CAMPTOSAR
`sNDA 20-571/S008
`
`For Intravenous Use Only
`WARNINGS
`
`CAMPTOSAR Injection should be administered only under the supervision of a physician who is
`experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is
`possible only when adequate diagnostic and treatment facilities are readily available.
`
` CAMPTOSAR can induce both early and late forms of diarrhea that appear to be mediated by
`different mechanisms. Both forms of diarrhea may be severe. Early diarrhea (occurring during or
`shortly after infusion of CAMPTOSAR) may be accompanied by cholinergic symptoms of rhinitis,
`increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can
`cause abdominal cramping. Early diarrhea and other cholinergic symptoms may be prevented or
`ameliorated by atropine (see PRECAUTIONS, General). Late diarrhea (generally occurring more than
`24 hours after administration of CAMPTOSAR) can be prolonged, may lead to dehydration and
`electrolyte imbalance, and can be life threatening. Late diarrhea should be treated promptly with
`loperamide; patients with severe diarrhea should be carefully monitored and given fluid and electrolyte
`replacement if they become dehydrated (see WARNINGS section). Administration of CAMPTOSAR
`should be interrupted and subsequent doses reduced if severe diarrhea occurs (see DOSAGE AND
`ADMINISTRATION).
`
` Severe myelosuppression may occur (see WARNINGS section).
`
`DESCRIPTION
`
`CAMPTOSAR Injection (irinotecan hydrochloride injection) is an antineoplastic agent of the
`topoisomerase I inhibitor class. Irinotecan hydrochloride was clinically investigated as CPT-11.
`
`CAMPTOSAR is supplied as a sterile, pale yellow, clear, aqueous solution. It is available in two
`single-dose sizes: 2 mL-fill vials contain 40 mg irinotecan hydrochloride and 5 mL-fill vials contain
`100 mg irinotecan hydrochloride. Each milliliter of solution contains 20 mg of irinotecan hydrochloride
`(on the basis of the trihydrate salt), 45 mg of sorbitol NF powder, and 0.9 mg of lactic acid, USP. The
`
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`FMI v. Caris MPI
`Exhibit 1165
`IPR2019-00170
`
`

`

`CAMPTOSAR
`sNDA 20-571/S008
`
`pH of the solution has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric
`acid. CAMPTOSAR is intended for dilution with 5% Dextrose Injection, USP (D5W), or 0.9%
`Sodium Chloride Injection, USP, prior to intravenous infusion. The preferred diluent is 5% Dextrose
`Injection, USP.
`
`Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extract from plants
`such as Camptotheca acuminata. The chemical name is (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperi-
`dinopiperidino)carbonyloxy]-1H-pyrano[3’,4’:6,7]
`indolizino[1,2-b]quinoline-3,14(4H,12H)dione hydrochloride trihydrate. Its structural formula is as
`follows:
`
`N
`
`N
`
`O
`
`C
`O
`
`C 3H
`C 2H
`
`N
`
`O
`
`N
`
`O
`
`H
`
`O
`
`O
`C 2H
`
`C 3H
`
`ClH
`O2H3
`PNU-101440E
`
`Irinotecan hydrochloride is a pale yellow to yellow crystalline powder, with the empirical formula
`C33H38N4O6•HCl•3H2O and a molecular weight of 677.19. It is slightly soluble in water and organic
`solvents.
`
`CLINICAL PHARMACOLOGY
`
`Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme
`topoisomerase I which relieves torsional strain in DNA by inducing reversible single-strand breaks.
`Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent
`religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is
`due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact
`with the ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38.
`Mammalian cells cannot efficiently repair these double-strand breaks.
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`Page 2
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`

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`CAMPTOSAR
`sNDA 20-571/S008
`
`Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed
`from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the
`camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 1000 times as potent as
`irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumor cell lines. In vitro
`cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold.
`However, the plasma area under the concentration versus time curve (AUC) values for SN-38 are 2%
`to 8% of irinotecan and SN-38 is 95% bound to plasma proteins compared to approximately 50%
`bound to plasma proteins for irinotecan (see Pharmacokinetics). The precise contribution of SN-38 to
`the activity of CAMPTOSAR is thus unknown. Both irinotecan and SN-38 exist in an active lactone
`form and an inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the two
`forms such that an acid pH promotes the formation of the lactone, while a more basic pH favors the
`hydroxy acid anion form.
`
`Administration of irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin
`and in human carcinoma xenografts of various histological types.
`
`Pharmacokinetics
`After intravenous infusion of irinotecan in humans, irinotecan plasma concentrations decline in a
`multiexponential manner, with a mean terminal elimination half-life of about 6 to 12 hours. The mean
`terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. The half-lives of
`the lactone (active) forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as
`the lactone and hydroxy acid forms are in equilibrium.
`
`Over the recommended dose range of 50 to 350 mg/m2, the AUC of irinotecan increases linearly with
`dose; the AUC of SN-38 increases less than proportionally with dose. Maximum concentrations of the
`active metabolite SN-38 are generally seen within 1 hour following the end of a 90-minute infusion of
`irinotecan. Pharmacokinetic parameters for irinotecan and SN-38 following a 90-minute infusion of
`irinotecan at dose levels of 125 and 340 mg/m2 determined in two clinical studies in patients with solid
`tumors are summarized in Table 1.
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`

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`Table 1. SUMMARY OF MEAN (± STANDARD DEVIATION) IRINOTECAN AND SN-38
`PHARMACOKINETIC PARAMETERS IN PATIENTS WITH SOLID TUMORS
`Irinotecan
`SN-38
`t½
`AUC0-24
`(h)
`(ngh/mL)
`5.8a
`229
`± 108
`± 0.7
`11.7b
`474
`± 245
`± 1.0
`
`CL
`(L/h/m2)
`13.3
`± 6.01
`13.9
`± 4.00
`
`Cmax
`(ng/mL)
`26.3
`± 11.9
`56.0
`± 28.2
`
`Vz
`(L/m2)
`110
`± 48.5
`234
`± 69.6
`
`AUC0-24
`Cmax
`(ng/mL)
`(ngh/mL)
`10,200
`1,660
`125
`± 3,270
`± 797
`(N=64)
`20,604
`3,392
`340
`± 6,027
`± 874
`(N=6)
`Cmax - Maximum plasma concentration
`AUC0-24 - Area under the plasma concentration-time curve from time 0 to 24 hours after the end of the 90-minute
`infusion
`t½ - Terminal elimination half-life
`Vz - Volume of distribution of terminal elimination phase
`CL - Total systemic clearance
`a Plasma specimens collected for 24 hours following the end of the 90-minute infusion.
`b Plasma specimens collected for 48 hours following the end of the 90-minute infusion. Because of the longer
`collection period, these values provide a more accurate reflection of the terminal elimination half-lives of irinotecan
`and SN-38.
`
`CAMPTOSAR
`sNDA 20-571/S008
`
`Dose
`(mg/m2)
`
`t½
`(h)
`10.4a
`± 3.1
`21.0b
`± 4.3
`
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`107
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`Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound to
`human plasma proteins (approximately 95% bound). The plasma protein to which irinotecan and
`SN-38 predominantly binds is albumin.
`Metabolism and Excretion: The metabolic conversion of irinotecan to the active metabolite SN-38 is
`mediated by carboxylesterase enzymes and primarily occurs in the liver. SN-38 subsequently
`undergoes conjugation to form a glucuronide metabolite. SN-38 glucuronide had 1/50 to 1/100 the
`activity of SN-38 in cytotoxicity assays using two cell lines in vitro. The disposition of irinotecan has
`not been fully elucidated in humans. The urinary excretion of irinotecan is 11% to 20%; SN-38, <1%;
`and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its
`metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of
`irinotecan in two patients ranged from approximately 25% (100 mg/m2) to 50% (300 mg/m2).
`
`Page 4
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`

`

`CAMPTOSAR
`sNDA 20-571/S008
`
`Pharmacokinetics in Special Populations
`Geriatric: In studies using the weekly schedule, the terminal half-life of irinotecan was
`6.0 hours in patients who were 65 years or older and 5.5 hours in patients younger than 65 years.
`Dose-normalized AUC0-24 for SN-38 in patients who were at least 65 years of age was 11% higher
`than in patients younger than 65 years. No change in the starting dose is recommended for geriatric
`patients receiving the weekly dosage schedule of irinotecan.
`The pharmacokinetics of irinotecan given once every 3 weeks have not been studied in the geriatric
`population; a lower starting dose is recommended in patients 70 years or older based on clinical
`toxicity experience with this schedule (see DOSAGE and ADMINISTRATION).
`Pediatric: Information regarding the pharmacokinetics of irinotecan is not available.
`Gender: The pharmacokinetics of irinotecan do not appear to be influenced by gender.
`Race: The influence of race on the pharmacokinetics of irinotecan has not been evaluated.
`Hepatic Insufficiency: The influence of hepatic insufficiency on the pharmacokinetic characteristics of
`irinotecan and its metabolites has not been formally studied. Among patients with known hepatic tumor
`involvement (a majority of patients), irinotecan and SN-38 AUC values were somewhat higher than
`values for patients without liver metastases. (See Precautions)
`
`Renal Insufficiency: The influence of renal insufficiency on the pharmacokinetics of irinotecan has not
`been evaluated.
`
`Drug-Drug Interactions
`Possible pharmacokinetic interactions of CAMPTOSAR with other concomitantly administered
`medications have not been formally investigated.
`
`CLINICAL STUDIES
`
`Two dosage schedules have been studied in clinical trials of irinotecan (see DOSAGE and
`ADMINISTRATION). In U.S. clinical trials, irinotecan was administered on a weekly dosage
`schedule (125 mg/m2). In clinical trials conducted in Europe, the Middle East, and South Africa,
`irinotecan was administered on a once-every-3-week dosage schedule (350 mg/m2). Clinical studies
`using these two dosage schedules are described below.
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`

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`CAMPTOSAR
`sNDA 20-571/S008
`
`Studies Evaluating the Weekly Dosage Schedule
`Data from three open-label, single-agent, single arm clinical studies, involving a total of 304 patients in
`59 centers, support the use of CAMPTOSAR in the treatment of patients with metastatic cancer of the
`colon or rectum that has recurred or progressed following treatment with fluorouracil (5-FU)-based
`therapy. These studies were designed to evaluate tumor response rate and do not provide information
`on actual clinical benefit, such as effects on survival and disease-related symptoms. In each study,
`CAMPTOSAR was administered in repeated 6-week courses consisting of a 90-minute intravenous
`infusion once weekly for 4 weeks, followed by a 2-week rest period. Starting doses of CAMPTOSAR
`in these trials were 100, 125, or 150 mg/m2, but the 150 mg/m2 dose was poorly tolerated (due to
`unacceptably high rates of grade 4 late diarrhea and febrile neutropenia). Study 1 enrolled 48 patients
`and was conducted by a single investigator at several regional hospitals. Study 2 was a multicenter
`study conducted by the North Central Cancer Treatment Group. All 90 patients enrolled in Study 2
`received a starting dose of 125 mg/m2. Study 3 was a multicenter study that enrolled 166 patients from
`30 institutions. The initial dose in Study 3 was 125 mg/m2 but was reduced to 100 mg/m2 because the
`toxicity seen at the 125 mg/m2 dose was perceived to be greater than that seen in previous studies. All
`patients in these studies had metastatic colorectal cancer, and the majority had disease that recurred or
`progressed following a 5-FU-based regimen administered for metastatic disease.
`
`The results of the individual studies are shown in Table 2:
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`Page 6
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`CAMPTOSAR
`sNDA 20-571/S008
`
`Number of Patients
`Dose (mg/m2/wk x 4)
`
`Table 2. WEEKLY DOSAGE SCHEDULE: STUDY RESULTS
`Study
`
`3
`
`64
`125
`
`Female/Male (%)
`Median Age in years (range)
`Ethnic Origin (%)
`White
`African American
`Hispanic
`Oriental/Asian
`Performance Status (%)
`0
`1
`2
`Primary Tumor (%)
`Colon
`Rectum
`Unknown
`Prior 5-FU Therapy (%)
`For Metastatic Disease
` 6 months after Adjuvant
`> 6 months after Adjuvant
`Classification Unknown
`Prior Pelvic/Abdominal Irradiation (%)
`Yes
`Other
`None
`Duration of treatment with
`CAMPTOSAR (median, months)
`Relative Dose Intensity b (median %)
`
`2
`1
`90
`48
`125a
`125
`Demographics and Treatment Administration
`46/54
`36/64
`63 (29-78)
`63 (32-81)
`
`102
`100
`
`51/49
`64 (25-84)
`
`91
`
`522
`
`44
`51
`5
`
`87
`
`85
`
`68
`28
`
`23
`
`04
`
`96
`3
`
`50/50
`61 (42-84)
`
`81
`11
`
`80
`
`59
`33
`8
`
`89
`11
`0
`
`73
`27
`
`00
`
`029
`
`8
`4
`
`96
`
`400
`
`38
`48
`14
`
`71
`29
`0
`
`66
`7
`16
`12
`
`29
`9
`62
`4
`
`79
`12
`
`80
`
`60
`38
`2
`
`100
`
`00
`
`81
`15
`
`22
`
`30
`
`97
`5
`
`67
`
`73
`
`81
`
`74
`Efficacy
`Objective Response Rate (%) c
`21
`9
`14
`13
`(3.3 - 14.3)
`(5.5 - 22.6)
`(6.3 - 20.4)
`(9.3 - 32.3)
`(95% CI)
`2.8
`2.8
`1.5
`2.6
`Time to Response (median, months)
`6.4
`5.6
`5.9
`6.4
`Response Duration (median, months)
`9.3
`10.7
`8.1
`10.4
`Survival (median, months)
`43
`45
`31
`46
`1-Year Survival (%)
`a Nine patients received 150 mg/m2 as a starting dose; two (22.2%) responded to CAMPTOSAR.
`b Relative dose intensity for CAMPTOSAR based on planned dose intensity of 100, 83.3, and 66.7
`mg/m2/wk corresponding with 150, 125, and 100 mg/m2 starting doses, respectively.
`c There were 2 complete responses and 38 partial responses.
`
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`166
`167
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`In the intent-to-treat analysis of the pooled data across all three studies, 193 of the 304 patients began
`therapy at the recommended starting dose of 125 mg/m2. Among these 193 patients, 2 complete and 27
`partial responses were observed, for an overall response rate of 15.0% (95% Confidence Interval [CI],
`10.0% to 20.1%) at this starting dose. A considerably lower response rate was seen with a starting
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`Page 7
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`

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`CAMPTOSAR
`sNDA 20-571/S008
`
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`dose of 100 mg/m2. The majority of responses were observed within the first two courses of therapy,
`but responses did occur in later courses of treatment (one response was observed after the eighth
`course). The median response duration for patients beginning therapy at 125 mg/m2 was 5.8 months
`(range, 2.6 to 15.1 months).
`
`Of the 304 patients treated in the three studies, response rates to CAMPTOSAR were similar in males
`and females and among patients older and younger than 65 years. Rates were also similar in patients
`with cancer of the colon or cancer of the rectum and in patients with single and multiple metastatic
`sites. The response rate was 18.5% in patients with a performance status of 0 and 8.2% in patients
`with a performance status of 1 or 2. Patients with a performance status of 3 or 4 have not been studied.
`Over half of the patients responding to CAMPTOSAR had not responded to prior 5-FU. Patients who
`had received previous irradiation to the pelvis responded to CAMPTOSAR at approximately the same
`rate as those who had not previously received irradiation.
`
`Studies Evaluating the Once-Every-3-Week Dosage Schedule
`Single Arm Studies: Data from an open-label, single-agent, single arm, multicenter, clinical study
`involving a total of 132 patients support a once every-3-week dosage schedule of irinotecan in the
`treatment of patients with metastatic cancer of the colon or rectum that recurred or progressed
`following treatment with 5-FU. Patients received a starting dose of 350 mg/m2 given by 30-minute
`intravenous infusion once every 3 weeks. Among the 132 previously treated patients in this trial, the
`intent-to-treat response rate was 12.1% (95% CI, 7.0% to 18.1%).
`
`Randomized Trials: Two multicenter, randomized, clinical studies further support the use of irinotecan
`given by the once-every-three-weeks dosage schedule in patients with metastatic colorectal cancer
`whose disease has recurred or progressed following prior 5-FU therapy. In the first study, second-line
`irinotecan therapy plus best supportive care was compared with best supportive care alone. In the
`second study, second-line irinotecan therapy was compared with infusional 5-FU-based therapy. In
`both studies, irinotecan was administered intravenously at a starting dose of 350 mg/m2 over
`90 minutes once every 3 weeks. The starting dose was 300 mg/m2 for patients who were 70 years and
`older or who had a World Health Organization (WHO) performance status of 2. The highest total dose
`permitted was 700 mg. Dose reductions and/or administration delays were permitted in the event of
`severe hematologic and/or nonhematologic toxicities while on treatment. Best supportive care was
`
`Page 8
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`

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`CAMPTOSAR
`sNDA 20-571/S008
`
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`provided to patients in both arms of Study 1 and included antibiotics, analgesics, corticosteroids,
`transfusions, psychotherapy, or any other symptomatic therapy as clinically indicated. Concomitant
`medications such as antiemetics, atropine, and loperamide were given to patients in the irinotecan arm
`for prophylaxis and/or management of symptoms from treatment. If late diarrhea persisted for greater
`than 24 hours despite loperamide, a 7-day course of fluoroquinolone antibiotic prophylaxis was
`given.Patients in the control arm of the second study received one of the following 5-FU regimens: (1)
`Leucovorin, 200 mg/m2 i.v. over 2 hours; followed by 5-FU, 400 mg/m2 i.v. bolus; followed by 5-FU,
`600 mg/m2 continuous i.v. infusion over 22 hours on days 1 and 2 every 2 weeks; (2) 5-FU, 250 to
`300 mg/m2/day protracted continuous i.v. infusion until toxicity; (3) 5-FU, 2.6 to 3 g/m2 i.v. over
`24 hours every week for 6 weeks with or without leucovorin, 20 to 500 mg/m2/day every wk i.v. for
`6 weeks with 2-week rest between courses. Patients were to be followed every 3 to 6 weeks for 1 year.
`
`A total of 535 patients were randomized in the two studies at 94 centers in Europe, the Middle East,
`and South Africa. The primary endpoint in both studies was survival. The studies demonstrated a
`significant overall survival advantage for irinotecan compared with best supportive care (p=0.0001)
`and infusional 5-FU-based therapy (p=0.035) as shown in Figures 1, 2 and Table 3. In Study 1,
`median survival for patients treated with irinotecan was 9.2 months compared with 6.5 months for
`patients receiving best supportive care. In Study 2, median survival for patients treated with irinotecan
`was 10.8 months compared with 8.5 months for patients receiving infusional 5-FU-based therapy.
`Multiple regression analyses determined that patients’ baseline characteristics also had a significant
`effect on survival. When adjusted for performance status and other baseline prognostic factors,
`survival among patients treated with irinotecan remained significantly longer than in the control
`populations. (p=0.001 for Study 1 and p=0.017 for Study 2). The overall results of the two phase 3
`studies are shown in Table 3.
`
`Measurements of pain, performance status, and weight loss were collected prospectively in the two
`studies; however, the plan for the analysis of these data was defined retrospectively. When comparing
`irinotecan with best supportive care in study 1, this analysis showed a statistically significant
`advantage for irinotecan, with longer time to development of pain (6.9 months versus 2.0 months), time
`to performance status deterioration (5.7 months versus 3.3 months), and time to  5% weight loss (6.4
`months versus 4.2 months). Additionally, 33.3% (33/99) of patients with a baseline performance
`status of 1 or 2 showed an improvement in performance status when treated with irinotecan versus
`
`Page 9
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`

`

`CAMPTOSAR
`sNDA 20-571/S008
`
`232
`233
`
`11.3% (7/62) of patients receiving best supportive care (p=0.002). Because of the inclusion of patients
`with non-measurable disease, intent-to-treat response rates could not be assessed.
`
`Page 10
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`

`

`CAMPTOSAR
`sNDA 20-571/S008
`
`Figure 1. Survival in Phase 3 Trial of Second-Line Irinotecan
`versus Best Supportive Care (BSC)
`Study 1
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`235
`236
`237
`
`238
`239
`240
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`N
`Median follow-up
`Median (mo)
`Log Rank probability
`
`Irinotecan
`
`BSC
`
`0
`
`3
`Censored
`
`6
`
`9
`
`12
`Months
`
`15
`
`18
`
`21
`
`Irinotecan
`189
`
`BSC
`90
`
`13 mo
`
`9.2
`
`p=0.0001
`
`6.5
`
`Page 11
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`

`

`CAMPTOSAR
`sNDA 20-571/S008
`
`241
`242
`243
`244
`245
`
`246
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Figure 2. Survival in Phase 3 Trial of Second-Line Irinotecan
`versus Infusional 5-FU Regimen
`Study 2
`
`Irinotecan
`127
`
`N
`Median follow-up
`Median (mo)
`Log Rank probability
`
`10.8
`
`5-FU
`129
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`8.5
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`15 mo
`
`p=0.035
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`Irinotecan
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`5-FU
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`0
`
`3
`Censored
`
`6
`
`9
`
`12
`Months
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`15
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`18
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`21
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`sNDA 20-571/S008
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`Number of Patients
`
`Female/Male (%)
`Median Age in years (range)
`
`Table 3. ONCE-EVERY-3-WEEK DOSAGE SCHEDULE: STUDY RESULTS
`Study 1
`Study 2
`BSCa
`Irinotecan
`Irinotecan
`90
`189
`127
`Demographics and Treatment Administration
`32/68
`42/58
`59 (22-75)
`62 (34-75)
`
`5-FU
`129
`
`35/65
`58 (25-
`75)
`
`54
`43
`3
`
`62
`38
`
`68
`32
`20
`2.8
`
`81-99
`
`8.5
`
`43/57
`58 (30-75)
`
`Performance Status (PS)
`0 (%)
`1 (%)
`2 (%)
`Primary Tumor (%)
`Colon
`Rectum
`Prior 5-FU Therapy (%)
`For Metastatic Disease
`As Adjuvant Treatment
`Prior Irradiation (%)
`Duration of Study Treatment (median, months)
`(Log-Rank Test)
`Relative Dose Intensity (median %)b
`
`47
`39
`14
`
`55
`45
`
`70
`30
`26
`4.1
`
`94
`
`31
`46
`23
`
`52
`48
`
`63
`37
`27
`--
`
`--
`
`58
`35
`8
`
`57
`43
`
`58
`42
`18
`4.2
`(p=0.02)
`95
`
`Survival (median, months)
`(Log-Rank Test)
`a BSC = Best Supportive Care
`bRelative dose intensity for irinotecan based on planned dose intensity of 116.7 and 100 mg/m2/wk
`corresponding with 350 and 300 mg/m2 starting doses, respectively.
`
`6.5
`
`10.8
`(p=0.035)
`
`Survival
`9.2
`(p=0.0001)
`
`In the two randomized studies, the European Organization of Research and Treatment of Cancer
`Quality of Life Questionnaire (EORTC QLQ-C30) instrument was utilized. At each visit, patients
`completed a questionnaire consisting of 30 questions, such as “Did pain interfere with daily activities?”
`(1 = Not at All, to 4= Very Much and “Do you have any trouble taking a long walk?” (Yes or No). The
`answers from the 30 questions were converted into 15 subscales, that were scored from 0 to 100. The
`global health status subscale was derived from two questions about the patient’s sense of general well
`being in the past week. The results as summarized in Table 4 are based on patients’ worst post-baseline
`scores.
`
`In Study 1, a multivariate analysis and univariate analyses of the individual subscales were performed
`and corrected for multivariate testing. Patients receiving irinotecan reported significantly better results
`for the global health status, on two of five functional subscales, and on four of nine symptom
`subscales. As expected, patients receiving irinotecan noted significantly more diarrhea than those
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`sNDA 20-571/S008
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`receiving best supportive care. In Study 2, the multivariate analysis on all 15 subscales did not indicate
`a statistically significant difference between irinotecan and infusional 5-FU.
`
`Table 4. EORTC QLQ-C30: Mean Worst Post-Baseline Scorea
`
`QLQ-C30 Subscale
`
`Study 1
`Irinotecan BSC p-value
`47
`37
`0.03
`
`Irinotecan
`53
`
`Study 2
`5-FU p-value
`52
`0.9
`
`77
`68
`58
`60
`53
`
`68
`64
`47
`40
`35
`
`0.07
`0.4
`0.06
`0.0003
`0.02
`
`79
`64
`65
`66
`54
`
`83
`68
`67
`66
`57
`
`0.9
`0.9
`0.9
`0.9
`0.9
`
`Global Health Status
`Functional Scales
`Cognitive
`Emotional
`Social
`Physical
`Role
`Symptom Scales
`0.9
`46
`47
`0.03
`63
`51
`Fatigue
`0.9
`38
`35
`0.0007
`57
`37
`Appetite Loss
`0.9
`34
`38
`0.009
`56
`41
`Pain Assessment
`0.9
`33
`39
`0.3
`47
`39
`Insomnia
`0.9
`191
`25
`0.03
`41
`28
`Constipation
`0.9
`24
`25
`0.2
`40
`31
`Dyspnea
`0.09
`16
`25
`0.5
`29
`27
`Nausea/Vomiting
`0.3
`15
`24
`0.5
`26
`22
`Financial Impact
`0.2
`22
`32
`0.01
`19
`32
`Diarrhea
`aFor the five functional subscales and global health status subscales, higher scores imply better functioning,
`whereas, on the nine symptom subscales, higher scores imply more severe symptoms. The subscale scores of
`each patient were collected at each visit until the patient dropped out of the study.
`
`INDICATIONS AND USAGE
`
`CAMPTOSAR Injection is indicated for the treatment of patients with metastatic carcinoma of the
`colon or rectum whose disease has recurred or progressed following 5-FU-based therapy.
`
`CONTRAINDICATIONS
`
`CAMPTOSAR is contraindicated in patients with a known hypersensitivity to the drug.
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`CAMPTOSAR
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`WARNINGS
`
`Diarrhea
`CAMPTOSAR Injection can induce both early and late forms of diarrhea that appear to be mediated
`by different mechanisms. Early diarrhea (occurring during or shortly after infusion of CAMPTOSAR)
`is cholinergic in nature. It is usually transient and only infrequently is severe. It may be accompanied
`by symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal
`hyperperistalsis that can cause abdominal cramping. Early diarrhea and other cholinergic symptoms
`may be prevented or ameliorated by administration of atropine (see PRECAUTIONS, General, for
`dosing recommendations for atropine).
`
`Late diarrhea (generally occurring more than 24 hours after administration of CAMPTOSAR) can be
`prolonged, may lead to dehydration and electrolyte imbalance, and can be life threatening. Late
`diarrhea should be treated promptly with loperamide (see PRECAUTIONS, Information for Patients,
`for dosing recommendations for loperamide). Patients with severe diarrhea should be carefully
`monitored and given fluid and electrolyte replacement if they become dehydrated. National Cancer
`Institute (NCI) grade 3 diarrhea is defined as an increase of 7 to 9 stools daily, or incontinence, or
`severe cramping and NCI grade 4 diarrhea is defined as an increase of 10 stools daily, or grossly
`bloody stool, or need for parenteral support. If grade 3 or 4 late diarrhea occurs, administration of
`CAMPTOSAR should be delayed until the patient recovers and subsequent doses should be decreased
`(see DOSAGE and ADMINISTRATION).
`
`Myelosuppression
`Deaths due to sepsis following severe myelosuppression have been reported in patients treated with
`CAMPTOSAR. Therapy with CAMPTOSAR should be temporarily omitted if neutropenic fever
`occurs or if the absolute neutrophil count drops below 1000/mm3. After the patient recovers to an
`absolute neutrophil count > 1500/mm3, subsequent doses of CAMPTOSAR should be reduced
`depending upon the level of myelosuppression observed (see DOSAGE AND ADMINISTRATION).
`Routine administration of a colony-stimulating factor (CSF) is not necessary, but physicians may wish
`to consider CSF use in individual patients experiencing significant neutropenia.
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`CAMPTOSAR
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`
`Pregnancy
`CAMPTOSAR may cause fetal harm when administered to a pregnant woman. Radioactivity related to
`14C-irinotecan crosses the placenta of rats following intravenous administration of 10 mg/kg (which in
`separate studies produced an irinotecan Cmax and AUC about 3 and 0.5 times, respectively, the
`corresponding values in patients administered 125 mg/m2). Administration of 6 mg/kg/day intravenous
`irinotecan to rats (which in separate studies produced an irinotecan Cmax and AUC about 2 and 0.2
`times, respectively, the corresponding values in patients administered 125 mg/m2) and rabbits (about
`one-half the recommended human weekly starting dose on a mg/m2 basis) during the period of
`organogenesis, is embryotoxic as characterized by increased post-implantation loss and decreased
`numbers of live fetuses. Irinotecan was teratogenic in rats at doses greater than 1.2 mg/kg/day (which
`in separate studies produced an irinotecan Cmax and AUC about 2/3 and 1/40th, respectively, of the
`corresponding values in patients administered 125 mg/m2) and in rabbits at 6.0 mg/kg/day (about one
`half the recommended human weekly starting dose on a mg/m2 basis). Teratogenic effects included a
`variety of external, visceral, and skeletal abnormalities. Irinotecan administered to rat dams for the
`period following organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning
`ability and decreased female body weights in the offspring. There are no adequate and well-controlled
`studies of irinotecan in pregnant women. If the drug is used during pregnancy, or if the patient becomes
`pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
`Women of childbearing potential should be advised to avoid becoming pregnant while receiving
`treatment with CAMPTOSAR.
`
`PRECAUTIONS
`
`General
`Care of Intravenous Site: CAMPTOSAR is administered by intravenous infusion. Care should be
`taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation.
`Should extravasation occur, flushing the site with sterile water and applications of ice are
`recommended.
`Premedication with Antiemetics: Irinotecan is emetigenic. It is recommended that patients receive
`premedication with antiemetic agents. In clinical studies of the weekly dosage schedule, the majority of
`patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent,
`
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`such as a 5-HT3 blocker (e.g., ondansetron or granisetron). Antiemetic agents should be given on the
`day of treatment, starting at least 30 minutes before administration of CAMPTOSAR. Physicians
`should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for
`subsequent use as needed.
`Treatment of Cholinergic Symptoms: Prophylactic or therapeutic administration of 0.25 to 1 mg of
`intravenous or subcutaneous atropine should be considered (unless clinically contraindicated) in
`patients experiencing rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing,
`abdominal cramping, or diarrhea (occurring during or shortly after infusion of CAMPTOSAR). These
`symptoms are expected to occur more frequently with higher irinotecan doses.
`Patients at Particular Risk: Physicians should exercise particular caution in monitoring the effects of
`CAMPTOSAR in the elderly (65 years) and in patients who had previously received pelvic/abdominal
`irradiation (see ADVERSE REACTIONS).
`
`The use of CAMPTOSAR in patients with significant hepatic dysfunction has not been established. In
`clinical trials of either dosing schedule, irinotecan was not administered to patients with serum bilirubin
`>2.0 mg/dL, or transaminase >3 times the upper limit of normal if no liver metastasis, or transaminase
`>5 times the upper limit of normal with liver metastasis.
`
`However in clinical trials of the weekly dosage schedule, it has been noted that patients with modestly
`elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) have had a significantly greater
`likelihood of experiencing first-course grade 3 or 4 neutropenia than those with bilirubin levels that
`were less than 1.0 mg/dL (50.0% [19/38] versus 17.7% [47/226]; p<0.001). Patients with abnormal
`glucuronidation of bilirubin, such as those with Gilbert’s syndrome, may also be at greater risk of
`myelosuppression when receiving therapy with CAMPTOSAR. An association between baseline
`bilirubin elevations and an increased risk of late diarrhea has not been observed in studies of the weekly
`dosage schedule.
`
`Information for Patients
`Patients and pa