CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -2 2 7
`
`APPROVED DRAFT LABELING
`
`AMNEAL EX. 1010
`
`AMNEAL EX. 1010
`
`

`

`Q MERCK&CO., INC
`WhitehouseStation, NJ 08889, USA
`XXXXXXX
`
`INTRAVENOUS INFUSION-(not for IV Bolus Injection)
`CANCIDAS”
`
`(caspofungin acetate) FOR INJECTION
`
`DESCRIPTION
`
`CANCIDAS' is a sterile. lyophilized product for intravenous (IV) infusion that contains a semisynthetic
`Iipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea Iozoyensis.
`CANCIDAS is the first of a new class of antifungal drugs (glucan synthesisinhibitors) that inhibit the
`synthesis of B (1, 3)-D--glucan. an integral component of the fungal cell wall
`CANCIDAS
`(caspofungin
`acetate)
`is
`1-[(4R55)- 5--[(2—-aminoethyl)amino}-N2--(10. 12--dimethyl- 1-
`oxotetradecyI)-4-hydroxy-L‘omithine]~5-[(3R)—3-hydroxy—L-ornithine] pneumocandin Bo diacetate (salt).
`In
`addition to the active ingredient caspofungin acetate. CANCIDAS contains the following inactive
`ingredients: sucrose. mannitol. acetic acid. and sodium hydroxide. Caspofungin acetate is a hygroscopic.
`white to off-white powder. It is freely soluble in water and methanol. and slightly soluble in ethanol. The pH
`of a saturated aqueous solution of caspofungin acetate is approximately 6.6. The empirical formula is
`
`CszHagNmOI5~2C2H402 and the formula weightis 1213.42. The structural formula is:
`W321?CH: CH:
`WY?)
`~2CH)CO,H
`0
`
`"13H
`
`CH:
`
`CLINICAL PHARMACOLOGY
`
`Pharmacokinefics
`~Distribution .
`'
`Plasma concentrations of Caspofungin decline in a polyphasic manner following single 1-hour IV
`>_ infusions. A shorttit-phase occurs immediately postinfusion, followed by a B«phase (half-life ms to
`11 hours) that characterizes much of the profile and exhibits clear log-linear behavior from 6 to 48 hours
`postdose during which the plasma concentration decreases 10-fold. An additional. longer half-life phase.
`y—phase. (half-life of 40-50 hours). also occurs. Distn'bution. rather than excretion'or biotransformation; is
`the dominant mechanism influencing plasma clearance. Caspofungin is extensively bound to albumin
`(~97%) and distribution into red blood cells is minimal. Mass balance results showed that approximately
`92% of the administered radioactivity was distributed to tissues by 36 to 48 hours after a single TO—mg
`dose of [3H] caspofungin acetate. ThereIs little excretion or biotransformation of caspofungin during the
`first 30 hours after administration.
`Metabolism
`Caspofungin is slowly metabolized by hydrolysis and N--acetyiation. Caspofungin also undergoes
`spontaneous chemical degradation to an open-ring peptide compound, L-747969. At later time points (5 to
`20 days postdose). there is a low level (3 to 7 picomoleslmg protein. or 0.6 to 1.3% of administered dose)
`
`'Registered trademark of MERCK a. CO., Inc.
`COPYRIGHTQ MERCK & Co. Inc.. 2001
`All rights reserved
`
`1
`
`JAN26 3:30 '
`
`AMNEAL EX. 1010
`
`AMNEAL EX. 1010
`
`

`

`CAN CIDAS9
`(caspofungin acetate)
`
`xxxxxxx
`
`in plasma following single—dose administration of [3chaspofungin
`of covalent binding of radLolabel
`acetate, which may be due to two reactive intermediates formed during the chemical degradation of
`caspofungin to L-747969. Additional metabolism involves hydrolysis into constitutive amino acids and their
`degradates.
`including dihydroxyhomotyrosine and. N-acetyI-dihydroxyhomotyrosine. These two tyrosine
`derivatives are found only in urine, suggesting rapid‘clearance of these derivatives by the kidneys.
`Excretion
`
`In a single-dose radiolabeled pharmacokinetic study, plasma. urine. and feces were collected over
`27 days. Plasma concentrations of radioactivity and of caspofungin were similar during the first 24 to
`48 hours postdose; thereafter drug levels fell more rapidly. Radiolabel remained quantifiable through
`Day 27 whereas caspofungin concentrations fell below the limit of quantitationafter 6 to 8 days postdose.
`After single intravenous administration of [3Hjcaspofungin acetate,-excretion of caspofungin and its
`metabolites in humans were 35% of dose in feces and 41% of dose in urine. A small amount of
`
`caspofungin is excreted unchanged in urine (~ 1.4% of dose). Renal clearance of parent drug is low
`(~0 15 mL/min) and total clearance of caspofunginIs 12 mUmiri
`Special Populations
`.
`_
`'
`Gender
`Plasma concentrations of caspofungin in healthy men and women were similar following a single
`70-mg dose. After 13 daily 50-mg doses. caspofungin plasma concentrations in women were elevated
`slightly (approximately 22% in area under the curve [AUC]) relative to men. No dosage adjustment is
`necessary based on gender.
`Geriatn'c
`
`Plasma concentrations of caspofungin in healthy older men and women (265 years of age) were
`increased slightly (approximately 28% in area under the curve [AUC]) compared to young healthy men
`after a single 70-mg dose of caspofungin. Age is' not a significant determinant of caspofungin
`pharmacokinetics in patients with fungal infections. No dosage adjustment is necessary for the elderly
`(see PRECAUTIONS Geriatric Use).
`Race
`Regression analyses of patient pharmacokinetic data indicated that no clinically significant differences
`in the pharmacokinetics of caspofungin were seen among Caucasians Blacks, and Hispanics. No dosage
`adjustment Is necessary on the basis of race.
`Renal Insufficiency
`In a clinical study of single 70-mg doses. caspofungin pharmacokinetics were similar in volunteers with
`mild renal insufficiency (creatinine clearance 50 to 80 mL/min) and control subjects. Moderate (creatinine
`clearance 31 to 49 mL/min). advanced (creatinine clearance 5 to 30 mL/min), and end‘stage (creatinine
`clearance <10 mUmin and dialysis dependent) renal
`insufficiency moderately increased caspofungin
`plasma concentrations after single-dose administration (range: 30 to 49% for AUC). However. in patients
`with invasive aspergillosis who received multiple daily doses of CANCIDAS 50mg.
`there was no
`significant effect of mild to advanced renal impairment on caspofungin trough concentrations. No dosage
`adjustment
`is necessary for patients with renal
`insufficiency. Caspofungin is not dialyzable,
`thus
`supplementary dosing is not required following hemodialysis.
`Hepatic Insufficiency
`Plasma concentrations of caspofungin alter a single 70—mg dose In patients with mild hepatic
`insufficiency (ChildPugh score 5 to 6) were increased by approximately 55%in AUC compared to healthy
`control subjects.
`In a 14-day multiple-dose study (70 mg on Day1 followed by 50 mg daily thereafter),
`plasma concentrations in pan‘ents with mild hepatic insufficiency were increased modestly (19 to 25% in
`AUC) on Days 7 and 14 relative to healthy control subjects. No dosage adjustment is recommended for
`patients with mild hepatic insufficiency. Patients with moderate hepatic insufficiency (Child-Pugh score 7
`to 9) who received a single 70-mg dose of CANCIDAS had an average plasma caspofungin increase of
`76% in AUC compared to control subjects. A dosage reduction is recommended for patients with
`moderate hepatic insufficiency (see DOSAGE AND ADMINISTRATION). There is no clinical experience in
`patients with severe hepatic insufficiency (Child-Pugh score >9).
`Pediatric Patients
`CANCIDAS has not been adequately studied in patients under 18 years of age.
`
`2
`
`JAN26 3:30
`
`‘
`
`~'
`
`AMNEAL EX. 1010
`
`AMNEAL EX. 1010
`
`

`

`CANClDAS®
`(caspofungin acetate)
`
`MICROBIOLOGY
`
`Mechanism of Action
`
`xxxxxxx
`
`Caspofungin acetate, the active ingredient of CANCIDAS, inhibits the synthesis of B (1,3)-D-glucan, an
`essential component of the cell wall of susceptible filamentous fungi. B (1.3)—D-glucan is not present in
`mammalian cells. Caspofungin has shown activity in regions of active cell growth of the hyphae of
`Aspergi/Ius fumigatus.
`Activity in vitro
`Caspofungin exhibits in vitro activity against Aspergil/us fumigatus, Aspergillus flavus, and Aspergi/Ius
`terreus. Susceptibility testing was performed according to the National Committee for Clinical Laboratory
`Standards
`(NCCLS) proposed method (M38-P). Standardized susceptibility testing methods
`for
`[3 (1,3)-D-glucan synthesis inhibitors have not been established, and results of susceptibility studies do not
`correlate with clinical outcome.
`Activity in vivo
`Caspofungin, administered parenterally to immunocompetent and immunosuppressed rodents, as long
`as 24 hours after disseminated or pulmonary infection with Aspergillus fumigatus, has shown prolonged
`survival, which has not been consistently associated with a reduction in mycological burden.
`Drug Resistance
`in vitro resistance development to caspofungin by Aspergiilus species has not been studied. In limited
`clinical experience, drug resistance in patients with invasive aspergillosis has not been observed. The
`incidence of drug resistance by various clinical isolates of Aspergi/ius species is unknown.
`Drug Interactions
`Studies in vitro and in vivo of caspofungin, in combination with amphotericin B. suggest no antagonism
`of antifungal activity against A. fumigatus. The clinical significance of these results is unknown.
`
`‘
`
`CLINICAL STUDIES
`
`Invasive Aspergillosis
`Sixty-nine patients between the ages of 18 and 80 with invasive aspergillosis were enrolled in an
`open-label, noncomparative study to evaluate the safety, tolerability. and efficacy of CANCIDAS. Enrolled
`patients had previously been refractory to or intolerant of other antifungal therapy(ies). Refractory patients
`were classified as those who had disease progression or failed to improve despite therapy for at least
`7 days with amphotericin B. lipid formulations of amphotericin B. itraconazole. or an investigational azole
`with reported activity against Aspergillus. Intolerance to previous therapy was defined as a doubling of
`creatinine (or creatlnine 22.5 mgIdL while on therapy), other acute reactions. or infusion-related toxicity.
`To be included in the study. patients with pulmonary disease must have had definite (positive tissue
`histopathology or positive culture from tissue obtained by an invasive procedure) or probable (positive
`radiographic or computed tomography evidence with supporting culture from bronchoalveolar lavage or
`sputum, galactomannan enzyme-linked immunosorbent assay, and/or polymerase chain reaction) invasive
`aspergillosis. Patients with extrapulmonary disease had to have definite invasive aspergillosis. The
`definitions were modeled after the Mycoses Study Group Criteria.‘ Patients were administered a single
`70—mg loading dose of CANCIDAS and subsequently dosed with 50 mg daily. The mean duration of
`therapy was 33.7 days. with a range of 1 to 162 days.
`including diagnosis of invasive aspergillosis,
`An independent expert panel evaluated patient data.
`response and tolerability to previous antifungal therapy, treatment course on CANCIDAS, and clinical
`outcome.
`
`A favorable response was defined as either complete resolution (complete response) or clinically
`meaningful
`improvement (partial response) of all signs and symptoms and attributable radiographic
`findings. Stable. nonprogressive disease was considered to be an unfavorable response.
`Among the 69 patients enrolled in the study, 63 met entry diagnostic criteria and had outcome data:
`and of these, 52 patients received treatment for >7 days. Fifty-three (84%) were refractory to previous
`
`I Denning CW. Lee JY. Hostetler JS. et al. NIAID Mycoses Study Group multicenter trial of oral itraoonazole therapy for invasive
`aspergillosis. Am J Med 1994;97:135-144.
`
`3
`
`JAN26 3:30
`
`AMNEAL EX. 1010
`
`AMNEAL EX. 1010
`
`

`

`CANCIDAS®
`(caspofungin acetate)
`
`xxxxxxx
`
`antifungal therapy and 10 (16%) were intolerant. Forty«five patients had pulmonary disease and 18 had
`extrapulmonary disease. Underlying conditions were hematologic malignancy (N=24), allogeneic bone
`marrow transplant or stem cell transplant (N=18). organ transplant (N=8). solid tumor (N=3), or other
`conditions (N=10). All patients in the study received concomitant therapies for their other underlying
`conditions. Eighteen patients received tacrolimus and CANClDAS concomitantly, of whom 8 also received
`mycophenolate mofetil.
`Overall.
`the expert panel determined that 41% (26/63) of patients receiving at least one dose of
`CANClDAS had a favorable response. For those patients who received >7 days of therapy with
`CANClDAS. 50% (26/52) had a favorable response. The favorable response rates for patients who were
`either refractory to or intolerant of previous therapies were 36% (19/53) and 70% (7/10). respectively. The
`response rates among patients with pulmonary disease and extrapulmonary'disease were 47% (21/45)
`and 28% (5/18). respectively. Among patients with extrapulmonary disease. 2 of 8 patients who also had
`definite, probable. or possible CNS involvement had a favorable response. Two of these 8 patients had
`progression of disease and manifested CNS involvement while on therapy.
`There is substantial evidence that CANCIDAS is well
`tolerated and effective for the treatment of
`invasive aspergillosis in patients who are refractory to or intolerant of itraconazole, amphotericin B. and/or
`lipid formulations of amphotericin B. However, the efficacy of CANCIDAS has not been evaluated in
`concurrently controlled clinical studies. with other antifungal therapies.
`
`INDICATIONS AND USAGE
`
`CANCIDAS is indicated for the treatment of invasive aspergillosis in patients who are refractory to or
`intolerant of other
`therapies
`(i.e..
`amphotericin B.
`lipid
`formulations of amphotericin B.
`and/or
`itraconazole).
`CANCIDAS has not been studied as initial therapy for invasive aspergillosis.
`
`CONTRAINDICATIONS
`
`CANCiDAS is contraindicated in patients with hypersensitivity to any component of this product.
`
`WARNINGS
`
`Concomitant use of CANCIDAS with cyclosporine is not recommended unless the potential benefit
`outweighs the potential risk to the patient. In one clinical study, 3of 4 healthy subjects who received
`CANCIDAS 70 mg on Days 1 through 10. and also received two 3 mglkg doses of cyclosporine 12 hours
`apart on Day 10, developed transient elevations of alanine transaminase (ALT) on Day 11 that were 2 to
`3 times the upper limit of normal (ULN).
`In a separate panel of subjects in the same study. 2 of 8 who
`received CANCIDAS 35 mg daily for 3 days and cyclosporine (two 3 mg/kg doses administered 12 hours
`apart) on Day 1 had small increases in ALT (slightly above the ULN) on Day 2. in both groups. elevations
`in aspartate transaminase (AST) paralleled ALT elevations, but were of lesser magnitude (see ADVERSE
`REACTIONS, Laboratory Abnormalities.) Hence. concomitant use of CANCIDAS with cyclosporine is not
`recommended until multiple-dose use in patients is studied.
`a
`
`PRECAUTIONS
`
`General
`
`The efficacy of a 70~mg dose regimen in patients who are not clinically responding to the 50 mg daily
`dose is not known. Limited safety data suggest that an increase In dose to 70 mg daily is well tolerated.
`The safety and efficacy of doses above 70 mg have not been adequately studied.
`The safety information on treatment durations longer than 2 weeks is limited. however. available data
`suggest that CANCIDAS continues to be well
`tolerated with longer courses of therapy (68 patients
`received from 15 to 60 days of therapy. 12 patients received from 61 to 162 days of therapy).
`Drug Interactions
`Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome
`P450 (CYP) system.
`In clinical studies. caspofungin did not induce the CYP3A4 metabolism of other
`
`4
`
`JAN26 3:30
`
`AMNEAL EX. 1010
`
`AMNEAL EX. 1010
`
`

`

`CAN CIDAS’D
`(caspofungin acetate)
`
`xxxxxxx
`
`drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450
`enzymes
`-
`-
`Clinical studies in healthy volunteers show that the pharmacokinetics of CANClDAS are not altered by
`itraconazole.
`amphotericin B mycophenolate or
`tacrolimus. CANClDAS has no effect on the
`pharmacokinetics of itraconazole. amphotericin B, or the active metabolite of mycophenolate.
`CANClDAS reduced the blood AUCMZ of tacrolimus (FK-506, Prografm) by approximately 20%, peak
`blood concentration (Cma‘) by 16%. and 12-hour blood concentration (012,") by 26% in healthy subjects
`when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANClDAS
`70 mg daily as compared to results from a control period in which tacrolimus was administered alone. For
`patients receiving both therapies standard monitoring of tacrolimus blood concentrations and appropriate
`tacrolimus dosage adjustments are recommended
`In two clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of
`caspofungin by approximately 35%. CANClDAS did not increase the plasma levels of cyclosporine. There
`were transient increases in liver ALT and AST when CANClDAS and cyclosporine were coadministered
`(see WARNlNGS and ADVERSE EFFECTS, Laboratory Abnormalities).
`The results from regression analyses of patient pharmacokinetic data suggest that coadministration of
`inducers of drug clearance and/or mixed inducer/inhibitors with CANClDAS may result
`in clinically
`meaningful reductions in caspofungin concentrations. This is based on results from a small number of
`patients who were administered the inducers and/or mixed inducer/inhibitors efavirenz, nelfinavir,
`nevirapine, phenytoin,
`rifampin. dexamethasone, or carbamazepine prior to and/or concomitant with
`caspofungin. There are presently no data from formal drug interaction studies to evaluate these
`regression analyses of patient pharmacokinetic data, and it
`is not known which drug clearance
`mechanism involved in caspofungin disposition may be inducible; When coadministen‘ng CANClDAS with
`efavirenz. nelfinavir, nevirapine, phenytoin, rifampin. dexamethasone, or carbamazepine, an increase in
`the daily dose of CANClDAS to 70 mg, following the usual 70—mg loading dose, should be considered in
`patients who are not clinically responding.
`Carcinogenesis, Mutagenesis, and Impairment of Fertility
`No long-term studies in animals have been performed to evaluate the carcinogenic potential of
`caspofungin.
`Caspofungin did not show evidence of mutagenic or genotoxic potential when evaluated in the
`following in vitro assays: bacterial (Ames) and mammalian cell (V79 Chinese hamster lung fibroblasts)
`mutagenesis assays, the alkaline elution/rat hepatocyte DNA strand break test, and the chromosome
`aberration assay in Chinese hamster ovary cells. Caspofungin was not genotoxic when assessed in the
`mouse bone marrow chromosomal test at doses up to 12.5 mg/kg (equivalent to a human dose of
`1 mg/kg based on body surface area comparisons). administered intravenously.
`Fertility and reproductive performance were not affected by the intravenous administration of
`caspofungin to rats at doses up to 5 mg/kg. At 5 mg/kg exposures were similar to those seen in patients
`treated with the 70--mg dose.
`Pregnancy
`Pregnancy Category C CANClDAS was shown to be embryotoxic in rats and rabbits Findings included
`incomplete ossification of the skull and torso and an increased incidence of cervical rib in rats
`rabbits.
`An increased incidence of
`incomplete ossifications of
`the talus/calcaneus‘ was seen in
`Caspofungin also produced increases in resorptions in rats and rabbits and periimplantation losses in rats.
`These findings were observed at doses which produced exposures similar to those seen in patients
`treated with a 70—mg dose. Caspofungin crossed the placental barrier in rats and rabbits and was detected
`in the plasma of fetuses of pregnant animals dosed with CANClDAS. There are no adequate and well-
`controlled studies in pregnant women. CANClDAS should be used during pregnancy only if the potential
`benefitjustifies the potential risk to the fetus.
`
`~
`
`a
`
`2 Registered trademark of Fujisawa Healthcare. inc.
`
`5
`
`JANZG 3:30
`
`AMNEAL EX. 1010
`
`AMNEAL EX. 1010
`
`

`

`CANCIDASE
`(caspofungin acetate)
`
`xxxxxxx
`
`Nursing Mothers
`Caspofungin was found in‘the milk of lactating, drug-treated rats. it is not known whether caspofungin
`is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised
`when caspofungin is administered to a nursing woman.
`Patients with Hepatic Insufficiency
`Patients with mild hepatic insufficiency (Child-Pugh score 5 to 6) do not need a dosage adjustment. For
`patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), after the initial 70-mg loading dose.
`CANCIDAS 35 mg daily is recommended. There is no clinical experience in patients with severe hepatic
`insufficiency (Child-Pugh score >9).
`Pediatric Use
`
`Safety and effectivenessin pediatric patients have not been established.
`‘
`Geriatric Use
`Clinical studies of CANClDAS did not include sufficient numbers of patients aged 65 and over to
`determine whether they respond differently from younger patients Although the number of elderly patients
`was not large enough for a statistical analysis, no overall differences in safety or efficacy were observed
`between these and younger patients. Plasma concentrations of caspofungin in healthy older men and
`women (265 years of age) were increased slightly (approximately 28% in AUC) compared to young
`healthy men. No dose adjustment is recommended for the elderly. however. greater sensitivity of some
`older individuals cannot be ruled out.
`
`ADVERSE REACTIONS
`
`“
`
`General
`Possible histamine-mediated Symptoms have been reported in clinical studies including isolated
`reports of rash. facial swelling, pruritus, or sensation of warmth. One case of anaphylaxis characterized by
`dyspnea. stridor. and worsening of rash during initial administration of CANCIDAS was reported.
`Clinical Adverse Experiences
`The overall safety of caspofungin was assessed in 623 individuals who received single or multiple
`doses of caspofungin acetate. 01‘ the 623 individuals, 349 patients were enrolled in phase ll and phase III
`clinical studies. Patients in clinical studies often had serious underlying medical conditions (e.g., HlV. bone
`marrow transplant. hematologic malignancy)
`requiring multiple concomitant medications. Sixty-nine
`patients with invasive aspergillosis were enrolled in an open-label noncomparative study: the majority of
`these patients had underlying hematologic malignancies.
`Clinical adverse experiences with an incidence 22%. reported in patients treated with CANClDAS in
`the noncomparative aspergillosis study are presented in Table 1.
`
`-
`
`TABLE 1
`-
`,
`.Drug-«elated Clinical Adverse Experiences in Patients with
`Invasive Aspergillosis (open-label. noncomparative study)‘
`incidence _2% by Body System
`
`'
`
`'
`
`6
`
`JANZS 3230
`
`AMNEAL EX. 1010
`
`AMNEAL EX. 1010
`
`

`

`xxxxxxx
`
`CANCIDAS”
`(caspofungin acetate)
`
` -
`
`-
`
`-'
`
`CANCIDAS 50 mg
`N=69
`(percentl
`
`Body as a Whole
`Fever
`Peripheral Vascular System
`Infused vein complications
`Digestive Swim
`
`Nausea
`
`29
`
`2.9
`
`2.9
`
`__
`
`Vomiting
`‘
`Skin 5 Skin Append”.
`
`Flushing 2.9
`'Reiationsnip to drug was determined by the investigator to be possbly. probably, or
`definitely drug related. Patients received CANClDAS 70 mg on Day 1, then 50 mg daily tor
`the remainder of their treati'nenL
`
`,_
`
`3’
`
`2.9
`
`Also reported infrequently in this patient population were pulmonary edema. ARDS, and radiographic
`infiltrates.
`
`Laboratory abnormalities with an incidence 22%, reported in patients treated with CANCIDAS in the
`noncomparative aspergillosis study are presented in Table 2.
`
`TABLE 2
`Drugorelated Laboratory Abnormalities Reported Among Patients
`with Invasive Aspergillosis (open-label. noncomparative study)‘
`incidence 22% by Body System
`CANCIDAS 50 mg
`N=69
`
` (percent)
`Blood Chlmiatry
`Serum alkaline phosphatase inaeased
`Serum potassium decreased
`Hematology
`
`2.9
`29
`
`>
`
`.
`
`3,2
`
`Eosinophils increased
`Urinalysis
`,
`:19
`7
`i
`,
`'
`~7tinneprot'einirw‘aased
`
`
`
`
`' 7 ‘Urine RBC's messed 22
`‘Relationship to drug was determined by the imestigata' to be possibly, probably, or
`definitely (tug related. Patients remived CANCIDAS 70 mg on Day I. then 50 mg daily for
`the remained! of mew treatment
`I
`
`Drug-related clinical adverse experiences occurring in 22% of patients in 3 active-control studies for
`investigational indications other than aspergillosis are presented in Table 3.
`
`
`
`TABLE 3
`Drug-related Clinical Adverse Experiences Among Patients Treated
`for lnvestigatlonal Indications Other than Asperglllosis'
`Incidence 22% for at least one treatment dose
`er com arison b Bod S
`
`
`Amphotericin B
`CANCIDAS 70
`CANCIDAS 50
`CANCIDAS 50
`0.5 mngg"
`mg"
`mgr
`,
`. mg"
`N=89
`N365
`N=
`N=80
`
`
`(percent)(percent) (percent)
`
`
`'
`
`.7
`
`JAN26 3:30
`
`AMNEAL EX. 1010
`
`AMNEAL EX. 1010
`
`

`

`CANCIDASE
`(caspofungin acetate)
`
`XXXXXXX
`
`Body as a Whole
`Aslhenialfatigue °
`Chills
`Edema/swelling
`Edema. faoai
`Fever
`Flu-like Illness
`Malaise
`Pan
`Pain. abdominal
`Warrn sensation
`Peripheral vascular System
`Infused vein complication
`Phlebitis/thrornbopnlebltis
`Cardiovascular System
`Tachywdia
`Vasoutitis
`Digestive System
`Anoreiua
`Diarrhea
`Nausea
`Vomiting
`Hemic 8. Lymphatic System
`Anemia
`MetabolldNutritionalllmI-nune
`Anaphy1axis
`Museuleskatetai System
`wwwga
`Pain. back
`Pain. musculoskeletal
`Nervous System & Psychiatric
`Headache
`Imomrua
`Paresthesia
`Tremor
`Respiratory Spurn
`Tachypnea
`Skin 3 Skin Appendage
`Erythema
`lnduration
`Prurilus
`Rash
`Sweati
`‘Relationship to drug was determmed by the investigator to be possible. probably or definitely drug-related.
`"inadence <2%
`' Derived imm a Phase lil comparator-controlled dinimi study
`" Derived from Phase ll camcorder-controlled clinical studies
`
`w
`'
`
`0.0
`1.5
`0.0
`3.1
`26.2
`3.1
`0.0
`(6
`0 0
`1.5
`
`1.5
`138
`
`0.0
`0.0
`
`0.0
`3.1
`3.1
`3.1
`
`0.0
`
`0.0
`
`3.1
`0.0
`0.0
`
`7.7
`0 0
`3.1
`0.0
`
`0.0
`
`1.5
`3.1
`1.5
`4.5
`
`67
`753
`5.5
`0.0
`697
`0.0
`5.6
`5.6
`9.0
`4.5
`
`0.0
`22.5
`
`4.5
`3.4
`
`3.4
`11.2
`21.3
`13.5
`
`9.0
`
`2.2
`
`2.2
`4.5
`
`19.1
`2.2
`1.1
`7.9
`
`4.5
`
`7.9
`6.7
`0.0
`3.4
`
`12.0
`15.7
`
`0.0
`2.5
`0.0
`O.0
`213
`0.0
`0.0
`1.3
`2.5
`0.0
`
`2.5
`11.3
`
`1.3
`0.0
`
`1.3
`1.3
`2.5
`1.3
`
`3.8
`
`0.0
`
`0.0
`0.0
`1.3
`
`11.3
`0.0
`1.3
`0.0
`
`1.3
`1.3
`0.0
`2.5
`1,3
`
`
`
`Laboratory abnormalities occurring in .2% of patients in 3active—controlstudies for investigational
`indications other than aspergiilosis. are presentedin Table 4.
`TABLE 4
`
`Drug-«elated Laboratory Abnormalities Reported Among Patients Treated
`for lnvestigational indications Other than Aspargillosls‘
`Incidence _2% (for at least one treatment dose) by Laboratoq Test Category
`CANCIDAS
`CANCIDAS Amman B
`05mm”
`70 mg"
`50 mg
`N=89
`N=163
`~=ss
`l
`cent
`
`8
`
`'JAN26'3230
`
`AMNEAL EX. 1010
`
`AMNEAL EX. 1010
`
`

`

`CAN ClDAS'E
`(caspofungin acetate)
`
`xxxxxxx
`
`10 8
`10,8
`0.0
`0 0
`4.6
`71
`0.0
`1.5
`10.8
`0.0
`0.0
`0.0
`
`3.1
`1 .5
`3.1
`3.1
`1.5
`1.5
`4 6
`
`22.7
`22.?
`10.3
`2.5
`14.9
`19.3
`6.6
`28.1
`31.5
`14
`4.5
`3.4
`.
`1.1
`32.6
`37.1
`1.1
`3.4
`2.3
`7,9
`
`Blood Chemistry
`ALIlncreasgd
`-~
`AST Increased
`Blood urea increased
`Direct serum blllfllbln inceased
`Serum albumin deceased
`Serum alkaline phosphatase Increased
`Serum bicarbonate deceased
`Serum creatmine Increased
`Serum potassmm deceased
`Serum urlc acd Increased
`Total serum bilirubin increased
`Total serum protein deceased
`Hematology
`Eosrnophils inceased
`Hematoont deceased
`Hemoglobm deceased '
`Neutrootlls deceased
`Platelet count deceased
`Prothrombm time inceased
`WBC count deceased
`Urinalysis
`4.0
`0 0
`0.0
`Urine blood Increased
`3.0
`0.0
`0.0
`Urine casts increased
`3.6
`0.0
`0.8
`Unne pH inceased
`4,5
`0.0
`1.2
`Urine protetn inceased
`12.0
`3.5
`1.1
`Unne RECs inceased
`24.0
`7.7
`0.0
`Urine WBCs inceased
`'Relationship to drug was determined by the Investigator to be possible. probably or definitely
`mug-related.
`' Derived from Phase II and Phase III comparator-controlled clinical studies.
`" Derived from Phase II oomparatorconu'olled clinical studies.
`
`10 6
`13 0
`0.0
`0.6
`8.6
`10 5
`0.9
`0.0
`3.7
`06
`0.0
`3.1
`
`3.1
`11 . 1
`12.3
`1.9
`3.1
`1.3
`6.2
`
`’
`
`~
`
`1.1
`
`in one clinical study, 3 of 4 subjects who received CANClDAS 70 mg daily on Days 1 through 10. and
`also received two 3 mg/kg doses of cyclosporine 12 hours apart on Day 10. developed transient elevations
`of ALT on Day 11 that were 2 to 3 times the upper limit of normal (ULN). In a separate panel of subjects in
`the same study, 2 of 8 subjects who received CANClDAS 35 mg daily for 3 days and cyclosporine (two
`3 mg/kg doses administered 12 hours apart) on Day1 had small increases in ALT (slightly above the
`ULN) on Day 2. In another clinical study. 2 of 8 healthy men developed transient ALT elevations of less
`than 2X ULN. In this study. cyclosporine (4 mg/kg) was administered on Days 1 and 12. and CANClDAS
`was administered (70 mg) daily on Days 3 through 13. In one subject, the ALT elevation occurred on
`Days 7 and 9 and. in the other subject. the ALT elevation occurred on Day 19. These elevations returned
`to normal by Day 27.
`In all groups. elevations in AST paralleled ALT elevations but were of lesser
`magnitude. In these clinical studies. cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the
`AUC of caspofungin by‘approximately 35% (see WARNINGS).
`
`OVERDOSAGE '
`
`ln clinical studies the highest dose was 100 mg, administered as a single dose to 5 patients. This dose
`was generally we'll tolerated. No overdosages have been reported. Caspofungin is not dialyzable. The
`minimum lethal dose of'caspofungin'in rats was 50 mglkg, a dose which is equivalent to 10 times the
`recommended daily dose based on relative body surface area comparison.
`
`ANIMAL PHARMACOLOGY AND TOXICOLOGY
`
`In one 5-week study in monkeys at doses which produced exposures approximately 4 to 6 times those
`seen in patients treated with a 70-mg dose. scattered small foci of subcapsular necrosis were observed
`microscopically in the livers of some animals (2/8 monkeys at 5 mg/kg and 4/8 monkeys at 8 mg/kg);
`however, this histopathological finding was not seen in another study of 27 weeks duration at similar
`doses.
`
`9
`
`JAN26 3:30
`
`AMNEAL EX. 1010
`
`AMNEAL EX. 1010
`
`

`

`CANCIDAS”
`(caspofungin acetate)
`
`DOSAGE AND ADMINISTRATION
`
`xxxxxxx
`
`“
`General Recommendations
`A single 70-mg loading dose should be administered on Day 1. followed by 50 mg daily thereafter.
`CANCIDAS should be administered by slow IV infusion of approximately 1 hour. Duration of treatment
`should be based upon the severity of the patient '5 underlying disease, recovery from immunosuppression,
`and clinical response. Do not mix or co-infuse CANCIDAS with other medications. DO NOT USE
`
`DILUENTS CONTAINING DEXTROSE (a-D-GLUCOSE). The efficacy of a 70 mg dose regimen in
`patients who are not clinically responding to the 50mg daily dose is not known. Limited safety data
`suggests that an increase in dose to 70 mg daily is well tolerated. The safety and efficacy of doses above
`70 mg have not been adequately studied.
`—
`Hepatic Insufficiency
`Patients with mild hepatic insufficiency (Child-P-ugh score 5 to 6) do not need a dosage adjustment
`However, for patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9) after the initial TO-mg
`loading dose, CANCIDAS 35 mg daily is recommended. There is no clinical experience In patients with
`severe hepatic insufficiency (Child-Pugh score >9) (see CLINICAL PHARMACOLOGY, Pharmacoklnetics,
`Special Populations. ).
`Preparation of the 70-mg Day 1 loading~dose infusion
`1. Equilibrate the refrigerated vial of CANCIDAS to room temperature.
`2. Aseptically add 10.5 mL of 0.9% Sodium Chloride Injection to the vial. ‘ This reconstituted solution may
`be stored for up to one hour at <25° C (<77°F).°
`3. Aseptically transfer 10 mLc of dreconstituted CANCIDAS to an IV bag (or bottle) containing 250 mL
`0. 9% Sodium Chloride Injection.
`(If a 70-mg vial
`is unavailable, see below: Alternative Infusion
`Preparation Methods, Preparation of 70-mg Day 1 loading dose from two 50-mg vials.)
`Preparation of the daily 50—mg infusion
`1. Equilibrate the refrigerated vial of CANCIDAS to room temperature.
`2. Aseptically add 10.5 mL of 0.9% Sodium Chloride Injection to the vial. ' This reconstituted solution may
`be stored for up to one hour at <25“C (<77° F).b
`3 Aseptically transfer 10 mL° of reconstituted CANCIDAS to an IV bag (or bottle) containing 250 mL
`0 9% Sodium Chloride Injection.
`(If a reduced infusion volume is medically necessary. see below.
`Alternative Infusion Preparation Methods Preparation of 50—mg daily doses at reduced volume.)
`Alternative Infusion Preparation Methods
`Preparation of 70-mg Dag 1 loading dose from two fiO-m vials
`Reconstitute two 50-mg vials with 10 5 mL of diluent each (see Preparation of the daily 50-mg infusion).
`Aseptically transfer a total of 14 mL of the reconstituted CANCIDAS from the two vials to 250 mL of
`O. 9% Sodium Chloride injection.
`,
`Preparation of 50--mg daily doses at redupeg vplume
`When medically necessary, the SO-mg daily doses can be prepared by adding 10 mL of reponstituted
`CANCIDAS to 100 mL of O.9% Sodium Chloride Injection (see Preparation of the daily 50—mg infusion).
`Preparation of a 35-mg daily dose for patients with modegtp Hepatic Inpufficiencz
`Reconstitute one 50-m-g