NDA 20-571/S-024/S-027/S-028
`Camptosar®(irinotecan HCl)
`
`Camptosar®
`irinotecan hydrochloride injection
`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
` July 21, 2005, Final Label
`Page 1
`
`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 life
`threatening since it may be prolonged and may lead to dehydration, electrolyte
`imbalance, or sepsis. Late diarrhea should be treated promptly with loperamide. Patients
`with diarrhea should be carefully monitored and given fluid and electrolyte replacement
`if they become dehydrated or antibiotic therapy if they develop ileus, fever, or severe
`neutropenia (see WARNINGS). Administration of CAMPTOSAR should be interrupted
`and subsequent doses reduced if severe diarrhea occurs (see DOSAGE AND
`ADMINISTRATION).
`Severe myelosuppression may occur (see WARNINGS).
`
`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 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 (S)-4,11-
`diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1H-pyrano[3’,4’:6,7]-
`indolizino[1,2-b]quinolin-9-yl-[1,4’bipiperidine]-1’-carboxylate, monohydrochloride,
`trihydrate. Its structural formula is as follows:
`
`AVENTIS EXHIBIT 2202
`Mylan v. Aventis IPR2016-00712
`
`

`
`NDA 20-571/S-024/S-027/S-028
`Camptosar®(irinotecan HCl)
`
`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`
` July 21, 2005, Final Label
`
`Page 2
`
`
`
`
`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.
`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.
`
`

`
`NDA 20-571/S-024/S-027/S-028
`Camptosar®(irinotecan HCl)
`
`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`
` July 21, 2005, Final Label
`
`Page 3
`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:
`
`
`Dose
`(mg/m2)
`
`Vz
`(L/m2)
`110
`±48.5
`234
`±69.6
`
`CL
`(L/h/m2)
`13.3
`±6.01
`13.9
`±4.0
`
`Table 1.Summary of Mean (±Standard Deviation)
`Irinotecan and SN-38 Pharmacokinetic
`Parameters in Patients with Solid Tumors
`Irinotecan
`t1/2
`AUC0-24
`Cmax
`(h)
`(ng·h/mL)
`(ng/mL)
`5.8a
`10,200
`1,660
`125
`±0.7
`±3,270
`±797
`(N=64)
`11.7b
`20,604
`3,392
`340
`±1.0
`±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
`t1/2 - 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.
`
`SN-38
`AUC0-24
`(ng·h/mL)
`229
`±108
`474
`±245
`
`Cmax
`(ng/mL)
`26.3
`±11.9
`56.0
`±28.2
`
`t1/2
`(h)
`10.4a
`±3.1
`21.0b
`±4.3
`
`
`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 is subsequently conjugated predominantly by the enzyme UDP-glucuronosyl
`transferase 1A1 (UGT1A1) to form a glucuronide metabolite. UGT1A1 activity is
`reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity
`such as the UGT1A1*28 polymorphism. Approximately 10% of the North American
`population is homozygous for the UGT1A1*28 allele. In a prospective study, in which
`irinotecan was administered as a single-agent on a once-every-3-week schedule, patients
`who were homozygous for UGT1A1*28 had a higher exposure to SN-38 than patients
`with
`the wild-type UGT1A1 allele
`(See WARNINGS and DOSAGE AND
`ADMINISTRATION). 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).
`
`

`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`NDA 20-571/S-024/S-027/S-028
`
` July 21, 2005, Final Label
`Camptosar®(irinotecan HCl)
`
`Page 4
`
`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 has 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: See Pediatric Use under PRECAUTIONS.
`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: Irinotecan clearance is diminished in patients with hepatic
`dysfunction while exposure to the active metabolite SN-38 is increased relative to that in
`patients with normal hepatic function. The magnitude of these effects is proportional to
`the degree of liver impairment as measured by elevations in total bilirubin and
`transaminase concentrations. However, the tolerability of irinotecan in patients with
`hepatic dysfunction (bilirubin greater than 2 mg/dl) has not been assessed sufficiently,
`and no
`recommendations
`for dosing can be made. See DOSAGE AND
`RECOMMENDATIONS and PRECAUTIONS: Patients at Particular Risk Sections.
`Renal Insufficiency: The influence of renal insufficiency on the pharmacokinetics of
`irinotecan has not been evaluated.
`Drug-Drug Interactions
`5-fluorouracil (5-FU) and leucovorin (LV): In a phase 1 clinical study involving
`irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) in 26 patients with solid tumors,
`the disposition of irinotecan was not substantially altered when the drugs were co-
`administered. Although the Cmax and AUC0-24 of SN-38, the active metabolite, were
`reduced (by 14% and 8%, respectively) when irinotecan was followed by 5-FU and
`LV administration compared with when irinotecan was given alone, this sequence
`of administration was used in the combination trials and is recommended (see
`DOSAGE AND ADMINISTRATION). Formal in vivo or in vitro drug interaction
`studies to evaluate the influence of irinotecan on the disposition of 5-FU and LV
`have not been conducted.
`Anticonvulsants: Exposure to irinotecan and its active metabolite SN-38 is
`substantially reduced in adult and pediatric patients concomitantly receiving the
`CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital or
`carbamazepine. The appropriate starting dose for patients taking these
`anticonvulsants has not been formally defined. The following drugs are also
`CYP3A4 inducers: rifampin, rifabutin. For patients requiring anticonvulsant
`treatment, consideration should be given to substituting non-enzyme inducing
`anticonvulsants at least 2 weeks prior to initiation of irinotecan therapy.
`Dexamethasone does not appear to alter the pharmacokinetics of irinotecan.
`St. John’s Wort: St. John’s Wort is an inducer of CYP3A4 enzymes. Exposure to
`the active metabolite SN-38 is reduced in patients receiving concomitant St.
`
`

`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`NDA 20-571/S-024/S-027/S-028
`
` July 21, 2005, Final Label
`Camptosar®(irinotecan HCl)
`
`Page 5
`
`John’s Wort. St. John’s Wort should be discontinued at least 2 weeks prior to the
`first cycle of irinotecan, and St. John’s Wort is contraindicated during irinotecan
`therapy.
`Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 enzymes. Patients
`receiving concomitant ketoconazole have increased exposure to irinotecan and its
`active metabolite SN-38. Patients should discontinue ketoconazole at least 1 week
`prior to starting irinotecan therapy and ketoconazole is contraindicated during
`irinotecan therapy.
`CLINICAL STUDIES
`Irinotecan has been studied in clinical trials in combination with 5-fluorouracil (5-FU)
`and leucovorin (LV) and as a single agent (see DOSAGE AND ADMINISTRATION).
`When given as a component of combination-agent treatment, irinotecan was either given
`with a weekly schedule of bolus 5-FU/LV or with an every-2-week schedule of infusional
`5-FU/LV. Weekly and a once-every-3-week dosage schedules were used for the single-
`agent irinotecan studies. Clinical studies of combination and single-agent use are
`described below.
`First-Line Therapy in Combination with 5-FU/LV for the Treatment of
`Metastatic Colorectal Cancer
`Two phase 3, randomized, controlled, multinational clinical trials support the use of
`CAMPTOSAR Injection as first-line treatment of patients with metastatic carcinoma of
`the colon or rectum. In each study, combinations of irinotecan with 5-FU and LV were
`compared with 5-FU and LV alone. Study 1 compared combination irinotecan/bolus 5-
`FU/LV therapy given weekly with a standard bolus regimen of 5-FU/LV alone given
`daily for 5 days every 4 weeks; an irinotecan-alone treatment arm given on a weekly
`schedule was also included. Study 2 evaluated two different methods of administering
`infusional 5-FU/LV, with or without irinotecan. In both studies, concomitant medications
`such as antiemetics, atropine, and loperamide were given to patients for prophylaxis
`and/or management of symptoms from treatment. In Study 2, a 7-day course of
`fluoroquinolone antibiotic prophylaxis was given in patients whose diarrhea persisted for
`greater than 24 hours despite loperamide or if they developed a fever in addition to
`diarrhea. Treatment with oral fluoroquinolone was also initiated in patients who
`developed an absolute neutrophil count (ANC) <500/mm3, even in the absence of fever or
`diarrhea. Patients in both studies also received treatment with intravenous antibiotics if
`they had persistent diarrhea or fever or if ileus developed.
`In both studies, the combination of irinotecan/5-FU/LV therapy resulted in significant
`improvements in objective tumor response rates, time to tumor progression, and survival
`when compared with 5-FU/LV alone. These differences in survival were observed in
`spite of second-line therapy in a majority of patients on both arms, including crossover to
`irinotecan-containing regimens in the control arm. Patient characteristics and major
`efficacy results are shown in Table 2.
`
`
`
`Irinotecan
`weekly x 4 q
`6 weeks
`226
`
`
`
`Study 2
`
`
`Irinotecan +
`Infusional
`5-FU/LV
`198
`
`
`Infusional
`5-FU/LV
`187
`
`
`
`
`
`
`
`
`
`
`
`
`Number of Patients
`
`Irinotecan +
`Bolus 5-FU/LV
`weekly x 4 q
`6 weeks
`231
`
`Table 2. Combination Dosage Schedule: Study Results
`Study 1
`
`Bolus 5-FU/LV
`daily x 5 q
`4 weeks
`226
`
`

`
`46
`8
`
`84
`15
`
`1.8
`(0.1-185)
`
`90
`10
`3.9
`
`75
`—
`
`18
`
`
`4.2
`
`12.0
`
`
`(p<0.0001)c
`
`(p=0.004)d
`
`45
`13
`
`85
`14
`
`1.7
`(0-203)
`
`92
`8
`4.1
`
`—
`86
`
`21
`
`4.3
`
`12.6
`
`
`
`NDA 20-571/S-024/S-027/S-028
`Camptosar®(irinotecan HCl)
`
`Demographics and Treatment Administration
`Female/Male (%)
`34/65
`Median Age in years (range)
`62 (25-85)
`Performance Status (%)
`
`0
`39
`1
`2
`
`46
`15
`
`81
`17
`
`1.9
`(0-161)
`
`89
`11
`5.5
`
`72
`71
`
`39
`
`7.0
`
`14.8
`
`
`
`Primary Tumor (%)
`Colon
`Rectum
`Median Time from Diagnosis to
`Randomization
`(months, range)
`Prior Adjuvant 5-FU Therapy (%)
`No
`Yes
`Median Duration of Study
`Treatmenta (months)
`Median Relative Dose Intensity (%)a
`Irinotecan
`5-FU
`Efficacy Results
`Confirmed Objective Tumor
`Response Rateb (%)
`Median Time to Tumor Progressiond
`(months)
`Median Survival
`(p<0.05)d
`(months)
`a Study 1: N=225 (irinotecan/5-FU/LV),N=219 (5-FU/LV),N=223 (irinotecan)
` Study 2: N=199 (irinotecan/5-FU/LV),N=186 (5-FU/LV)
`b Confirmed > 4 to 6 weeks after first evidence of objective response
`c Chi-square test
`d Log-rank test
`
`Improvement was noted with irinotecan-based combination therapy relative to 5-FU/LV
`when response rates and time to tumor progression were examined across the following
`demographic and disease-related subgroups (age, gender, ethnic origin, performance
`status, extent of organ involvement with cancer, time from diagnosis of cancer, prior
`adjuvant therapy, and baseline laboratory abnormalities). Figures 1 and 2 illustrate the
`Kaplan-Meier survival curves for the comparison of irinotecan/5-FU/LV versus 5-FU/LV
`in Studies 1 and 2, respectively.
`
`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`
` July 21, 2005, Final Label
`
`Page 6
`
`45/54
`61 (19-85)
`
`41
`
`35/64
`61 (30-87)
`
`46
`
`33/67
`62 (27-75)
`
`51
`
`47/53
`59 (24-75)
`
`51
`
`42
`7
`
`55
`45
`
`4.5
`(0-88)
`
`74
`26
`5.6
`
`87
`86
`
`35
`
`(p<0.005)c
`
`6.7
`
`(p<0.001)d
`17.4
`
`(p<0.05)d
`
`41
`8
`
`65
`35
`
`2.7
`(0-104)
`
`76
`24
`4.5
`
`—
`93
`
`22
`
`4.4
`
`14.1
`
`

`
`NDA 20-571/S-024/S-027/S-028
`Camptosar®(irinotecan HCl)
`
`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`
` July 21, 2005, Final Label
`
`Page 7
`
`Figure 1. Survival
`First-Line Irinotecan/5-FU/LV vs 5-FU/LV
`Study 1
`
`Irinotecan/5-FU/LV
`
`5-FU/LV
`
`p<0.05*
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
`
`Probability
`
`0
`
`3
`
`6
`
`9
`
`*log-rank test
`
`12 15 18 21 24 27 30 33 36 39 42
`Months
`
`
`
`

`
`NDA 20-571/S-024/S-027/S-028
`Camptosar®(irinotecan HCl)
`
`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`
` July 21, 2005, Final Label
`
`Page 8
`
`
`
`Figure 2. Survival
`First-Line Irinotecan/5-FU/LV vs 5-FU/LV
`Study 2
`
`Irinotecan/5-FU/LV
`
`5-FU/LV
`
`p<0.05*
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
`
`Probability
`
`0
`
`3
`
`6
`
`9
`
`*log-rank test
`
`15
`12
`Months
`
`18
`
`21
`
`24
`
`27
`
`30
`
`
`
`
`
`Second-Line Treatment for Recurrent or Progressive Metastatic Colorectal Cancer
`After 5-FU-Based Treatment
`Weekly Dosage Schedule
`Data from three open-label, single-agent, 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
`
`

`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`NDA 20-571/S-024/S-027/S-028
`
` July 21, 2005, Final Label
`Camptosar®(irinotecan HCl)
`
`Page 9
`
`following treatment with 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 cycles 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 3.
`
`
`

`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`
` July 21, 2005, Final Label
`
`Page 10
`
`
`
`NDA 20-571/S-024/S-027/S-028
`Camptosar®(irinotecan HCl)
`
`
`Table 3. Weekly Dosage Schedule: Study Results
`
`Study
`
` 5
`
`
`74
`
`
`
`
`
`
`1
`
`48
`Number of Patients
`125a
`Starting Dose (mg/m2/wk x 4)
`Demographics and Treatment Administration
`Female/Male (%)
`46/54
`Median Age in years (range)
`63 (29-78)
`
`Ethnic Origin (%)
`79
` White
`12
`
`African American
`8
`
`Hispanic
`0
`
`Oriental/Asian
`Performance Status (%)
`
`
`0
`60
`
`1
`38
`
`2
`2
`
`Primary Tumor (%)
`100
`
`Colon
`0
`
`Rectum
`0
`
`Unknown
`
`Prior 5-FU Therapy (%)
`81
`
`For Metastatic Disease
`15
`
`≤ 6 months after Adjuvant
`2
`
`> 6 months after Adjuvant
`2
`
`Classification Unknown
`Prior Pelvic/Abdominal Irradiation (%)
`
`3
`
`Yes
`0
`
`Other
`97
`
`None
`Duration of Treatment with
`CAMPTOSAR (median, months)
`Relative Dose Intensityb (median %)
`Efficacy
`Confirmed Objective Response Rate (%)c
`9
`14
`13
`21
`(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 Confirmed ≥ 4 to 6 weeks after first evidence of objective response.
`
`3
`
`102
`100
`
`51/49
`64 (25-84)
`
`91
`5
`2
`2
`
`44
`51
`5
`
`87
`8
`5
`
`68
`28
`2
`3
`
`0
`4
`96
`
` 3
`
`
`81
`
`64
`125
`
`50/50
`61 (42-84)
`
`81
`11
`8
`0
`
`59
`33
`8
`
`89
`11
`0
`
`73
`27
`0
`0
`
`0
`2
`98
`
` 4
`
`
`73
`
`2
`90
`125
`
`36/64
`63 (32-81)
`
`96
`4
`0
`0
`
`38
`48
`14
`
`71
`29
`0
`
`66
`7
`16
`12
`
`29
`9
`62
`
` 4
`
`
`67
`
`

`
`NDA 20-571/S-024/S-027/S-028
`Camptosar®(irinotecan HCl)
`
`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`
` July 21, 2005, Final Label
`
`Page 11
`
`
`
`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 dose of 100 mg/m2.
`The majority of responses were observed within the first two cycles of therapy, but
`responses did occur in later cycles of treatment (one response was observed after the
`eighth cycle). 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.
`
`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-3-week 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 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 provided to patients in both arms of Study 1 and included antibiotics, analgesics,
`corticosteroids, transfusions, psychotherapy, or any other symptomatic therapy as
`clinically indicated. In both studies, concomitant medications such as antiemetics,
`atropine, and loperamide were given to patients 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
`
`

`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`NDA 20-571/S-024/S-027/S-028
`
` July 21, 2005, Final Label
`Camptosar®(irinotecan HCl)
`
`Page 12
`
`in the control arm of the second study received one of the following 5-FU regimens: (1)
`LV, 200 mg/m2 IV over 2 hours; followed by 5-FU, 400 mg/m2 IV bolus; followed by
`5-FU, 600 mg/m2 continuous IV infusion over 22 hours on days 1 and 2 every 2 weeks;
`(2) 5-FU, 250 to 300 mg/m2/day protracted continuous IV infusion until toxicity; (3) 5-
`FU, 2.6 to 3 g/m2 IV over 24 hours every week for 6 weeks with or without LV, 20 to
`500 mg/m2/day every week IV for 6 weeks with 2-week rest between cycles. 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. 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 3 and 4. 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). 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 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.
`
`

`
`NDA 20-571/S-024/S-027/S-028
`Camptosar®(irinotecan HCl)
`
`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`
` July 21, 2005, Final Label
`
`Page 13
`Figure 3. Survival
` Second-Line Irinotecan vs Best Supportive Care (BSC)
`Study 1
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
`
`Probability
`
` Irinotecan BSC
`N 189 90
`Median follow-up 13 mo
`Median (mo) 9.2 6.5
`
`Irinotecan
`
`BSC
`
`p=0.0001*
`
`0
`
`3
`
`6
`
`*log-rank test
`
`12
`
`9
`Months
`
`15
`
`18
`
`21
`
`Figure 4. Survival
`Second-Line Irinotecan vs Infusional 5-FU
`Study 2
`
` Irinotecan 5-FU
`N 127 129
`Median follow-up 15 mo
`Median (mo) 10.8 8.5
`
`Irinotecan
`
`5-FU
`
`p=0.035*
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
`
`Probability
`
`0
`
`3
`
`6
`
`*log-rank test
`
`12
`
`9
`Months
`
`15
`
`18
`
`21
`
`

`
`NDA 20-571/S-024/S-027/S-028
`Camptosar®(irinotecan HCl)
`
`
`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`
` July 21, 2005, Final Label
`
`Page 14
`
`In the two randomized studies, the EORTC QLQ-C30 instrument was utilized. At the
`start of each cycle of therapy, 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,
`and the global health status subscale that was derived from two questions about the
`patient’s sense of general well being in the past week. In addition to the global health
`status subscale, there were five functional (i.e., cognitive, emotional, social, physical,
`role) and nine symptom (i.e., fatigue, appetite loss, pain assessment, insomnia,
`constipation, dyspnea, nausea/vomiting, financial impact, diarrhea) subscales. The results
`as summarized in Table 5 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 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.
`
`

`
`NDA 20-571/S-024/S-027/S-028
`Camptosar®(irinotecan HCl)
`
`
`
`
` Hepatic Dysfunction, Pancreatitis, UGT1A1
`
` July 21, 2005, Final Label
`
`Page 15
`
`Table 4. Once-Every-3-Week Dosage Schedule: Study Results
`Study 1
`Irinotecan
`189
`
`BSCa
`90
`
`Study 2
`Irinotecan
`127
`
`
`
`Number of Patients
`Demographics and Treatment Administration
`Female/Male (%)
`Median Age in years (range)
`Performance Status (%)
`
`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
`Survival
`Survival