320
`321
`322
`323
`324
`325
`326
`327
`328
`329
`330
`331
`332
`333
`334
`335
`
`336
`
`337
`338
`339
`340
`341
`342
`343
`
`344
`
`345
`346
`347
`348
`349
`350
`351
`
`daptomycin should be monitored more frequently. Among patients with abnormal CPK (>500
`U/L) at baseline, 2/19 (10.5%) treated with Cubicin and 4/24 (16.7%) treated with comparator
`developed further increases in CPK while on therapy. In this same population, no patients
`developed myopathy. Daptomycin-treated patients with baseline CPK >500 U/L (n=19) did not
`experience an increased incidence of CPK elevations or myopathy relative to those treated with
`comparator (n=24).
`
`Cubicin should be discontinued in patients with unexplained signs and symptoms of myopathy in
`conjunction with CPK elevation >1000 U/L (~5X ULN), or in patients without reported
`symptoms who have marked elevations in CPK (>10X ULN). In addition, consideration should
`be given to temporarily suspending agents associated with rhabdomyolysis, such as HMG-CoA
`reductase inhibitors, in patients receiving Cubicin.
`In a small number of patients in Phase 1 and Phase 2 studies, administration of Cubicin was
`associated with decreases in nerve conduction velocity and with adverse events (e.g.,
`paresthesias, Bell’s palsy) possibly reflective of peripheral or cranial neuropathy. Nerve
`conduction deficits were also detected in a similar number of comparator subjects in these
`studies. In Phase 3 cSSSI and CAP studies 7/989 (0.7%) daptomycin-treated patients and 7/1018
`(0.7%) comparator-treated patients experienced paresthesias. New or worsening peripheral
`neuropathy was not diagnosed in any of these patients. In animals, effects of daptomycin on
`peripheral nerve were observed (see ANIMAL PHARMACOLOGY). Therefore, physicians
`should be alert to the possibility of signs and symptoms of neuropathy in patients receiving
`Cubicin.
`Drug Interactions
`
`Warfarin
`
`Concomitant administration of daptomycin (6 mg/kg once every 24 hours for 5 days) and
`warfarin (25 mg single oral dose) had no significant effect on the pharmacokinetics of either
`drug and the INR was not significantly altered. As experience with the concomitant
`administration of daptomycin and warfarin is limited to volunteer studies, anticoagulant activity
`in patients receiving daptomycin and warfarin should be monitored for the first several days after
`initiating therapy with Cubicin (see CLINICAL PHARMACOLOGY, Drug-Drug
`Interactions).
`
`HMG CoA Reductase Inhibitors
`
`Inhibitors of HMG-CoA reductase may cause myopathy, which is manifested as muscle pain or
`weakness associated with elevated levels of CPK. There were no reports of skeletal myopathy in
`a placebo-controlled Phase I trial in which 10 healthy subjects on stable simvastatin therapy were
`treated concurrently with daptomycin (4 mg/kg once every 24 hours) for 14 days. Experience
`with co-administration of HMG-CoA reductase inhibitors and Cubicin in patients is limited,
`therefore, consideration should be given to temporarily suspending use of HMG-CoA reductase
`inhibitors in patients receiving Cubicin.
`
`11
`
`AMNEAL EX. 1004
`
`

`

`9/12/03
`
`Drug-Laboratory Test Interactions
`
`There are no reported drug-laboratory test interactions.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`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, 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.
`
`Daptomycin did not affect the fertility or reproductive performance of male and female rats when
`administered intravenously at doses up to 150 mg/kg/day, which is approximately 9 times the
`estimated human exposure level based upon AUCs.
`
`Pregnancy
`
`Teratogenic effects: Pregnancy Category B
`
`Reproductive and teratology studies performed in rats and rabbits at doses of up to 75 mg/kg, 3
`and 6 times the human dose respectively on a body surface area basis, have revealed no evidence
`of harm to the fetus due to Cubicin. There are, however, no adequate and well controlled studies
`in pregnant women. Because animal reproduction studies are not always predictive of human
`response, this drug should be used during pregnancy only if clearly needed.
`
`Nursing Mothers
`
`It is not known if daptomycin is excreted in human milk. Caution should be exercised when
`Cubicin is administered to nursing women.
`
`Pediatric Use
`
`Safety and efficacy of Cubicin in patients under the age of 18 have not been established.
`
`Geriatric Use
`
`Of the 534 patients treated with Cubicin in Phase 3 controlled clinical trials of complicated skin
`and skin structure infection, 27.0% were 65 years of age or older and 12.4% were 75 years or
`older. In the two Phase 3 clinical studies in patients with cSSSI, 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 in both cSSSI studies.
`
`352
`
`353
`
`354
`
`355
`356
`357
`358
`359
`360
`
`361
`362
`363
`
`364
`
`365
`
`366
`367
`368
`369
`370
`
`371
`
`372
`373
`
`374
`
`375
`
`376
`
`377
`378
`379
`380
`381
`382
`
`12
`
`AMNEAL EX. 1004
`
`

`

`9/12/03
`
`ANIMAL PHARMACOLOGY
`
`In animals, daptomycin administration has been associated with effects on skeletal muscle with
`no changes in cardiac or smooth muscle. Skeletal muscle effects were characterized by
`degenerative/regenerative changes and variable elevations in CPK. No fibrosis or
`rhabdomyolysis was evident in repeat dose studies up to the highest doses tested in rats (150
`mg/kg/day) and dogs (100 mg/kg/day). 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 (3.5 times the
`human AUC), with some clinical improvement noted within 2 weeks of the cessation of dosing.
`However, at 75 mg/kg daily 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 for 2 weeks, minimal residual histological changes were noted at 6
`months after cessation of dosing. However, recovery of peripheral nerve function was evident.
`
`Tissue distribution studies in rats have shown that daptomycin is retained in the kidney, but does
`not appear to penetrate across the blood-brain barrier following single and multiple doses.
`
`ADVERSE REAC