CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-227
`
`APPROVED DRAFT LABELING
`
`AMNEALEX.1010
`
`AMNEAL EX. 1010
`
`

`

`MERCK & CO, INC.
`Whitehouse Station, NJ 08889, USA
`
`INTRAVENOUS INFUSION(not for IV Bolus Injection)
`CANCIDAS”
`(caspofungin acetate) FOR INJECTION
`
`ae
`
`DESCRIPTION
`
`CANCIDAS is a sterile, lyophilized productfor intravenous (IV) infusion that contains a semisynthetic
`lipopeptide (echinocandin) compound synthesized from a fermentation praduct of Glarea lozoyensis.
`CANCIDASis the first of a new class of antifungal drugs (glucan synthesis.inhibitors) that inhibit the
`synthesis of B (1,3)-D-glucan, an integral componentof the fungal cell wall.
`CANCIDAS
`(caspofungin
`acetate)
`is
`1-{(4R,5S)-5-{(2--aminoethyljamino}N"--(10,12-dimethyl-1-
`oxotetradecyl)-4-hydroxy-L-omithine]-5-((3 R)-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 empiricai formula is
`CsaHagN 19O15*2C2H4«O2 and the formula weight is 1213.42. The structural formulais:
`4
`
`.
`
`te
`
`:
`
`eo PHul
`CH, CH,
`VP" Se“on”
`if
`NH ontCHy
`o
`re “2CHhCO,H
`
`q
`
`"OH
`
`CLINICAL PHARMACOLOGY
`
`Pharmacokinetics
`- Distribution .
` -Plasma concentrations of caspofungin decline in a4 polyphasic manner. following: single 1-hour IV ©
`- _ infusions. A short’‘o-phase occurs immediately postinfusion, followed -by a B-ptiase(half-life af 9to
`11 hours) that characterizes much ofthe 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,
`phase,(half-life of 40-50 hours), also occurs. Distribution, rather than excretion or biotransformation; is
`the dominant mechanism influencing piasma 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 70-mg
`doseof PH] caspofungin acetate. Thereislittle excretion or biotransformation of caspofungin during the
`first 30 hours after administration.
`Metabolism
`Caspofungin is slowly metabolized by hydrolysis and N-acetylation. Caspofungin also undergoes
`spontaneous chemical degradation to an open-ring peptide compound, L-747969. Atlater time points (5 to
`20 days postdose), there is a low level (3 to 7 picomoles/mg protein, or 0.6 to 1.3% of administered dose)
`
`“Registered trademark of MERCK & CO., inc.
`COPYRIGHT © MERCK & Co.Inc., 2001
`All rights reserved
`
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`CAN cipas”
`(caspofungin acetate)
`
`XXXXXXX
`
`in plasma following single-dose administration of [7H] caspofungin
`of covalent binding of radiolabel
`acetate, which may be dué 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 dihydroxyhamotyrosine and. N-acetyl-dihydroxyhomotyrosine. These two tyrosine
`derivatives are found only in urine, suggesting rapid:clearanceof 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 [PH] caspofungin 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 caspofungin|is 12 mL/min.”
`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 adjustmentis
`necessary based on gender.
`Geriatric
`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 noclinically significant differences
`in the pharmacokinetics of caspofungin were seen among Caucasians, Blacks, and Hispanics. No dosage
`adjustmentis necessary on the basis of race.
`Renalinsufficiency
`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 mL/min 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 dialyzabie,
`thus
`supplementary dosing is not required following hemodialysis.
`Hepatic Insufficiency
`Plasma concentrations of caspofungin after a single 70-mg dose in patients with mild hepatic
`insufficiency (Child-Pugh 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 Day 1 followed by 50 mg daily thereafter),
`plasma concentrations in patients with mild hepatic insufficiency were increased modestly (19 to 25% in
`AUC) on Days 7 and 14 relative to healthy control subjects. No dosage adjustmentis 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). Thereis no clinical experiencein
`patients with severe hepatic insufficiency (Child-Pugh score >9).
`Pediatric Patients
`CANCIDAShas not been adequately studied in patients under 18 years of age.
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`CANCIDAS®
`(caspofungin acetate)
`
`MICROBIOLOGY
`
`XXXXXXX
`
`Mechanism of Action
`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
`Aspergillus fumigatus.
`Activity in vitro
`Caspofungin exhibits in vitro activity against Aspergillus fumigatus, Aspergillus flavus, and Aspergillus
`terreus. Susceptibility testing was performed according to the National Committee for Clinical Laboratory
`Standards
`(NCCLS) proposed method (M38-P). Standardized susceptibility testing methods
`for
`B (1,3)-O0-giucan 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 Aspergillus species has not been studied. !n limited
`clinical experience, drug resistance in patients with invasive aspergillosis has not been observed. The
`incidence of drug resistance by variousclinical isolates of Aspergillus species is unknown.
`Drug Interactions
`Studies jin vitro and in vivo of caspofungin, in combination with amphotericin B, suggest no antagonism
`of antifungal activity against A. fumigatus. Theclinical 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 8, 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 creatinine >2.5 mg/dl. 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
`histapathology 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,andclinical
`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. Stabie, nonprogressive disease was considered to be an unfavorable response.
`Amongthe 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
`
`' Denning OW,Lee JY, Hostetler JS,et al. NIAID Mycoses Study Group multicentertrial of oral itraconazole therapy for invasive
`aspergillosis. Am J Med 1994,97:135-144.
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`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 CANCIDASconcomitantly, of whom 8 also received
`mycophenoiate mofatil.
`Overall,
`the expert panel determined that 41% (26/63) of patients receiving at least one dose of
`CANCIDAS had a favorable response. For those patients who received >7 days of therapy with
`CANCIDAS,50% (26/52) had a favorable response. The favorable responserates 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 orintolerantofitraconazole, 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
`
`CANCIDASis indicated for the treatment of invasive aspergillosis in patients who are refractory to or
`intolerant of other
`therapies
`(i.e, amphotericinB,
`lipid
`formulations of amphotericinB,
`and/or
`itraconazole).
`CANCIDAShasnot beenstudied asinitial therapy for invasive aspergillosis.
`
`CONTRAINDICATIONS
`
`CANCIDASis contraindicated in patients with hypersensitivity to any componentofthis 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, 3 of 4 healthy subjects who received
`CANCIDAS 70 mg 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 alanine transaminase (ALT) on Day 11 that were 2 to
`3 times the upper limit of normal (ULN).
`In a separate pane! 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 Day2. 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 usein patients is studied.
`‘
`
`PRECAUTIONS
`
`General
`The efficacy of a 70-mg dose regimenin patients who are notclinically responding to the 50 mg daily
`daseis 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 weeksis limited, however, available data
`suggest that CANCIDAS continues to be well
`tolerated with longer courses of therapy (68 patients
`received from 15 to 60 daysof therapy; 12 patients received from 61 to 162 days of therapy).
`Druginteractions
`Studies in vitro show that caspofungin acetate is not an inhibitor of any enzymein the cytochrome
`P450 (CYP) system.
`In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other
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`CAN CIDAS”
`(caspofungin acetate)
`
`XXXXXXX
`
`drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450
`enzymes.
`-
`-
`Clinica! studies in healthy volunteers show that the pharmacokinetics of CANCIDASare not altered by
`itraconazole,
`amphotericin B, mycophenolate, or
`tacrolimus. CANCIDAS has no effect on the
`pharmacokineticsof itraconazole, amphotericin B, or the active metabolite of mycophenoiate.
`CANCIDASreduced the blood AUC 9.12 of tacrolimus (FK-506, Prograf®2) by approximately 20%, peak
`blood concentration (C,,,,) by 16%, and 12-hour blood concentration (C ja) by 26% in healthy subjects
`whentacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS
`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 36%. CANCIDASdid not increase the plasmalevels of cyclosporine. There
`were transient increases in liver ALT and AST when CANCIDASand cyclosporine were coadministered
`(see WARNINGS 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 CANCIDAS may result
`in clinically
`meaningful reductions in caspofungin concentrations. This is based on results from a small numberof
`patients who were administered the inducers and/or mixed inducerfinhibitors 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 coadministering CANCIDAS with
`efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, dexamethasone, or carbamazepine, an increase in
`the daily dose of CANCIDASto 70 mg, following the usual 70-mg loading dose, should be considered in
`patients who are not clinically responding.
`Carcinogenesis, Mutagenesis, and Impairmentof 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 ceil (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 ceils. 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. CANCIDAS was shown to be embryotoxic in rats and rabbits. Findings included
`incomplete ossification of the skull and torso and an increased incidence ofcervicalrib in rats.
`rabbits.
`An increased incidence of
`incomplete ossifications of
`the talus/calcaneus‘ was seen in
`Caspofungin aiso producedincreases in resorptions in rats and rabbits and periimplantation lossesin 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 CANCIDAS. There are no adequate and well-
`controlled studies in pregnant women. CANCIDAS should be used during pregnancyonly if the potential
`benefit justifies the potentialrisk to the fetus.
`
`~
`
`“
`
`2 Registered trademark of Fujisawa Healthcare,Inc.
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`

`CANCIDAS”
`(caspofungin acetate)
`
`XXXXXXX
`
`Nursing Mothers
`Caspofungin was found irtthe 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 theinitial 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 CANCIDAS did not include sufficient numbers of patients aged 65 and over to
`determine whether they respond differently from younger patients. Although the numberofelderly 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 recommendedfor 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 duringinitial administration of CANCIDAS wasreported.
`Clinical Adverse Experiences
`The overall safety of caspofungin was assessed in 623 individuals wha received single or multiple
`doses of caspofungin acetate. Of the 623 individuals, 349 patients were enrolled in phase Il and phaseIl
`clinical studies. Patients in clinical studies often had serious underlying medical conditions (e.9., HIV, 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 CANCIDASin
`the noncomparative aspergillosis study are presented in Table 1.
`
`,
`TABLE 1
`Drug:-related Clinical Adverse Experiences inPatients with
`Invasive Aspergillosis (open-label, noncomparative study)* ——
`Incidence >2% by Body System
`
`.
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`XXXXKKX
`
`CANCIDAS”
`(caspofungin acetate)
`
` -
`
`-
`
`-
`
`CANCIDAS 50 mg
`N=69
`{percent}
`
`Body as a Whole
`Fever
`Peripheral Vascular System
`Infused vein complications
`Digestive System
`
`29
`
`29
`
`Nausea
`.
`Vomiting
`Skin & Skin Appendage
`29
`Flushing
`*Retationsnip to drug was determined by the investigator to be possibly, probably, or
`definitely drug retated. Patients received CANCIDAS 70 mg on Day1, then 50 mg daily for
`the remainder of their treatment.
`
`-
`
`>
`
`29
`29
`
`.
`
`‘
`
`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 CANCIDASin the
`noncomparative aspergillosis study are presented in Table 2.
`
`TABLE 2
`Orug-related Laboratory Abnormalities Reported Among Patients
`with Invasive Aspergillosis (open-label, noncomparative study)*
`Incidence 22% by Body System
`CANCIDAS 50 mg
`N=69
`(percent)
`
`Blood Chemistry
`Serum aikaline phosphatase increased
`Serum potassium decreased
`Hematology
`
`29
`2.9
`
`/
`
`3.2
`Eosinophits increased
`.
`.
`Urinalysis
`;
`ag
`Urine protein increased
`et gg
`Urine RBC’s increased
`“Relationship to drug was determined by the investigator to be possibly, probably, or
`definitely drug related. Patients received CANCIDAS 70 mg on Day 1, then 50 mg daily for
`the remainder of thew treatment.
`’
`
`.
`
`a
`
`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 Investigational Indications Other than Aspergillosis”
`Incidence 22% for at least one treatment dose
`(per comparison)
`b'
`
`
`
`CANCIDAS 50|CANCIDAS 50 CANCIDAS 70 Amphotericin B
`
`t 0.5 mgkKg™ _ mgt mg”
`
`
`
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`CANCIDAS”
`(caspofungin acetate)
`
`-
`
`Body as a Whole
`Asthenia/fatique >
`Chills
`Edema/swelling
`Edema,facial
`Fever
`Fiu-like illness
`Maiaise
`Pain
`Pain, abdominat
`Warm sensation
`Peripherai vascular System
`Infused vein comptication
`Phiebitis/thrombophiebitis
`Cardiovascular System
`Tachycardia
`Vasculits
`Digestive System
`Anorexia
`Diarrnea
`Nausea
`Vomiting
`Hemic & Lymphatic System
`Anema
`Metabolic/Nutritional/immune
`Anaphylaxis
`Musculoskeletal System
`Myalgia
`Pain, back
`Pain, musculoskeletat
`Nervous System & Psychiatric
`Headache
`Insomrua
`Paresthesia
`Tremor
`Respiratory System
`Tachypnea
`Skin & Skin Appendage
`Erthema
`induration
`Pruritus
`Rash
`Sweati
`“Relationship to drug was determined by the investigator to be possible, probably or definitely drug-reiated.
`“Incidence <2%
`" Derived from a Phase Il comparator-controlled clinical study
`™ Derived from Phase !! comparator-controlled clinical studies
`
`MXXXXXX
`
`45
`3.4
`
`3.4
`11.2
`21.3
`13.5
`
`9.0
`
`\
`
`
`
`12.0
`
`6.0
`
`.
`
`‘Laboratory abnormatities occurring in 22% of ‘patients.in 3active-controtStudies for investigational
`
`indications other than aspergillosis. are presented in Table 4.
`
`TABLE 4
`Drug-related Laboratory Abnormalities Reported Among Patients Treated
`for Investigational Indications Other than Aspergillosis*’
`Incidence 22% (for at least one treatment dose) by Laboratory Test Category
`CANCIDAS
`CANCIDAS
`Amphotericin B
`0.5 mg"!
`7omg'?
`50mg"
`N=89
`N=163
`N=65
`U
`cent!
`
`8
`
`JAN26 3:30
`
`AMNEALEX. 1010
`
`AMNEAL EX. 1010
`
`

`

`CAN CIDAS”
`(caspofungin acetate)
`
`XXXKKKX
`
`10.6
`13.0
`0.0
`0.6
`8.6
`10.5
`09
`0.0
`37
`0.6
`0.0
`3.1
`
`3.1
`1144
`12.3
`1.9
`31
`13
`6.2
`
`10.8
`10.8
`0.0
`0.0
`4.6
`77
`0.0
`1.5
`10.8
`0.0
`0.0
`00
`
`34
`15
`3.1
`3.1
`WS
`15
`46
`
`22.7
`22.7
`10.3
`2.5
`14.9
`19.3
`6.6
`28.1
`5
`3.4
`45
`34
`.
`4.1
`32,6
`37.1
`a
`3.4
`2.3
`79
`
`Blood Chemistry
`ALTincreased
`-
`ASTincreased
`Blood urea increased
`Direct serum diitrudin increased
`Serum albumin decreased
`Serum alkaline phosphatase increased
`Serum bicarbonate decreased
`Serum creatinine increased
`Serum potassium decreased
`Serum uric acd increased
`Total serum bilirubin increased
`Total serum protein decreased
`Haematology
`Eosinophils increased
`Hematocnt decreased
`Hemoglobin decreased“
`Neutropris decreased
`Platelet count cecreased
`Prothrombin time increased
`WSCcount decreased
`Urinalysis
`4.0
`0.0
`0.0
`Unie blood increased
`8.0
`0.0
`0.0
`Urine casts increased
`36
`0.0
`08
`Unine pH increased
`45
`0.0
`12
`Unne protein increased
`12.0
`3.8
`14
`Urine RBCsincreased
`24.0
`77
`0.0
`Urine W8Csincreased
`“Relationship to drug was determined by the investigator to be possible. probably or definitely
`drug-related.
`T Derived from Phase It and Phase Il! comparator-controlled clinical studies.
`* Derived from Phase Il comparator-controlled clinical studies.
`
`~-
`
`ry
`
`In one clinical study, 3 of 4 subjects who received CANCIDAS 70 mg daily on Days 1 through 10, and
`also received two 3 mg/kg dosesof cyclosporine 12 hours apart on Day 10, developedtransient 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 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 Day2. 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 CANCIDAS
`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 byapproximately 35% (see WARNINGS).
`
`OQVERDOSAGE_
`
`in clinical studies the highest dose was 100 mg, administered as a single dose to 5 patients. This dose
`was generally well toterated. No overdosages have been reported. Caspofungin is not dialyzable. The
`minimum lethal dose of caspofungin’in rats was 50 mg/kg, a dose which is equivalent to 10 times the
`recommended daily dose based onrelative 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
`seenin 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
`
`AMNEALEX. 1010
`
`AMNEAL EX. 1010
`
`

`

`CANCIDAS>
`(caspofungin acetate)
`
`DOSAGE AND ADMINISTRATION
`
`XXKKKKX
`
`=~
`General Recommendations ~
`A single 70-mg loading dose should be administered on Day1, followed by 50 mg daily thereafter.
`CANCIDAS should be administered by siow IV infusion of approximately 1 hour. Duration of treatment
`should be based upon the severity of the patient's underlying disease, recovery fram 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 70mg dose regimen in
`patients who are notclinically responding to the 50mg daily dose is not known. Limited safety data
`suggests that an increase in dose to 70 mgdaily 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-Pugh 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 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) (see CLINICAL PHARMACOLOGY, Pharmacokinetics,
`Special Populations.).
`Preparation of the 70-mq 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 Chioride Injection to the vial. * This reconstituted solution may
`be stored for up to one hour at <25°C (<77°F).°
`3. Aseptically transfer 10 mL° of reconstituted CANCIDAS to an IV bag (or bottle) containing 250 mL
`0.9% Sodium Chloride Injectian.4 (if a 70-mg vial
`is unavailable, see below: Alternative Infusion
`Preparation Methods, Preparation of 70-mg Oay 1 loading dase from two 50-mgvials. )
`Preparation of the daily 50-mg infusion
`1, Equilibrate the refrigerated vial of CANCIDASto room temperature.
`2. Asepticaily add 10.5 mL of 0.9% Sodium Chloride Injection to the vial. * This reconstituted solution may
`be stored for up to one hourat <25°C (<77°F).°
`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-mq daily doses at reduced volume. )
`Alternative infusion Preparation Methods
`Preparation of 70-mg Day 1 loading dose from two 50-mg 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
`0.9% Sodium Chioride tnjection.
`:
`Preparation of50-mq daily doses at reduced volume
`When medically necessary, the 50-mg daily doses can be’prepared by adding 10 mL- of reconstituted.
`CANCIDASto 100 mLof 0.9% Sodium Chioride Injection (see Preparation ofthe daily. 50-mg infusion).
`Preparation of a 35-mq daily dose for patients with moderate Hepatic Insufficiency
`Reconstitute one 50-mgvial (see above: Preparation of the daily 50-mg infusion). Aseptically transfer
`7 mL ofthe reconstituted CANCIDASfrom thevial to 250 mL of 0.9% Sodium: Chloride Injection or,if
`medically necessary, to 100 mL of 0.9% Sadium Chloride injection.
`
`~
`
`
`
`Preparation notes:
`a The white to off-white cake will dissolve completely. Mix gently until a clear solution is obtained.
`
`
`
`b Visually inspect the reconstituted solution for particulate matter or discoloration during reconstitution and prior to