Download Tailoring treatment for metastatic colorectal cancer

Pfizer Oncology Presents
Optimizing Treatment Strategies in
Colorectal Cancer
Tailoring treatment
for metastatic
colorectal cancer
Considerations for first-line therapy
Edward Lin, MD
Associate Professor, University of Washington
Associate Member, Fred Hutchinson Cancer Research Center
Seattle, Washington
Edith Mitchell, MD
Clinical Professor of Medicine and Medical Oncology
Gastrointestinal Oncology, Thomas Jefferson University
Philadelphia, Pennsylvania
Pfizer Oncology Presents
Optimizing Treatment Strategies in
Colorectal Cancer
Tailoring treatment
for metastatic
colorectal cancer
Considerations for first-line therapy
Edward Lin, MD
Associate Professor, University of Washington
Associate Member, Fred Hutchinson Cancer Research Center
Seattle, Washington
Edith Mitchell, MD
Clinical Professor of Medicine and Medical Oncology
Gastrointestinal Oncology, Thomas Jefferson University
Philadelphia, Pennsylvania
Editorial support and publishing was provided by Current Medicine Group LLC and funded by Pfizer Inc.
Tailoring treatment for metastatic
colorectal cancer: considerations for
first-line therapy
Key Points
•Colorectal cancer (CRC) will affect an estimated 153,760 people in the USA in
2007; a third of these patients will die from metastatic disease.
•Treatment strategies need to be tailored to the defined goal of treatment and tumor
presentation.
•The goal of therapy needs to be defined upfront with the patient and therapy
reassessed as treatment evolves.
• More than one regimen is recognized as a standard approach to treating advanced metastatic disease.
• For patients who can tolerate intensive therapy, two primary options recommended
by the National Comprehensive Cancer Network® (NCCN) guidelines for initial
therapy are FOLFIRI and FOLFOX; different factors may influence the choice.
•Integration of multimodality therapy, including surgery and radiation, may be necessary.
Introduction
The annual incidence of new cases of CRC is approximately 150,000 in the USA alone
(Figure 1), with about a third of these patients expected to die as a result of metastatic
colorectal cancer (mCRC).1
Figure 1. Estimated
new colorectal cancer
cases and deaths in the
USA in 20071
For many years, 5-fluorouracil (5-FU) has been available for treating patients with colorectal
cancer and remains the backbone of mCRC treatment, even with the introduction of irinotecan,2
oxaliplatin,3 capecitabine,4 bevacizumab,5 cetuximab,6 and more recently, panitumumab.7
Combining continuous infusion 5-FU with either irinotecan (FOLFIRI) or oxaliplatin
(FOLFOX) is now the de facto first-line standard for the treatment of advanced CRC, resulting
in a median overall survival of almost 2 years.8–11 Although FOLFOX is used more frequently
Please see the full CAMPTOSAR® (irinotecan HCl) prescribing information on pages 8 to 13.
as first-line therapy, data show that FOLFIRI is equally effective.8–12 Further consideration
for adding a targeted agent, such as bevacizumab, may be appropriate as indicated in the
NCCN guidelines.13
Given the proven effectiveness of several regimens, an increasing number of patients
now receive multiple lines of therapy. Considering the heterogeneous nature of tumor
presentations, and the many parallel treatment options set out by the NCCN guidelines,13
the goals of this bulletin are to help clinicians:
•Better understand how to tailor treatment strategies to the individual needs of
patients;
•Recognize the need, based on the disease characteristics and the patient’s needs, to
consider more than one regimen as the standard approach to treating mCRC.
Tenets of tailored therapy
Given the significant heterogeneity of mCRC and the many therapeutic options, treatment
decisions should consider the following:
1. Define and redefine the goal of therapy;
2. Assess disease patterns and comorbidities;
3. Discuss treatment options, including clinical trials, with patients;
4. Manage and reduce toxicity;
5. Integrate a multimodality therapy, including surgery and radiation.
Define and redefine the goal of therapy
The first step in treating a patient with CRC is to determine the extent of involvement
of distant organs and to determine the goal of therapy with the patient. For the group of
patients who present with extensive, unresectable metastases, the goal of therapy would be
largely palliative. Therefore, the therapeutic decision should focus on extending survival
with an optimal sequence of therapeutic agents and on quality of life by reducing treatmentrelated toxicities.
On the other hand, if the disease can be treated with locoregional therapy such as surgery,
an ablative technique, or radiation therapy, the goal may be to render the patient free
of visible disease to achieve long-term remission or cure. Throughout the management
process, it is important to redefine the goals of therapy with the patient.
Assess disease patterns and comorbidities
The next step toward tailored treatment is to evaluate other disease processes that could
potentially have an impact on the effectiveness of treatment. For those patients with
extensive multivisceral metastases, the chosen therapy should take into account the
response rate, toxicity profiles, and the subsequent planned care that may allow the
optimal exposure to the therapeutic agents.
Please see the full CAMPTOSAR® (irinotecan HCl) prescribing information on pages 8 to 13.
Preexisting medical conditions, for example, may shape the use of some therapies and
limit the administration of others. The chosen therapy should be tailored based on the
patients’ comorbidities and stated goal, taking into account the toxicity profiles of the
therapeutic agents and a full understanding of their relative contraindications.
Discuss treatment options
It is important to thoroughly discuss all of the available treatment options with patients
and evaluate each individual’s needs. While it is ideal to enroll patients into well-designed
clinical trials, unfortunately this is not a viable option for all patients. Deciding which
regimen to use first-line will be influenced not only by whether or not the patients can
tolerate effective, intensive chemotherapy but also if they are willing to.13
FOLFIRI and FOLFOX are both proven effective for first-line treatment. In a Tournigand
et al phase 3 sequencing study of first-line FOLFIRI followed by second-line FOLFOX or the
reverse, there were equivalent first-line response rates and median overall survival.8 In terms
of safety, no significant difference was shown between FOLFOX and FOLFIRI in grade 3
or 4 diarrhea. The FOLFIRI arm was associated with more grade 3 or 4 febrile neutropenia,
nausea and vomiting, mucositis, and fatigue. The FOLFOX arm was associated with more
grade 3 sensory neurotoxicity, grade 3 or 4 neutropenia, and thrombocytopenia.8
FOLFOX is an effective first-line treatment option to be discussed. The most common
oxaliplatin-associated adverse events are peripheral sensory neuropathies, fatigue,
neutropenia, nausea, emesis, and diarrhea.14 Many practitioners are now facing the challenges
of managing grade 2 or 3 cumulative peripheral neurotoxicity that can frequently occur
in patients exposed to oxaliplatin as part of the FOLFOX regimen. Neurotoxicities can
present as initially subtle, such as difficulty in buttoning a shirt, and may become as severe
as full gait disturbances with prolonged use of oxaliplatin. It is, therefore, important to
discuss with patients the potential neurotoxicity of oxaliplatin.
FOLFIRI is also an effective first-line treatment choice to be discussed. The most common
irinotecan-associated adverse events are diarrhea, neutropenia, emesis, and nausea.15
Irinotecan is associated with both early and late forms of diarrhea, which may be severe.
Early diarrhea occurs during or shortly after infusion. It may be accompanied by cholinergic
symptoms. Late diarrhea generally occurs more than 24 hours after administration. Both
forms can be life threatening. Therefore, it is important to discuss the risks with patients,
and all attempts should be made to manage such an event.
Appropriate considerations should be given to adding bevacizumab as per NCCN
guidelines.13 As with other active agents, bevacizumab is associated with adverse
events, which need to be considered when treating patients. Among these are grade 3
or 4 hypertension, diarrhea, and leukopenia.9 Furthermore, treatment with bevacizumab
should be delayed for at least two half-lives (ie, 8 weeks) if there is a need for any surgical
intervention to minimize fistula or wound dehiscence risk.16
Other potential considerations when deciding first-line treatment are the patient’s age,
performance status, and underlying genetic polymorphisms. Studies continue to investigate
the role of microsatellite instability as a predictive marker, and further research is looking
at ethnicity and the impact of DNA polymorphisms on levels of response.
Please see the full CAMPTOSAR® (irinotecan HCl) prescribing information on pages 8 to 13.
Manage and reduce toxicity
In a palliative setting, overall toxicities and quality of life have become the number one
priority of treatment. Because toxicities are an important part of selecting both the initial
first-line treatment and subsequent therapies, research that evaluates strategies to decrease
and manage potential acute and cumulative toxicities is critical. Investigational approaches
to limit the toxicity associated with certain therapies17,18 may help to enhance patients’
tolerance of therapy in the future.
Once therapy is initiated, three guiding tenets can help to drive ongoing therapeutic
decisions.
1.Continue an effective therapy as long as possible and institute appropriate
treatment breaks due to adverse events.
2.Discontinue ineffective or toxic chemotherapy regimens as early as possible to
explore other parallel therapeutic options.
3.Provide early and optimal integration of multimodal therapy such as surgery and
possibly also radiotherapy for potential “cure” when this is feasible.
Strategic approaches to further reduce toxicity include assessing patient experience on prior
treatments. For example, adverse events experienced during prior adjuvant treatment is
one factor that should be considered when selecting first-line treatment. In some instances,
for patients previously treated with FOLFOX adjuvant, physicians may consider a different
regimen – such as FOLFIRI – in first-line mCRC, if a patient previously developed
cumulative neuropathy with FOLFOX. Other clinical management approaches may
involve consideration of whether a “stop and go” strategy has been used before to mitigate
cumulative toxicities.18
For patients who have progressed, the need to manage toxicity continues. Following
progression in first-line, there are several therapeutic options available, such as the use
of cetuximab with irinotecan for patients who have become refractory to irinotecan.
Recognizing and then minimizing the occurrence of cetuximab- or panitumumab-induced
skin toxicities and hypomagnesemia is the key to the therapy continuum of advanced CRC.
Use of palliative radiation should also be considered.
Integrate a multimodality therapy, including surgery
and radiation
Recognizing or selecting mCRC patients according to tumor biology (eg, long diseasefree interval, solitary metastasis, carcinoembryonic antigen <200 ng/mL) ensures the best
surgical outcome and may limit the role of adjuvant chemotherapy. Selective use of targeted
curative radiation may have the same merits as surgical resection.19
It should be borne in mind that for those patients with resectable liver metastases on
presentation, or those who are rendered operable by chemotherapy, there are eight unique
segmental hepatic blood supplies and surgical techniques (eg, left or right hepatectomy,
segmentectomy, extended left or right hepatectomy) that may be of benefit.20
Please see the full CAMPTOSAR® (irinotecan HCl) prescribing information on pages 8 to 13.
Conclusion
Although CRC remains a clinical challenge, selecting the most effective treatment for
individual patients requires taking into consideration multiple tenets. As clinicians,
these new regimens provide us with opportunities not only to tailor treatment to the
individual patient’s needs, but also to take into consideration the patient’s overall quality
of life.
Important information (CAMPTOSAR)
CAMPTOSAR® (irinotecan HCl) is indicated as a component of first-line therapy in
combination with 5-FU/LV for the treatment of mCRC. CAMPTOSAR is also indicated in
the treatment of patients with mCRC, whose disease has recurred or progressed following
initial FU-based therapy.
Both early and late forms of diarrhea can occur and may be life threatening. Late
diarrhea should be managed promptly with loperamide and supportive care
including antibiotics as needed.
CAMPTOSAR can induce severe myelosuppression. Depending on the severity of
neutropenia, dose delay, dose reduction or use of a colony-stimulating factor should
be considered.
Particular caution should be exercised in monitoring the effects of CAMPTOSAR in the
elderly (>65), in patients who have previously received pelvic/abdominal irradiation, in
patients with a performance status of 2 or higher, and in patients known to be homozygous
for the UGT1A1*28 allele. Rare cases of ileus, complicated colitis, or renal impairment
have been observed. It is recommended that patients receive premedication with antiemetic
agents. Prophylactic or therapeutic administration of atropine should be considered in
patients experiencing cholinergic symptoms. Provided intolerable toxicity does not develop,
treatment with additional courses may be continued indefinitely as long as patients continue
to experience clinical benefits. Thromboembolic events have been observed but the specific
cause has not been determined. CAMPTOSAR should not be used in patients with severe
bone marrow failure. In addition, patients with hereditary fructose intolerance should not
be given CAMPTOSAR, as this product contains sorbitol.
Please see the full CAMPTOSAR® (irinotecan HCl) prescribing information on pages 8 to 13.
References
1Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin 2007;57(1):43–66.
2Fuchs C, Mitchell EP, Hoff PM. Irinotecan in the
treatment of colorectal cancer. Cancer Treat Rev
2006;32(7):491–503.
3Simpson D, Dunn C, Curran M, Goa KL. Oxaliplatin: a review of its use in combination therapy
for advanced metastatic colorectal cancer. Drugs
2003;63(19):2127–2156.
4Ajani J. Review of capecitabine as oral treatment
of gastric, gastroesophageal, and esophageal
cancers. Cancer 2006;107(2):221–231.
5Hurwitz H, Kabbinavar F. Bevacizumab combined with standard fluoropyrimidine-based
chemotherapy regimens to treat colorectal
cancer. Oncology 2005;69(Suppl 3):17–24.
6Cerea G, Ricotta R, Schiavetto I, et al. Cetuximab for treatment of metastatic colorectal cancer.
Ann Oncol 2006;17(Suppl 7):vii66–vii67.
7Wainberg Z, Hecht JR. Panitumumab in colon
cancer: a review and summary of ongoing trials.
Expert Opin Biol Ther 2006;6(11):1229–1235.
8Tournigand C, Andre T, Achille E, et al. FOLFIRI
followed by FOLFOX6 or the reverse sequence
in advanced colorectal cancer: a randomized
GERCOR study. J Clin Oncol 2004;22(2):
229–237.
9Hurwitz H, Fehrenbacher L, Novotny W, et al.
Bevacizumab plus irinotecan, fluorouracil, and
leucovorin for metastatic colorectal cancer.
N Engl J Med 2004;350(23):2335–2342.
10Grothey A, Sargent D. Overall survival of
patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan,
and oxaliplatin regardless of whether doublet
or single-agent therapy is used first line. J Clin
Oncol 2005;23(36):9441–9442.
11Goldberg RM, Sargent DJ, Morton RF, et al. A
randomized controlled trial of fluorouracil plus
leucovorin, irinotecan, and oxaliplatin combi-
nations in patients with previously ­ untreated
metastatic colorectal cancer. J Clin Oncol
2004;22(1):23–30.
12Colucci G, Gebbia V, Paoletti G, et al;
Gruppo Oncologico Dell’Italia Meridionale.
Phase III randomized trial of FOLFIRI versus
FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo
Oncologico Dell’Italia Meridionale. J Clin Oncol
2005;23(22):4866–4875.
13National Comprehensive Cancer Network.
NCCN Clinical Practice Guidelines in Oncology Version 1. 2007: Colon Cancer. Available at:
www.nccn.org/professionals/physician_gls/PDF/
colon.pdf. Accessed April 18, 2007.
14 Eloxatin (US prescribing information). Bridge-­
water, NJ: sanofi-aventis US LLC; 2006.
15Camptosar (US prescribing information). New
York, NY: Pfizer Inc; 2006.
16 Avastin (US prescribing information). South San Francisco, CA: Genentech Inc; 2006.
17Highlights from the 2006 American Society
of Clinical Oncology Gastrointestinal Cancers
Symposium. Clin Colorectal Cancer 2006;5:
398–402.
18Tournigand C, Cervantes A, Figer A, et al.
OPTIMOX1: a randomized study of FOLFOX4
or FOLFOX7 with oxaliplatin in a stop-andgo fashion in advanced colorectal cancer – a
GERCOR study. J Clin Oncol 2006;24(3):
394–400.
19Fong Y, Fortner J, Sun RL, et al. Clinical score
for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of
1001 consecutive cases. Ann Surg 1999;230(3):
309-318.
20Herbert R, McCollum VT, Cassidy A, et al.
Imaging of the liver prior to hepatic resection:
basic anatomical considerations. Radiography
2003; 9(1):53–62.
Please see the full CAMPTOSAR® (irinotecan HCl) prescribing information on pages 8 to 13.
Camptosar
®
Camptosar
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 or is chemically synthesized. The chemical name is (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy3,14-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:
Irinotecan Hydrochloride
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 singlestrand 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.
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:
®
irinotecan hydrochloride injection
irinotecan hydrochloride injection
For Intravenous Use Only
Camptosar
®
irinotecan hydrochloride injection
Table 1. Summary of Mean (±Standard Deviation)
Irinotecan and SN-38 Pharmacokinetic
Parameters in Patients with Solid Tumors
Irinotecan
SN-38
Dose
(mg/m2) Cmax AUC0-24 t1/2
(ng/mL) (ng·h/mL) (h)
Vz
CL
Cmax AUC0-24 t1/2
(L/m2) (L/h/m2) (ng/mL)(ng·h/mL) (h)
a
125
(N=64)
1,660
±797
10,200 5.8
110
13.3
±3,270 ±0.7 ±48.5 ±6.01
26.3
±11.9
229
±108
10.4 a
±3.1
340
(N=6)
3,392
±874
20,604 11.7b 234
±6,027 ±1.0 ±69.6
56.0
±28.2
474
±245
21.0b
±4.3
13.9
±4.0
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.
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 UDPglucuronosyl 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).
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 ADMINISTRATION and PRECAUTIONS: Patients at Particular Risk
Sections).
Renal Insufficiency: The influence of renal insufficiency on the pharmacokinetics
of irinotecan has not been evaluated. Therefore, caution should be undertaken in
patients with impaired renal function. Irinotecan is not recommended for use in
patients on dialysis.
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.
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.
Neuromuscular blocking agents. Interaction between irinotecan and
neuromuscular blocking agents cannot be ruled out. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of
suxamethonium and the neuromuscular blockade of non-depolarizing drugs may
be antagonized.
Atazanavir sulfate: Coadministration of atazanavir sulfate, a CYP3A4 and
UGT1A1 inhibitor has the potential to increase systemic exposure to SN-38, the
active metabolite of irinotecan. Physicians should take this into consideration
when co-administering these drugs.
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 every2-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.
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.
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 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
Camptosar
Camptosar
®
Camptosar
®
irinotecan hydrochloride injection
®
irinotecan hydrochloride injection
Table 2. Combination Dosage Schedule: Study Results
Study 1
Irinotecan +
Bolus 5-FU/LV
weekly x 4 q
6 weeks
231
Bolus 5-FU/LV
daily x 5 q
4 weeks
226
Number of Patients
Demographics and Treatment Administration
Female/Male (%)
34/65
45/54
Median Age in years (range)
62 (25-85)
61 (19-85)
Performance Status (%)
0
39
41
1
46
45
2
15
13
Primary Tumor (%)
Colon
81
85
Rectum
17
14
Median Time from Diagnosis to
Randomization
1.9
1.7
(months, range)
(0-161)
(0-203)
Prior Adjuvant 5-FU Therapy (%)
No
89
92
Yes
11
8
Median Duration of Study Treatment a
(months)
5.5
4.1
Median Relative Dose Intensity (%)a
Irinotecan
72
—
5-FU
71
86
Efficacy Results
Confirmed Objective Tumor
39
21
Response Rateb (%)
(p<0.0001)c
Median Time to Tumor Progressiond
7.0
4.3
(months)
(p=0.004)d
Median Survival
14.8
12.6
(months)
(p<0.05)d
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
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.
Table 3. Weekly Dosage Schedule: Study Results
Study
Number of Patients
Starting Dose
(mg/m2/wk x 4)
1
2
48
90
64
102
125
125
100
36/64
50/50
51/49
125
a
3
Demographics and Treatment Administration
Female/Male (%)
Median Age in years (range)
46/54
63 (29-78) 63 (32-81) 61 (42-84) 64 (25-84)
Ethnic Origin (%)
White
African American
Hispanic
Oriental/Asian
79
12
8
0
96
4
0
0
81
11
8
0
91
5
2
2
Performance Status (%)
0
1
2
60
38
2
38
48
14
59
33
8
44
51
5
Primary Tumor (%)
Colon
Rectum
Unknown
100
0
0
71
29
0
89
11
0
87
8
5
Prior 5-FU Therapy (%)
For Metastatic Disease
≤ 6 months after Adjuvant
> 6 months after Adjuvant
Classification Unknown
81
15
2
2
66
7
16
12
73
27
0
0
68
28
2
3
Prior Pelvic/Abdominal
Irradiation (%)
Yes
Other
None
3
0
97
29
9
62
0
2
98
0
4
96
Duration of Treatment with
CAMPTOSAR (median, months)
5
4
4
3
Relative Dose Intensityb
(median %)
74
67
73
81
Efficacy
Confirmed Objective Response
Rate (%)c (95% CI)
Time to Response
(median, months)
21
(9.3-32.3)
13
14
9
(6.3-20.4) (5.5-22.6) (3.3 -14.3)
2.6
1.5
Response Duration
(median, months)
6.4
Survival (median, months)
10.4
46
1-Year Survival (%)
a
b
c
2.8
2.8
5.9
5.6
6.4
8.1
10.7
9.3
31
45
43
Nine patients received 150 mg/m2 as a starting dose; two (22.2%) responded to
CAMPTOSAR.
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.
Confirmed ≥ 4 to 6 weeks after first evidence of objective response.
irinotecan hydrochloride injection
Study 2
Irinotecan
weekly x 4 q
6 weeks
226
Irinotecan +
Infusional
5-FU/LV
198
Infusional
5-FU/LV
187
35/64
61 (30-87)
33/67
62 (27-75)
47/53
59 (24-75)
46
46
8
51
42
7
51
41
8
84
15
55
45
65
35
1.8
(0.1-185)
4.5
(0-88)
2.7
(0-104)
90
10
74
26
76
24
3.9
5.6
4.5
75
—
87
86
—
93
18
35
4.2
6.7
12.0
17.4
(p<0.005)c
(p<0.001)d
(p<0.05)d
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.
22
4.4
14.1
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-FUbased 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 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
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.
Table 4. Once-Every-3-Week Dosage Schedule: Study Results
Study 1
Irinotecan BSCa
Number of Patients
189
90
Demographics and Treatment Administration
Female/Male (%)
32/68
42/58
Median Age in years (range)
Study 2
Irinotecan
5-FU
127
129
43/57
35/65
59 (22-75) 62 (34-75) 58 (30-75) 58 (25-75)
Performance Status (%)
0
1
2
47
39
14
31
46
23
58
35
8
54
43
3
Primary Tumor (%)
Colon
Rectum
55
45
52
48
57
43
62
38
Prior 5-FU Therapy (%)
For Metastatic Disease
As Adjuvant Treatment
70
30
63
37
58
42
68
32
Prior Irradiation (%)
26
27
18
20
Duration of Study Treatment
(median, months)
(Log-rank test)
4.1
—
4.2
(p=0.02)
2.8
94
—
95
81-99
9.2
(p=0.0001)
6.5
10.8
(p=0.035)
8.5
Relative Dose Intensity
(median %)b
Survival
Survival (median, months)
(Log-rank test)
a
b
BSC = best supportive care
Relative 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.
Camptosar
Camptosar
®
®
irinotecan hydrochloride injection
Table 5. EORTC QLQ-C30: Mean Worst Post-Baseline Scorea
a For
37
0.03
53
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
51
37
41
39
28
31
27
22
32
63
57
56
47
41
40
29
26
19
0.03
0.0007
0.009
0.3
0.03
0.2
0.5
0.5
0.01
47
35
38
39
25
25
25
24
32
46
38
34
33
19
24
16
15
22
0.9
0.9
0.9
0.9
0.9
0.9
0.09
0.3
0.2
p-value
47
5-FU
Irinotecan
Functional Scales
Cognitive
Emotional
Social
Physical
Role
Symptom Scales
Fatigue
Appetite Loss
Pain Assessment
Insomnia
Constipation
Dyspnea
Nausea/Vomiting
Financial Impact
Diarrhea
Study 2
p-value
Global Health Status
Study 1
BSC
QLQ-C30 Subscale
Irinotecan
10
the five functional subscales and global health status subscale, 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 as a component of first-line therapy
in combination with 5-fluorouracil and leucovorin for patients with metastatic
carcinoma of the colon or rectum. CAMPTOSAR is also indicated for patients
with metastatic carcinoma of the colon or rectum whose disease has recurred or
progressed following initial fluorouracil-based therapy.
CONTRAINDICATIONS
CAMPTOSAR Injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.
WARNINGS
General
Outside of a well-designed clinical study, CAMPTOSAR Injection should not be
used in combination with the “Mayo Clinic” regimen of 5-FU/LV (administration
for 4-5 consecutive days every 4 weeks) because of reports of increased toxicity,
including toxic deaths. CAMPTOSAR should be used as recommended (see
DOSAGE AND ADMINISTRATION, Table 10).
In patients receiving either irinotecan/5-FU/LV or 5-FU/LV in the clinical trials,
higher rates of hospitalization, neutropenic fever, thromboembolism, first-cycle
treatment discontinuation, and early deaths were observed in patients with a
baseline performance status of 2 than in patients with a baseline performance
status of 0 or 1.
Diarrhea
CAMPTOSAR 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 life threatening since it may be prolonged and may lead to
dehydration, electrolyte imbalance, or sepsis. Late diarrhea should be treated
promptly with loperamide (see PRECAUTIONS, Information for Patients, for dosing recommendations for loperamide). Patients with diarrhea should be carefully
monitored, should be given fluid and electrolyte replacement if they become
dehydrated, and should be given antibiotic support if they develop ileus, fever, or
severe neutropenia. After the first treatment, subsequent weekly chemotherapy
treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without need for antidiarrhea medication. If grade 2, 3,
or 4 late diarrhea occurs subsequent doses of CAMPTOSAR should be decreased
within the current cycle (see DOSAGE AND ADMINISTRATION).
Neutropenia
Deaths due to sepsis following severe neutropenia have been reported
in patients treated with CAMPTOSAR. Neutropenic complications should be
managed promptly with antibiotic support (see PRECAUTIONS). Therapy with
CAMPTOSAR should be temporarily omitted during a cycle of therapy if
neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm3.
After the patient recovers to an absolute neutrophil count ≥1000/mm3, subsequent doses of CAMPTOSAR should be reduced depending upon the level of
neutropenia 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.
Patients with Reduced UGT1A1 Activity
Individuals who are homozygous for the UGT1A1*28 allele are at increased
risk for neutropenia following initiation of CAMPTOSAR treatment. A reduced
initial dose should be considered for patients known to be homozygous for the
UGT1A1*28 allele (see DOSAGE AND ADMINISTRATION). Heterozygous patients
(carriers of one variant allele and one wild-type allele which results in intermediate UGT1A1 activity) may be at increased risk for neutropenia; however, clinical
results have been variable and such patients have been shown to tolerate normal
starting doses.
Hypersensitivity
Hypersensitivity reactions including severe anaphylactic or anaphylactoid
reactions have been observed.
Camptosar
®
irinotecan hydrochloride injection
irinotecan hydrochloride injection
Colitis/Ileus
Cases of colitis complicated by ulceration, bleeding, ileus, and infection have
been observed. Patients experiencing ileus should receive prompt antibiotic support (see PRECAUTIONS).
Renal Impairment/Renal Failure
Rare cases of renal impairment and acute renal failure have been identified,
usually in patients who became volume depleted from severe vomiting and/or
diarrhea.
Thromboembolism
Thromboembolic events have been observed in patients receiving irinotecancontaining regimens; the specific cause of these events has not been determined.
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 Injection 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, 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: In patients receiving either irinotecan/5-FU/LV or
5-FU/LV in the clinical trials, higher rates of hospitalization, neutropenic fever,
thromboembolism, first-cycle treatment discontinuation, and early deaths were
observed in patients with a baseline performance status of 2 than in patients with
a baseline performance status of 0 or 1. Patients who had previously received
pelvic/abdominal radiation and elderly patients with comorbid conditions should
be closely monitored.
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. In clinical trials of the
weekly dosage schedule, patients with modestly elevated baseline serum total
bilirubin levels (1.0 to 2.0 mg/dL) had a significantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that
were less than 1.0 mg/dL (50.% [19/38] versus 18% [47/226]; p<0.001). (Also
see CLINICAL PHARMACOLOGY: Pharmacokinetics in Special Populations:
Hepatic Insufficiency). Patients with deficient glucuronidation of bilirubin, such as
those with Gilbert’s syndrome, may be at greater risk of myelosuppression when
receiving therapy with CAMPTOSAR.
Ketoconazole, enzyme-inducing anticonvulsants and St. John’s Wort are
known to have drug-drug interactions with irinotecan therapy. (See Drug-Drug
Interactions sub-section under CLINICAL PHARMACOLOGY)
Irinotecan commonly causes neutropenia, leucopenia, and anemia, any of
which may be severe and therefore should not be used in patients with severe
bone marrow failure.
Patients must not be treated with irinotecan until resolution of the bowel obstruction. Patients with hereditary fructose intolerance should not be given
CAMPTOSAR, as this product contains sorbitol.
Information for Patients
Patients and patients’ caregivers should be informed of the expected toxic
effects of CAMPTOSAR, particularly of its gastrointestinal complications, such as
nausea, vomiting, abdominal cramping, diarrhea, and infection. Each patient
should be instructed to have loperamide readily available and to begin treatment
for late diarrhea (generally occurring more than 24 hours after administration of
CAMPTOSAR) at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normally expected for the
patient. One dosage regimen for loperamide used in clinical trials consisted of the
following (Note: This dosage regimen exceeds the usual dosage
recommendations for loperamide.): 4 mg at the first onset of late diarrhea and
then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours.
Loperamide is not recommended to be used for more than 48 consecutive hours
at these doses, because of the risk of paralytic ileus. During the night, the patient
may take 4 mg of loperamide every 4 hours. Premedication with loperamide is
not recommended. The use of drugs with laxative properties should be avoided
because of the potential for exacerbation of diarrhea. Patients should be advised
to contact their physician to discuss any laxative use.
Patients should be instructed to contact their physician or nurse if any of the
following occur: diarrhea for the first time during treatment; black or bloody
stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; inability to get
diarrhea under control within 24 hours; or fever or evidence of infection.
Patients should be warned about the potential for dizziness or visual
disturbances which may occur within 24 hours following the administration of
CAMPTOSAR, and advised not to drive or operate machinery if these symptoms
occur.
Patients should be alerted to the possibility of alopecia.
Laboratory Tests
Careful monitoring of the white blood cell count with differential, hemoglobin,
and platelet count is recommended before each dose of CAMPTOSAR.
Drug Interactions
The adverse effects of CAMPTOSAR, such as myelosuppression and diarrhea,
would be expected to be exacerbated by other antineoplastic agents having
similar adverse effects.
Patients who have previously received pelvic/abdominal irradiation are
at increased risk of severe myelosuppression following the administration of
CAMPTOSAR. The concurrent administration of CAMPTOSAR with irradiation
has not been adequately studied and is not recommended.
Lymphocytopenia has been reported in patients receiving CAMPTOSAR, and
it is possible that the administration of dexamethasone as antiemetic prophylaxis
may have enhanced the likelihood of this effect. However, serious opportunistic
infections have not been observed, and no complications have specifically been
attributed to lymphocytopenia.
Hyperglycemia has also been reported in patients receiving CAMPTOSAR.
Usually, this has been observed in patients with a history of diabetes mellitus or
evidence of glucose intolerance prior to administration of CAMPTOSAR. It is
probable that dexamethasone, given as antiemetic prophylaxis, contributed to
hyperglycemia in some patients.
The incidence of akathisia in clinical trials of the weekly dosage schedule was
greater (8.5%, 4/47 patients) when prochlorperazine was administered on the
same day as CAMPTOSAR than when these drugs were given on separate days
(1.3%, 1/80 patients). The 8.5% incidence of akathisia, however, is within the
range reported for use of prochlorperazine when given as a premedication for
other chemotherapies.
It would be expected that laxative use during therapy with CAMPTOSAR would
worsen the incidence or severity of diarrhea, but this has not been studied.
In view of the potential risk of dehydration secondary to vomiting and/or
diarrhea induced by CAMPTOSAR, the physician may wish to withhold diuretics
during dosing with CAMPTOSAR and, certainly, during periods of active vomiting or diarrhea.
Drug-Laboratory Test Interactions
There are no known interactions between CAMPTOSAR and laboratory tests.
Carcinogenesis, Mutagenesis & Impairment of Fertility
Long-term carcinogenicity studies with irinotecan were not conducted. Rats
were, however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per week for 13 weeks (in separate studies, the 25 mg/kg dose produced an irinotecan Cmax and AUC that were about 7.0 times and 1.3 times the
respective values in patients administered 125 mg/m2 weekly) and were then
allowed to recover for 91 weeks. Under these conditions, there was a significant
linear trend with dose for the incidence of combined uterine horn endometrial
stromal polyps and endometrial stromal sarcomas. Neither irinotecan nor SN-38
was mutagenic in the in vitro Ames assay. Irinotecan was clastogenic both in vitro
(chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan in doses of up to 6 mg/kg/day to rats and rabbits. However, atrophy of male
reproductive organs was observed after multiple daily irinotecan doses both in
rodents at 20 mg/kg (which in separate studies produced an irinotecan Cmax and
AUC about 5 and 1 times, respectively, the corresponding values in patients
administered 125 mg/m2 weekly) and dogs at 0.4 mg/kg (which in separate studies produced an irinotecan Cmax and AUC about one-half and 1/15 th, respectively,
the corresponding values in patients administered 125 mg/m2 weekly).
Pregnancy
Pregnancy Category D—see WARNINGS.
Nursing Mothers
Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan and was concentrated up to 65-fold at 4 hours after
administration relative to plasma concentrations. Because many drugs are
excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when
receiving therapy with CAMPTOSAR.
Pediatric Use
The effectiveness of irinotecan in pediatric patients has not been established.
Results from two open-label, single arm studies were evaluated. One hundred and
seventy children with refractory solid tumors were enrolled in one phase 2 trial in
which 50 mg/m2 of irinotecan was infused for 5 consecutive days every 3 weeks.
Grade 3-4 neutropenia was experienced by 54 (31.8%) patients. Neutropenia was
complicated by fever in 15 (8.8%) patients. Grade 3-4 diarrhea was observed in 35
(20.6%) patients. This adverse event profile was comparable to that observed in
adults. In the second phase 2 trial of 21 children with previously untreated rhabdomyosarcoma, 20 mg/m2 of irinotecan was infused for 5 consecutive days on
weeks 0, 1, 3 and 4. This single agent therapy was followed by multimodal therapy. Accrual to the single agent irinotecan phase was halted due to the high rate
(28.6%) of progressive disease and the early deaths (14%). The adverse event profile was different in this study from that observed in adults; the most significant
grade 3 or 4 adverse events were dehydration experienced by 6 patients (28.6%)
associated with severe hypokalemia in 5 patients (23.8%) and hyponatremia in 3
patients (14.3%); in addition Grade 3-4 infection was reported in 5 patients (23.8%)
(across all courses of therapy and irrespective of causal relationship).
Pharmacokinetic parameters for irinotecan and SN-38 were determined in 2
pediatric solid-tumor trials at dose levels of 50 mg/m2 (60-min infusion, n=48)
and 125 mg/m2 (90-min infusion, n=6). Irinotecan clearance (mean ± S.D.) was
17.3 ± 6.7 L/h/m2 for the 50 mg/m2 dose and 16.2 ± 4.6 L/h/m2 for the 125
mg/m2 dose, which is comparable to that in adults. Dose-normalized SN-38 AUC
values were comparable between adults and children. Minimal accumulation of
irinotecan and SN-38 was observed in children on daily dosing regimens [daily x
5 every 3 weeks or (daily x 5) x 2 weeks every 3 weeks].
Geriatric Use
Patients greater than 65 years of age should be closely monitored because of
a greater risk of late diarrhea in this population (see CLINICAL PHARMACOLOGY,
Pharmacokinetics in Special Populations and ADVERSE REACTIONS, Overview
of Adverse Events). The starting dose of CAMPTOSAR in patients 70 years and
older for the once-every-3-week dosage schedule should be 300 mg/m2 (see
DOSAGE AND ADMINISTRATION).
Camptosar
Camptosar
®
Camptosar
®
irinotecan hydrochloride injection
irinotecan hydrochloride injection
irinotecan hydrochloride injection
Table 7. Study 2: Percent (%) of Patients Experiencing Clinically
Relevant Adverse Events in Combination Therapiesa (continued)
Table 6. Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapiesa
Study 1
Adverse Event
Irinotecan + Bolus 5-FU/LV
weekly x 4
q 6 weeks
N=225
Bolus 5-FU/LV
daily x 5
q 4 weeks
N=219
Study 2
Irinotecan
weekly x 4
q 6 weeks
N=223
Grade 1-4
Grade 3&4
Grade 1-4
Grade 3&4
Grade 1-4
Grade 3&4
TOTAL Adverse Events
100
53.3
100
45.7
99.6
45.7
Adverse Event
GASTROINTESTINAL
Diarrhea
late
grade 3
grade 4
early
Nausea
Abdominal pain
Vomiting
Anorexia
Constipation
Mucositis
84.9
—
—
45.8
79.1
63.1
60.4
34.2
41.3
32.4
22.7
15.1
7.6
4.9
15.6
14.6
9.7
5.8
3.1
2.2
69.4
—
—
31.5
67.6
50.2
46.1
42.0
31.5
76.3
13.2
5.9
7.3
1.4
8.2
11.5
4.1
3.7
1.8
16.9
83.0
—
—
43.0
81.6
67.7
62.8
43.9
32.3
29.6
31.0
18.4
12.6
6.7
16.1
13.0
12.1
7.2
0.4
2.2
DERMATOLOGIC
HEMATOLOGIC
Neutropenia
grade 3
grade 4
Leukopenia
Anemia
Neutropenic fever
Thrombocytopenia
Neutropenic infection
96.9
—
—
96.9
96.9
—
96.0
—
53.8
29.8
24.0
37.8
8.4
7.1
2.6
1.8
98.6
—
—
98.6
98.6
—
98.6
—
66.7
23.7
42.5
23.3
5.5
14.6
2.7
0
96.4
—
—
96.4
96.9
—
96.0
—
31.4
19.3
12.1
21.5
4.5
5.8
1.7
2.2
BODY AS A WHOLE
Asthenia
Pain
Fever
Infection
70.2
30.7
42.2
22.2
19.5
3.1
1.7
0
64.4
26.9
32.4
16.0
11.9
3.6
3.6
1.4
69.1
22.9
43.5
13.9
13.9
2.2
0.4
0.4
METABOLIC & NUTRITIONAL
↑ Bilirubin
87.6
7.1
92.2
8.2
83.9
7.2
DERMATOLOGIC
Exfoliative dermatitis
Rash
Alopecia b
0.9
19.1
43.1
0
0
—
3.2
26.5
26.5
0.5
0.9
—
0
14.3
46.1
0
0.4
—
RESPIRATORY
Dyspnea
Cough
Pneumonia
27.6
26.7
6.2
6.3
1.3
2.7
16.0
18.3
1.4
0.5
0
1.0
22.0
20.2
3.6
2.2
0.4
1.3
NEUROLOGIC
Dizziness
Somnolence
Confusion
23.1
12.4
7.1
1.3
1.8
1.8
16.4
4.6
4.1
0
1.8
0
21.1
9.4
2.7
1.8
1.3
0
CARDIOVASCULAR
Vasodilation
Hypotension
Thromboembolic events c
9.3
5.8
9.3
0.9
1.3
—
5.0
2.3
11.4
0
0.5
—
9.0
5.8
5.4
0
1.7
—
a
b
c
11
®
Irinotecan +
5-FU/LV
Infusional d 1&2
q 2 weeks
N=145
5-FU/LV
Infusional d 1&2
q 2 weeks
N=143
Grade 1-4 Grade 3&4 Grade 1-4 Grade 3&4
Hand & foot syndrome
Cutaneous signs
Alopecia c
0.7
0
—
RESPIRATORY
Dyspnea
9.7
1.4
4.9
0
CARDIOVASCULAR
Hypotension
Thromboembolic events d
3.4
11.7
1.4
—
0.7
5.6
0
—
Adjustments in the dose of CAMPTOSAR were made during the cycle of treatment and for subsequent cycles based on individual patient tolerance. The first
dose of at least one cycle of CAMPTOSAR was reduced for 67% of patients who
began the studies at the 125-mg/m2 starting dose. Within-cycle dose reductions
were required for 32% of the cycles initiated at the 125-mg/m2 dose level. The
most common reasons for dose reduction were late diarrhea, neutropenia, and
leukopenia. Thirteen (4.3%) patients discontinued treatment with CAMPTOSAR
because of adverse events. The adverse events in Table 8 are based on the experience of the 304 patients enrolled in the three studies described in the CLINICAL
STUDIES, Studies Evaluating the Weekly Dosage Schedule, section.
Table 8. Adverse Events Occurring in >10% of 304 Previously
Treated Patients with Metastatic Carcinoma
of the Colon or Rectuma
Body System & Event
Study 2
Adverse Event
12.6
20.3
16.8
Severity of adverse events based on NCI CTC (version 1.0)
Includes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping or diarrhea (occurring during or shortly after infusion of irinotecan)
c Complete hair loss = Grade 2
d Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular
accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary
embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder.
One hundred nineteen (39.1%) of the 304 patients were hospitalized a total of
156 times because of adverse events; 81 (26.6%) patients were hospitalized for
events judged to be related to administration of CAMPTOSAR. The primary reasons for drug-related hospitalization were diarrhea, with or without nausea and/or
vomiting (18.4%); neutropenia/leukopenia, with or without diarrhea and/or fever
(8.2%); and nausea and/or vomiting (4.9%).
Table 7. Study 2: Percent (%) of Patients Experiencing Clinically
Relevant Adverse Events in Combination Therapiesa
Irinotecan +
5-FU/LV
Infusional d 1&2
q 2 weeks
N=145
0.7
0.7
—
a
b
Severity of adverse events based on NCI CTC (version 1.0)
Complete hair loss = Grade 2
Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest,
myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder.
ADVERSE REACTIONS
First-Line Combination Therapy
A total of 955 patients with metastatic colorectal cancer received the recommended regimens of irinotecan in combination with 5-FU/LV, 5-FU/LV alone, or
irinotecan alone. In the two phase 3 studies, 370 patients received irinotecan in
combination with 5-FU/LV, 362 patients received 5-FU/LV alone, and 223 patients
received irinotecan alone. (See Table 10 in DOSAGE AND ADMINISTRATION for
recommended combination-agent regimens.)
In Study 1, 49 (7.3%) patients died within 30 days of last study treatment:
21 (9.3%) received irinotecan in combination with 5-FU/LV, 15 (6.8%) received
5-FU/LV alone, and 13 (5.8%) received irinotecan alone. Deaths potentially related
to treatment occurred in 2 (0.9%) patients who received irinotecan in combination with 5-FU/LV (2 neutropenic fever/sepsis), 3 (1.4%) patients who received
5-FU/LV alone (1 neutropenic fever/sepsis, 1 CNS bleeding during thrombocytopenia, 1 unknown) and 2 (0.9%) patients who received irinotecan alone (2 neutropenic fever). Deaths from any cause within 60 days of first study treatment
were reported for 15 (6.7%) patients who received irinotecan in combination with
5-FU/LV, 16 (7.3%) patients who received 5-FU/LV alone, and 15 (6.7%) patients
who received irinotecan alone. Discontinuations due to adverse events were
reported for 17 (7.6%) patients who received irinotecan in combination with
5-FU/LV, 14 (6.4%) patients who received 5-FU/LV alone, and 26 (11.7%) patients
who received irinotecan alone.
In Study 2, 10 (3.5%) patients died within 30 days of last study treatment:
6 (4.1%) received irinotecan in combination with 5-FU/LV and 4 (2.8%) received
5-FU/LV alone. There was one potentially treatment-related death, which occurred
in a patient who received irinotecan in combination with 5-FU/LV (0.7%, neutropenic sepsis). Deaths from any cause within 60 days of first study treatment
were reported for 3 (2.1%) patients who received irinotecan in combination with
5-FU/LV and 2 (1.4%) patients who received 5-FU/LV alone. Discontinuations due
to adverse events were reported for 9 (6.2%) patients who received irinotecan in
combination with 5-FU/LV and 1 (0.7%) patient who received 5-FU/LV alone.
The most clinically significant adverse events for patients receiving irinotecanbased therapy were diarrhea, nausea, vomiting, neutropenia, and alopecia. The
most clinically significant adverse events for patients receiving 5-FU/LV therapy
were diarrhea, neutropenia, neutropenic fever, and mucositis. In Study 1, grade
4 neutropenia, neutropenic fever (defined as grade 2 fever and grade 4 neutropenia), and mucositis were observed less often with weekly irinotecan/5-FU/LV than
with monthly administration of 5-FU/LV.
Tables 6 and 7 list the clinically relevant adverse events reported in Studies 1
and 2, respectively.
Second-Line Single-Agent Therapy
Weekly Dosage Schedule
In three clinical studies evaluating the weekly dosage schedule, 304 patients
with metastatic carcinoma of the colon or rectum that had recurred or progressed
following 5-FU-based therapy were treated with CAMPTOSAR. Seventeen of the
patients died within 30 days of the administration of CAMPTOSAR; in five cases
(1.6%, 5/304), the deaths were potentially drug-related. These five patients
experienced a constellation of medical events that included known effects of
CAMPTOSAR. One of these patients died of neutropenic sepsis without fever.
Neutropenic fever occurred in nine (3.0%) other patients; these patients recovered with supportive care.
10.3
17.2
56.6
5-FU/LV
Infusional d 1&2
q 2 weeks
N=143
Grade 1-4 Grade 3&4 Grade 1-4 Grade 3&4
TOTAL Adverse Events
100
72.4
100
39.2
GASTROINTESTINAL
Diarrhea
late
grade 3
grade 4
Cholinergic syndrome b
Nausea
Abdominal pain
Vomiting
Anorexia
Constipation
Mucositis
72.4
—
—
28.3
66.9
17.2
44.8
35.2
30.3
40.0
14.4
10.3
4.1
1.4
2.1
2.1
3.5
2.1
0.7
4.1
44.8
—
—
0.7
55.2
16.8
32.2
18.9
25.2
28.7
6.3
4.2
2.1
0
3.5
0.7
2.8
0.7
1.4
2.8
HEMATOLOGIC
Neutropenia
grade 3
grade 4
Leukopenia
Anemia
Neutropenic fever
Thrombocytopenia
Neutropenic infection
82.5
—
—
81.3
97.2
—
32.6
—
46.2
36.4
9.8
17.4
2.1
3.4
0
2.1
47.9
—
—
42.0
90.9
—
32.2
—
13.4
12.7
0.7
3.5
2.1
0.7
0
0
BODY AS A WHOLE
Asthenia
Pain
Fever
Infection
57.9
64.1
22.1
35.9
9.0
9.7
0.7
7.6
48.3
61.5
25.9
33.6
4.2
8.4
0.7
3.5
METABOLIC & NUTRITIONAL
↑ Bilirubin
19.1
3.5
35.9
10.6
% of Patients Reporting
NCI Grades 1-4
NCI Grades 3 & 4
GASTROINTESTINAL
Diarrhea (late)b
7-9 stools/day (grade 3)
≥10 stools/day (grade 4)
Nausea
Vomiting
Anorexia
Diarrhea (early) c
Constipation
Flatulence
Stomatitis
Dyspepsia
88
—
—
86
67
55
51
30
12
12
10
31
(16)
(14)
17
12
6
8
2
0
1
0
HEMATOLOGIC
Leukopenia
Anemia
Neutropenia
500 to <1000/mm 3 (grade 3)
<500/mm3 (grade 4)
63
60
54
—
—
28
7
26
(15)
(12)
BODY AS A WHOLE
Asthenia
Abdominal cramping/pain
Fever
Pain
Headache
Back pain
Chills
Minor infection d
Edema
Abdominal enlargement
76
57
45
24
17
14
14
14
10
10
12
16
1
2
1
2
0
0
1
0
METABOLIC & NUTRITIONAL
↓ Body weight
Dehydration
↑ Alkaline phosphatase
↑ SGOT
30
15
13
10
1
4
4
1
DERMATOLOGIC
Alopecia
Sweating
Rash
60
16
13
NA e
0
1
RESPIRATORY
Dyspnea
↑ Coughing
Rhinitis
22
17
16
4
0
0
NEUROLOGIC
Insomnia
Dizziness
19
15
0
0
CARDIOVASCULAR
Vasodilation (flushing)
11
0
a Severity of adverse events based on NCI CTC (version 1.0)
b Occurring >24 hours after administration of CAMPTOSAR
c Occurring ≤24 hours after administration of CAMPTOSAR
d Primarily upper respiratory infections
e Not applicable; complete hair loss = NCI grade 2
12
Camptosar
Camptosar
Camptosar
Once-Every-3-Week Dosage Schedule
A total of 535 patients with metastatic colorectal cancer whose disease had
recurred or progressed following prior 5-FU therapy participated in the two phase
3 studies: 316 received irinotecan, 129 received 5-FU, and 90 received best supportive care. Eleven (3.5%) patients treated with irinotecan died within 30 days
of treatment. In three cases (1%, 3/316), the deaths were potentially related to
irinotecan treatment and were attributed to neutropenic infection, grade 4 diarrhea, and asthenia, respectively. One (0.8%, 1/129) patient treated with 5-FU died
within 30 days of treatment; this death was attributed to grade 4 diarrhea.
Hospitalizations due to serious adverse events (whether or not related to study
treatment) occurred at least once in 60% (188/316) of patients who received
irinotecan, 63% (57/90) who received best supportive care, and 39% (50/129)
who received 5-FU-based therapy. Eight percent of patients treated with irinotecan and 7% treated with 5-FU-based therapy discontinued treatment due to
adverse events.
Of the 316 patients treated with irinotecan, the most clinically significant
adverse events (all grades, 1-4) were diarrhea (84%), alopecia (72%), nausea
(70%), vomiting (62%), cholinergic symptoms (47%), and neutropenia (30%).
Table 9 lists the grade 3 and 4 adverse events reported in the patients enrolled to
all treatment arms of the two studies described in the CLINICAL STUDIES,
Studies Evaluating the Once-Every-3-Week Dosage Schedule, section.
Table 9. Percent Of Patients Experiencing Grade 3 & 4 Adverse Events In
Comparative Studies Of Once-Every-3-Week Irinotecan Therapya
icantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than
those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus
18% [47/266]; p<0.001). There were no significant differences in the frequency
of grade 3 and 4 neutropenia by age or gender. In the clinical studies evaluating
the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3% of the patients; 6%
of patients received G-CSF for the treatment of neutropenia. NCI grade 3 or 4
anemia was noted in 7% of the patients receiving weekly treatment; blood transfusions were given to 10% of the patients in these trials.
Body as a Whole: Asthenia, fever, and abdominal pain are generally the most
common events of this type.
Cholinergic Symptoms: Patients may have cholinergic symptoms of rhinitis,
increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal
hyperperistalsis that can cause abdominal cramping and early diarrhea. If these
symptoms occur, they manifest during or shortly after drug infusion. They are
thought to be related to the anticholinesterase activity of the irinotecan parent
compound and are expected to occur more frequently with higher irinotecan
doses.
Hepatic: In the clinical studies evaluating the weekly dosage schedule, NCI grade
3 or 4 liver enzyme abnormalities were observed in fewer than 10% of patients.
These events typically occur in patients with known hepatic metastases.
Dermatologic: Alopecia has been reported during treatment with CAMPTOSAR.
Rashes have also been reported but did not result in discontinuation of treatment.
Respiratory: Severe pulmonary events are infrequent. In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4 dyspnea was reported in
4% of patients. Over half the patients with dyspnea had lung metastases; the
extent to which malignant pulmonary involvement or other preexisting lung disease may have contributed to dyspnea in these patients is unknown.
Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Interstitial pulmonary disease can be fatal. Risk
factors possibly associated with the development of interstitial pulmonary disease include pre-existing lung disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating factors. Patients with risk factors should be closely
monitored for respiratory symptoms before and during irinotecan therapy.
Neurologic: Insomnia and dizziness can occur, but are not usually considered to
be directly related to the administration of CAMPTOSAR. Dizziness may sometimes represent symptomatic evidence of orthostatic hypotension in patients with
dehydration.
Cardiovascular: Vasodilation (flushing) may occur during administration of
CAMPTOSAR. Bradycardia may also occur, but has not required intervention.
These effects have been attributed to the cholinergic syndrome sometimes
observed during or shortly after infusion of CAMPTOSAR. Thromboembolic
events have been observed in patients receiving CAMPTOSAR; the specific cause
of these events has not been determined.
Other Non-U.S. Clinical Trials
Irinotecan has been studied in over 1100 patients in Japan. Patients in these
studies had a variety of tumor types, including cancer of the colon or rectum, and
were treated with several different doses and schedules. In general, the types of
toxicities observed were similar to those seen in U.S. trials with CAMPTOSAR.
There is some information from Japanese trials that patients with considerable
ascites or pleural effusions were at increased risk for neutropenia or diarrhea. A
potentially life-threatening pulmonary syndrome, consisting of dyspnea, fever,
and a reticulonodular pattern on chest x-ray, was observed in a small percentage
of patients in early Japanese studies. The contribution of irinotecan to these preliminary events was difficult to assess because these patients also had lung
tumors and some had preexisting nonmalignant pulmonary disease. As a result
of these observations, however, clinical studies in the United States have enrolled
few patients with compromised pulmonary function, significant ascites, or pleural effusions.
Post-Marketing Experience
The following events have been identified during postmarketing use of
CAMPTOSAR in clinical practice. Infrequent cases of ulcerative and ischemic colitis have been observed. This can be complicated by ulceration, bleeding, ileus,
obstruction, and infection, including typhlitis. Patients experiencing ileus should
receive prompt antibiotic support (see PRECAUTIONS). Rare cases of intestinal
perforation have been reported. Rare cases of symptomatic pancreatitis or
asymptomatic elevated pancreatic enzymes have been observed.
Hypersensitivity reactions including severe anaphylactic or anaphylactoid
reactions have also been observed (see WARNINGS).
Rare cases of hyponatremia mostly related with diarrhea and vomiting have
been reported. Transient and mild to moderate increases in serum levels of
transaminases (i.e., AST and ALT) in the absence of progressive liver metastasis;
transient increase of amylase and occasionally transient increase of lipase have
been very rarely reported.
Infrequent cases of renal insufficiency including acute renal failure, hypotension or circulatory failure have been observed in patients who experienced
episodes of dehydration associated with diarrhea and/or vomiting, or sepsis (see
WARNINGS).
Early effects such as muscular contraction or cramps and paresthesia have
been reported.
OVERDOSAGE
In U.S. phase 1 trials, single doses of up to 345 mg/m2 of irinotecan were
administered to patients with various cancers. Single doses of up to 750 mg/m2
of irinotecan have been given in non-U.S. trials. The adverse events in these
patients were similar to those reported with the recommended dosage and regimen. There have been reports of overdosage at doses up to approximately twice
the recommended therapeutic dose, which may be fatal. The most significant
adverse reactions reported were severe neutropenia and severe diarrhea. There
is no known antidote for overdosage of CAMPTOSAR. Maximum supportive care
should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.
®
®
irinotecan hydrochloride injection
irinotecan hydrochloride injection
Study 1
Irinotecan BSCb
N=189
N=90
Adverse Event
Study 2
Irinotecan 5-FU
N=127
N=129
TOTAL Grade 3/4
Adverse Events
79
67
69
54
GASTROINTESTINAL
Diarrhea
Vomiting
Nausea
Abdominal pain
Constipation
Anorexia
Mucositis
22
14
14
14
10
5
2
6
8
3
16
8
7
1
22
14
11
9
8
6
2
11
5
4
8
6
4
5
22
7
5
1
0
6
3
0
14
6
1
4
2
3
3
2
8
1
3
0
1
2
4
0
2
2
1
0
2
4
0
2
BODY AS A WHOLE
Pain
Asthenia
19
15
22
19
17
13
13
12
METABOLIC & NUTRITIONAL
Hepaticc
9
7
9
6
DERMATOLOGIC
Hand & foot syndrome
Cutaneous signs d
0
2
0
0
0
1
5
3
10
8
5
7
12
13
9
4
HEMATOLOGIC
Leukopenia/Neutropenia
Anemia
Hemorrhage
Thrombocytopenia
Infection
without grade 3/4 neutropenia
with grade 3/4 neutropenia
Fever
without grade 3/4 neutropenia
with grade 3/4 neutropenia
RESPIRATORY
e
NEUROLOGIC f
CARDIOVASCULAR g
9
3
4
2
OTHER h
32
28
12
14
a
b
c
d
e
f
g
h
®
Severity of adverse events based on NCI CTC (version 1.0)
BSC = best supportive care
Hepatic includes events such as ascites and jaundice
Cutaneous signs include events such as rash
Respiratory includes events such as dyspnea and cough
Neurologic includes events such as somnolence
Cardiovascular includes events such as dysrhythmias, ischemia, and
mechanical cardiac dysfunction
Other includes events such as accidental injury, hepatomegaly, syncope,
vertigo, and weight loss
Overview of Adverse Events
Gastrointestinal: Nausea, vomiting, and diarrhea are common adverse events following treatment with CAMPTOSAR and can be severe. When observed, nausea
and vomiting usually occur during or shortly after infusion of CAMPTOSAR. In
the clinical studies testing the every 3-week-dosage schedule, the median time
to the onset of late diarrhea was 5 days after irinotecan infusion. In the clinical
studies evaluating the weekly dosage schedule, the median time to onset of late
diarrhea was 11 days following administration of CAMPTOSAR. For patients
starting treatment at the 125-mg/m2 weekly dose, the median duration of any
grade of late diarrhea was 3 days. Among those patients treated at the 125-mg/m2
weekly dose who experienced grade 3 or 4 late diarrhea, the median duration of
the entire episode of diarrhea was 7 days. The frequency of grade 3 or 4 late diarrhea was somewhat greater in patients starting treatment at 125 mg/m2 than in
patients given a 100-mg/m2 weekly starting dose (34% [65/193] versus 23%
[24/102]; p=0.08). The frequency of grade 3 and 4 late diarrhea by age was significantly greater in patients ≥65 years than in patients <65 years (40% [53/133]
versus 23% [40/171]; p=0.002). In one study of the weekly dosage treatment,
the frequency of grade 3 and 4 late diarrhea was significantly greater in male than
in female patients (43% [25/58] versus 16% [5/32]; p=0.01), but there were no
gender differences in the frequency of grade 3 and 4 late diarrhea in the other two
studies of the weekly dosage treatment schedule. Colonic ulceration, sometimes
with gastrointestinal bleeding, has been observed in association with administration of CAMPTOSAR.
Hematology: CAMPTOSAR commonly causes neutropenia, leukopenia (including
lymphocytopenia), and anemia. Serious thrombocytopenia is uncommon. When
evaluated in the trials of weekly administration, the frequency of grade 3 and 4
neutropenia was significantly higher in patients who received previous
pelvic/abdominal irradiation than in those who had not received such irradiation
(48% [13/27] versus 24% [67/277]; p=0.04). In these same studies, patients
with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a signif-
irinotecan hydrochloride injection
DOSAGE AND ADMINISTRATION
Dosage in Patients with Reduced UGT1A1 Activity
When administered in combination with other agents, or as a single-agent, a
reduction in the starting dose by at least one level of CAMPTOSAR should be considered for patients known to be homozygous for the UGT1A1*28 allele (see
CLINICAL PHARMACOLOGY and WARNINGS). However, the precise dose reduction in this patient population is not known and subsequent dose modifications
should be considered based on individual patient tolerance to treatment (see
Tables 10-13).
Combination-Agent Dosage
Dosage Regimens
CAMPTOSAR Injection in Combination with 5-Fluorouracil (5-FU) and
Leucovorin (LV)
CAMPTOSAR should be administered as an intravenous infusion over 90 minutes (see Preparation of Infusion Solution). For all regimens, the dose of LV
should be administered immediately after CAMPTOSAR, with the administration
of 5-FU to occur immediately after receipt of LV. CAMPTOSAR should be used as
recommended; the currently recommended regimens are shown in Table 10.
Dosing for patients with bilirubin >2 mg/dL cannot be recommended because
there is insufficient information to recommend a dose in these patients. It is recommended that patients receive premedication with antiemetic agents.
Prophylactic or therapeutic administration of atropine should be considered in
patients experiencing cholinergic symptoms. See PRECAUTIONS, General.
Dose Modifications
Patients should be carefully monitored for toxicity and assessed prior to each
treatment. Doses of CAMPTOSAR and 5-FU should be modified as necessary to
accommodate individual patient tolerance to treatment. Based on the
recommended dose-levels described in Table 10, Combination-Agent Dosage
Regimens & Dose Modifications, subsequent doses should be adjusted as suggested in Table 11, Recommended Dose Modifications for Combination
Schedules. All dose modifications should be based on the worst
preceding toxicity. After the first treatment, patients with active diarrhea should
return to pre-treatment bowel function without requiring anti-diarrhea medications for at least 24 hours before the next chemotherapy administration.
A new cycle of therapy should not begin until the toxicity has recovered to NCI
grade 1 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery
from treatment-related toxicity. If the patient has not recovered, consideration
should be given to discontinuing therapy. Provided intolerable toxicity does not
develop, treatment with additional cycles of CAMPTOSAR/5-FU/LV may be continued indefinitely as long as patients continue to experience clinical benefit.
Single-Agent Dosage Schedules
Dosage Regimens
CAMPTOSAR should be administered as an intravenous infusion over 90 minutes for both the weekly and once-every-3-week dosage schedules (see
Preparation of Infusion Solution). Single-agent dosage regimens are shown in
Table 12.
A reduction in the starting dose by one dose level of CAMPTOSAR may be
considered for patients with any of the following conditions: age ≥65 years, prior
pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin
levels. Dosing for patients with bilirubin >2 mg/dL cannot be recommended
because there is insufficient information to recommend a dose in these patients.
It is recommended that patients receive premedication with antiemetic agents.
Prophylactic or therapeutic administration of atropine should be considered in
patients experiencing cholinergic symptoms. See PRECAUTIONS, General.
Dose Modifications
Patients should be carefully monitored for toxicity and doses of CAMPTOSAR
should be modified as necessary to accommodate individual patient tolerance to
treatment. Based on recommended dose-levels described in Table 12, SingleAgent Regimens of CAMPTOSAR and Dose Modifications, subsequent doses
should be adjusted as suggested in Table 13, Recommended Dose Modifications
for Single-Agent Schedules. All dose modifications should be based on the worst
preceding toxicity.
A new cycle of therapy should not begin until the toxicity has recovered to NCI
grade 1 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery from
treatment-related toxicity. If the patient has not recovered, consideration should
be given to discontinuing this combination therapy. Provided intolerable toxicity
does not develop, treatment with additional cycles of CAMPTOSAR may be continued indefinitely as long as patients continue to experience clinical benefit.
Table 10. Combination-Agent Dosage Regimens & Dose Modifications a
Regimen 1
6-wk cycle with
bolus 5-FU/LV
(next cycle
begins on
day 43)
CAMPTOSAR
LV
5-FU
Starting Dose & Modified Dose Levels (mg/m2)
CAMPTOSAR
LV
5-FU
Regimen 2
6-wk cycle
with infusional
5-FU/LV
(next cycle
begins on
day 43)
CAMPTOSAR
LV
5-FU Bolus
5-FU Infusion b
b
Starting Dose
Dose Level -1
Dose Level -2
125
20
500
100
20
400
75
20
300
180 mg/m2 IV over 90 min, d 1,15,29
200 mg/m2 IV over 2 h, d 1,2,15,16,29,30
400 mg/m2 IV bolus, d 1,2,15,16,29,30
600 mg/m2 IV over 22 h, d 1,2,15,16,29,30
Starting Dose & Modified Dose Levels (mg/m2)
CAMPTOSAR
LV
5-FU Bolus
5-FU Infusionb
a
125 mg/m2 IV over 90 min, d 1,8,15,22
20 mg/m2 IV bolus, d 1,8,15,22
500 mg/m2 IV bolus, d 1,8,15,22
Starting Dose
Dose Level -1
Dose Level -2
180
200
400
600
150
200
320
480
120
200
240
360
Dose reductions beyond dose level –2 by decrements of ≈ 20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does
not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
Infusion follows bolus administration.
Camptosar
Camptosar
®
Camptosar
®
irinotecan hydrochloride injection
®
irinotecan hydrochloride injection
irinotecan hydrochloride injection
Table 11. Recommended Dose Modifications for CAMPTOSAR/5-Fluorouracil (5-FU)/Leucovorin (LV) Combination Schedules
Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm3, and the platelet count has recovered to ≥100,000/mm3, and
treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has
not recovered after a 2-week delay, consideration should be given to discontinuing therapy.
Toxicity
NCI CTC Grade a (Value)
During a Cycle of Therapy
At the Start of Subsequent
Cycles of Therapy b
No toxicity
Maintain dose level
Maintain dose level
Neutropenia
1 (1500 to 1999/mm 3)
2 (1000 to 1499/mm 3)
3 (500 to 999/mm 3)
4 (<500/mm 3)
Maintain dose level
↓ 1 dose level
Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level
Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels
Maintain dose level
Maintain dose level
↓ 1 dose level
↓ 2 dose levels
Neutropenic fever
Omit dose until resolved, then ↓ 2 dose levels
Other hematologic toxicities
Dose modifications for leukopenia or thrombocytopenia during a cycle of therapy and at the start of subsequent cycles of
therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.
Diarrhea
1 (2-3 stools/day > pretx c)
2 (4-6 stools/day > pretx)
3 (7-9 stools/day > pretx)
4 (≥10 stools/day > pretx)
Delay dose until resolved to baseline, then give same dose
Omit dose until resolved to baseline, then ↓ 1 dose level
Omit dose until resolved to baseline, then ↓ 1 dose level
Omit dose until resolved to baseline, then ↓ 2 dose levels
Maintain dose level
Maintain dose level
↓ 1 dose level
↓ 2 dose levels
Other nonhematologic toxicities d
1
2
3
4
Maintain dose level
Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level
Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level
Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels
Maintain dose level
Maintain dose level
↓ 1 dose level
↓ 2 dose levels
For mucositis/stomatitis decrease only 5-FU, not CAMPTOSAR
For mucositis/stomatitis decrease only
5-FU, not CAMPTOSAR
a
b
c
d
National Cancer Institute Common Toxicity Criteria (version 1.0)
Relative to the starting dose used in the previous cycle
Pretreatment
Excludes alopecia, anorexia, asthenia
Table 12. Single-Agent Regimens of CAMPTOSAR and Dose Modifications
Weekly Regimena
125 mg/m2 IV over 90 min, d 1,8,15,22 then 2-wk rest
Starting Dose & Modified Dose Levels c (mg/m2)
Starting Dose
125
Dose Level -1
100
350 mg/m2 IV over 90 min, once every 3 wks c
Once-Every-3-Week
Regimenb
Starting Dose & Modified Dose Levels (mg/m2)
Starting Dose
350
a
b
c
Dose Level -2
75
Dose Level -1
300
Dose Level -2
250
Subsequent doses may be adjusted as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg/m2 decrements depending upon individual patient tolerance.
Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient tolerance.
Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
Table 13. Recommended Dose Modifications For Single-Agent Schedules a
A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm 3, and the platelet count has recovered
to ≥100,000/mm 3, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatmentrelated toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing CAMPTOSAR.
During a Cycle of Therapy
Worst Toxicity
NCI Grade b (Value)
At the Start of the Next Cycles of Therapy
(After Adequate Recovery), Compared with the
Starting Dose in the Previous Cyclea
Weekly
Weekly
Once Every 3 Weeks
No toxicity
Maintain dose level
↑ 25 mg/m2 up to a maximum
dose of 150 mg/m2
Maintain dose level
Neutropenia
1 (1500 to 1999/mm3)
2 (1000 to 1499/mm3)
3 (500 to 999/mm3)
4 (<500/mm3)
Maintain dose level
↓ 25 mg/m2
Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2
Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2
Maintain dose level
Maintain dose level
↓ 25 mg/m2
↓ 50 mg/m2
Maintain dose level
Maintain dose level
↓ 50 mg/m2
↓ 50 mg/m2
Neutropenic fever
Omit dose until resolved, then ↓ 50 mg/m2 when resolved
↓ 50 mg/m2
↓ 50 mg/m2
Other hematologic
toxicities
Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of
therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.
Diarrhea
1 (2-3 stools/day > pretx c)
2 (4-6 stools/day > pretx)
3 (7-9 stools/day > pretx)
4 (≥10 stools/day > pretx)
Maintain dose level
↓ 25 mg/m2
Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2
Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2
Other nonhematologicd
toxicities
1
2
3
4
a
b
c
d
Preparation & Administration Precautions
As with other potentially toxic anticancer agents, care should be exercised in
the handling and preparation of infusion solutions prepared from CAMPTOSAR
Injection. The use of gloves is recommended. If a solution of CAMPTOSAR contacts the skin, wash the skin immediately and thoroughly with soap and water. If
CAMPTOSAR contacts the mucous membranes, flush thoroughly with water.
Several published guidelines for handling and disposal of anticancer agents are
available.1-7
Preparation of Infusion Solution
Inspect vial contents for particulate matter and repeat inspection when drug
product is withdrawn from vial into syringe.
CAMPTOSAR Injection must be diluted prior to infusion. CAMPTOSAR should
be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride
Injection, USP, to a final concentration range of 0.12 to 2.8 mg/mL. In most clinical trials, CAMPTOSAR was administered in 250 mL to 500 mL of 5% Dextrose
Injection, USP.
The solution is physically and chemically stable for up to 24 hours at room
temperature (approximately 25°C) and in ambient fluorescent lighting. Solutions
diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures
(approximately 2° to 8°C), and protected from light are physically and chemically
stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride
Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates. Freezing CAMPTOSAR and admixtures of CAMPTOSAR may
result in precipitation of the drug and should be avoided. Because
of possible microbial contamination during dilution, it is advisable to use the
admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared with 5%
Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should
be used within 6 hours if kept at room temperature (15° to 30°C, 59° to 86°F).
Other drugs should not be added to the infusion solution. Parenteral drug
products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
HOW SUPPLIED
Each mL of CAMPTOSAR Injection contains 20 mg irinotecan (on the basis
of the trihydrate salt); 45 mg sorbitol; and 0.9 mg lactic acid. When necessary,
pH has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or
hydrochloric acid.
CAMPTOSAR Injection is available in single-dose amber glass vials in the
following package sizes:
2 mL
NDC 0009-7529-02
5 mL
NDC 0009-7529-01
This is packaged in a backing/plastic blister to protect against inadvertent
breakage and leakage. The vial should be inspected for damage and visible signs
of leaks before removing the backing/plastic blister. If damaged, incinerate the
unopened package.
Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from
light. It is recommended that the vial (and backing/plastic blister) should remain
in the carton until the time of use.
Maintain dose level
↓ 25 mg/m2
Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2
Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2
All dose modifications should be based on the worst preceding toxicity
National Cancer Institute Common Toxicity Criteria (version 1.0)
Pretreatment
Excludes alopecia, anorexia, asthenia
Maintain dose level
Maintain dose level
↓ 25 mg/m2
↓ 50 mg/m2
Maintain dose level
↓ 25 mg/m2
↓ 25 mg/m2
↓ 50 mg/m2
REFERENCES
1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and
Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society;
1999:32-41.
2. Recommendations for the safe handling of parenteral antineoplastic drugs.
Washington, DC: Division of Safety, National Institutes of Health; 1983.
US Dept of Health and Human Services, Public Health Service publication NIH
83-2621.
3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1592.
4. National Study Commission on Cytotoxic Exposure. Recommendations for
handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman,
National Study Commission on Cytotoxic Exposure. Massachusetts
College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue,
Boston, MA 02115.
5. Clinical Oncological Society of Australia. Guidelines and recommendations for
safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428.
6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a
report from the Mount Sinai Medical Center. CA-A Cancer J for Clin.
1983;33:258-263.
7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin
on handling cytotoxic and hazardous drugs. Am J Hosp Pharm.
1990;47:1033-1049.
8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WorkPractice Guidelines.) Am J Health-SystPharm. 1996;53;1669-1685.
Camptosar brand of irinotecan hydrochloride injection
Distributed by
Maintain dose level
Maintain dose level
↓ 50 mg/m2
↓ 50 mg/m2
Maintain dose level
↓ 50 mg/m2
↓ 50 mg/m2
↓ 50 mg/m2
Pharmacia & Upjohn Co
Division of Pfizer Inc, NY, NY 10017
Licensed from Yakult Honsha Co., LTD, Japan, and Daiichi Pharmaceutical Co.,
LTD, Japan
Revised June 2006
LAB-0134-10.0
13
Camptosar®
irinotecan hydrochloride injection
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 or is chemically synthesized. The
chemical name is (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1Hpyrano[3’,4’:6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4’bipiperidine]-1’-carboxylate,
monohydrochloride, trihydrate. Its structural formula is as follows:
Irinotecan hydrochloride is a pale yellow to yellow crystalline powder, with the
empirical formula C 33H38N4O6•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. SN38 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:
Table 1.Summary of Mean (±Standard Deviation)
Irinotecan and SN-38 Pharmacokinetic
Parameters in Patients with Solid Tumors
Dose
(mg/m2)
Irinotecan
SN-38
Cmax
AUC0-24
t1/2
Vz
CL
Cmax
AUC0-24
t1/2
(ng/mL) (ng·h/mL)
(h)
(L/m2)
(L/h/m2)
(ng/mL)
(ng·h/mL)
(h)
125
1,660
10,200
5.8a
110
13.3
26.3
229
10.4a
(N=64)
±797
±3,270
±0.7
±48.5
±6.01
±11.9
±108
±3.1
340
3,392
20,604
11.7b
234
13.9
56.0
474
21.0b
(N=6)
±874
±6,027
±1.0
±69.6
±4.0
±28.2
±245
±4.3
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.
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%; SN38, <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 ).
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
ADMINISTRATION and PRECAUTIONS: Patients at Particular Risk Sections).
Renal Insufficiency: The influence of renal insufficiency on the pharmacokinetics of
irinotecan has not been evaluated. Therefore, caution should be undertaken in patients
with impaired renal function. Irinotecan is not recommended for use in patients on
dialysis.
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 coadministered. 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.
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.
Neuromuscular blocking agents. Interaction between irinotecan and neuromuscular
blocking agents cannot be ruled out. Irinotecan has anticholinesterase activity, which may
prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular
blockade of non-depolarizing drugs may be antagonized.
Atazanavir sulfate: Coadministration of atazanavir sulfate, a CYP3A4 and UGT1A1
inhibitor has the potential to increase systemic exposure to SN-38, the active metabolite
of irinotecan. Physicians should take this into consideration when co-administering these
drugs.
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 singleagent 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 5FU/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.
Table 2. Combination Dosage Schedule: Study Results
Study 1
Irinotecan +
Bolus 5-FU/LV
Bolus 5-FU/LV
weekly x 4 q
daily x 5 q
6 weeks
4 weeks
Number of Patients
231
226
Demographics and Treatment Administration
Female/Male (%)
34/65
45/54
Median Age in years (range)
62 (25-85)
61 (19-85)
Performance Status (%)
0
39
41
1
46
45
2
15
13
Primary Tumor (%)
Colon
81
85
Rectum
17
14
Median Time from Diagnosis to
Randomization
1.9
1.7
(months, range)
(0-161)
(0-203)
Prior Adjuvant 5-FU Therapy (%)
No
89
92
Yes
11
8
Median Duration of Study
5.5
4.1
Treatmenta (months)
Median Relative Dose Intensity (%)a
Irinotecan
72
—
5-FU
71
86
Efficacy Results
Confirmed Objective Tumor
39
21
Response Rateb (%)
(p<0.0001)c
Median Time to Tumor Progressiond
(months)
Median Survival
(months)
7.0
4.3
Study 2
Irinotecan
weekly x 4 q
6 weeks
226
Irinotecan +
Infusional
5-FU/LV
198
Infusional
5-FU/LV
187
35/64
61 (30-87)
33/67
62 (27-75)
47/53
59 (24-75)
46
46
8
51
42
7
51
41
8
84
15
55
45
65
35
1.8
(0.1-185)
4.5
(0-88)
2.7
(0-104)
90
10
74
26
76
24
3.9
5.6
4.5
75
—
87
86
—
93
18
35
4.2
6.7
(p=0.004)d
14.8
22
(p<0.005)c
4.4
(p<0.001)d
12.6
(p<0.05)d
12.0
17.4
14.1
(p<0.05)d
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.
Figure 1. Survival
First-Line Irinotecan/5-FU/LV vs 5-FU/LV
Study 1
1.0
0.9
Probability
0.8
Irinotecan/5-FU/LV
0.7
0.6
0.5
0.4
5-FU/LV
0.3
0.2
p<0.05*
0.1
0.0
0
3
*log-rank test
6
9
12 15 18 21 24 27 30 33 36 39 42
Months
Figure 2. Survival
First-Line Irinotecan/5-FU/LV vs 5-FU/LV
Study 2
1.0
0.9
Probability
0.8
Irinotecan/5-FU/LV
0.7
0.6
0.5
5-FU/LV
0.4
0.3
0.2
p<0.05*
0.1
0.0
0
3
*log-rank test
6
9
12
15
18
21
24
27
30
Months
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
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 90minute 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.
Table 3. Weekly Dosage Schedule: Study Results
Study
1
48
125a
2
90
125
3
Number of Patients
64
102
Starting Dose (mg/m2/wk x 4)
125
100
Demographics and Treatment Administration
Female/Male (%)
46/54
36/64
50/50
51/49
Median Age in years (range)
63 (29-78)
63 (32-81)
61 (42-84)
64 (25-84)
Ethnic Origin (%)
91
81
96
79
White
5
11
4
12
African American
2
8
0
8
Hispanic
2
0
0
0
Oriental/Asian
Performance Status (%)
0
60
38
59
44
1
38
48
33
51
2
2
14
8
5
Primary Tumor (%)
87
89
71
100
Colon
8
11
29
0
Rectum
5
0
0
0
Unknown
Prior 5-FU Therapy (%)
68
73
66
81
For Metastatic Disease
28
27
7
15
≤ 6 months after Adjuvant
2
0
16
2
> 6 months after Adjuvant
3
0
12
2
Classification Unknown
Prior Pelvic/Abdominal Irradiation (%)
0
0
29
3
Yes
4
2
9
0
Other
96
98
62
97
None
Duration of Treatment with
CAMPTOSAR (median, months)
5
4
4
3
b
Relative Dose Intensity (median %)
74
67
73
81
Efficacy
Confirmed Objective Response Rate (%)c
21
13
14
9
(95% CI)
(9.3 - 32.3) (6.3 - 20.4) (5.5 - 22.6)
(3.3 - 14.3)
Time to Response (median, months)
2.6
1.5
2.8
2.8
Response Duration (median, months)
6.4
5.9
5.6
6.4
Survival (median, months)
10.4
8.1
10.7
9.3
1-Year Survival (%)
46
31
45
43
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.
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
in the control arm of the second study received one of the following 5-FU regimens: (1)
LV, 200 mg/m 2 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) 5FU, 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, intentto-treat response rates could not be assessed.
Figure 3. Survival
Second-Line Irinotecan vs Best Supportive Care (BSC)
Study 1
1.0
0.9
Irinotecan
BSC
N
189
90
Median follow-up
13 mo
Median (mo)
9.2
6.5
0.7
0.6
0.5
0.4
Irinotecan
0.3
BSC
0.2
p=0.0001*
0.1
0.0
0
3
6
9
12
15
18
21
Months
*log-rank test
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
1.0
0.9
0.8
Probability
Probability
0.8
0.7
0.6
0.5
Irinotecan
0.4
0.3
5-FU
0.2
p=0.035*
0.1
0.0
0
*log-rank test
3
6
9
Months
12
15
18
21
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.
Table 4. Once-Every-3-Week Dosage Schedule: Study Results
Study 1
Study 2
Irinotecan
BSCa
Irinotecan
5-FU
Number of Patients
189
90
127
129
Demographics and Treatment Administration
Female/Male (%)
32/68
42/58
43/57
35/65
Median Age in years (range)
59 (22-75)
62 (34-75)
58 (30-75)
58 (25-75)
Performance Status (%)
0
47
31
58
54
1
39
46
35
43
2
14
23
8
3
Primary Tumor (%)
Colon
55
52
57
62
Rectum
45
48
43
38
Prior 5-FU Therapy (%)
For Metastatic Disease
70
63
58
68
As Adjuvant Treatment
30
37
42
32
Prior Irradiation (%)
26
27
18
20
Duration of Study Treatment (median, months)
4.1
-4.2
2.8
(Log-rank test)
(p=0.02)
Relative Dose Intensity (median %)b
94
-95
81-99
Survival
Survival (median, months)
9.2
6.5
10.8
8.5
(Log-rank test)
(p=0.0001)
(p=0.035)
a
BSC = best supportive care
b
Relative 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.
QLQ-C30 Subscale
Global Health Status
Table 5. EORTC QLQ-C30: Mean Worst Post-Baseline Scorea
Study 1
Study 2
Irinotecan
BSC
p-value
Irinotecan
5-FU
47
37
0.03
53
52
p-value
0.9
Functional Scales
Cognitive
77
68
0.07
79
83
0.9
Emotional
68
64
0.4
64
68
0.9
Social
58
47
0.06
65
67
0.9
Physical
60
40
0.0003
66
66
0.9
Role
53
35
0.02
54
57
0.9
Symptom Scales
Fatigue
51
63
0.03
47
46
0.9
Appetite Loss
37
57
0.0007
35
38
0.9
Pain Assessment
41
56
0.009
38
34
0.9
Insomnia
39
47
0.3
39
33
0.9
Constipation
28
41
0.03
25
19
0.9
Dyspnea
31
40
0.2
25
24
0.9
Nausea/Vomiting
27
29
0.5
25
16
0.09
Financial Impact
22
26
0.5
24
15
0.3
Diarrhea
32
19
0.01
32
22
0.2
a
For the five functional subscales and global health status subscale, 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 as a component of first-line therapy in
combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of
the colon or rectum. CAMPTOSAR is also indicated for patients with metastatic
carcinoma of the colon or rectum whose disease has recurred or progressed following
initial fluorouracil-based therapy.
CONTRAINDICATIONS
CAMPTOSAR Injection is contraindicated in patients with a known hypersensitivity to
the drug or its excipients.
WARNINGS
General
Outside of a well-designed clinical study, CAMPTOSAR Injection should not be
used in combination with the “Mayo Clinic” regimen of 5-FU/LV (administration for
4-5 consecutive days every 4 weeks) because of reports of increased toxicity, including
toxic deaths. CAMPTOSAR should be used as recommended (see DOSAGE AND
ADMINISTRATION, Table 10).
In patients receiving either irinotecan/5-FU/LV or 5-FU/LV in the clinical trials, higher
rates of hospitalization, neutropenic fever, thromboembolism, first-cycle treatment
discontinuation, and early deaths were observed in patients with a baseline performance
status of 2 than in patients with a baseline performance status of 0 or 1.
Diarrhea
CAMPTOSAR 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 life threatening since it may be prolonged and may lead to
dehydration, electrolyte imbalance, or sepsis. Late diarrhea should be treated promptly
with loperamide (see PRECAUTIONS, Information for Patients, for dosing
recommendations for loperamide). Patients with diarrhea should be carefully monitored,
should be given fluid and electrolyte replacement if they become dehydrated, and should
be given antibiotic support if they develop ileus, fever, or severe neutropenia. After the
first treatment, subsequent weekly chemotherapy treatments should be delayed in patients
until return of pretreatment bowel function for at least 24 hours without need for antidiarrhea medication. If grade 2, 3, or 4 late diarrhea occurs subsequent doses of
CAMPTOSAR should be decreased within the current cycle (see DOSAGE AND
ADMINISTRATION).
Neutropenia
Deaths due to sepsis following severe neutropenia have been reported in patients treated
with CAMPTOSAR. Neutropenic complications should be managed promptly with
antibiotic support (see PRECAUTIONS). Therapy with CAMPTOSAR should be
temporarily omitted during a cycle of therapy if neutropenic fever occurs or if the
absolute neutrophil count drops <1000/mm3 . After the patient recovers to an absolute
neutrophil count ≥1000/mm3 , subsequent doses of CAMPTOSAR should be reduced
depending upon the level of neutropenia 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.
Patients with Reduced UGT1A1 Activity
Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for
neutropenia following initiation of CAMPTOSAR treatment. A reduced initial dose
should be considered for patients known to be homozygous for the UGT1A1*28 allele
(see DOSAGE AND ADMINISTRATION). Heterozygous patients (carriers of one
variant allele and one wild-type allele which results in intermediate UGT1A1 activity)
may be at increased risk for neutropenia; however, clinical results have been variable and
such patients have been shown to tolerate normal starting doses.
Hypersensitivity
Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions
have been observed.
Colitis/Ileus
Cases of colitis complicated by ulceration, bleeding, ileus, and infection have been
observed. Patients experiencing ileus should receive prompt antibiotic support (see
PRECAUTIONS).
Renal Impairment/Renal Failure
Rare cases of renal impairment and acute renal failure have been identified, usually in
patients who became volume depleted from severe vomiting and/or diarrhea.
Thromboembolism
Thromboembolic events have been observed in patients receiving irinotecan-containing
regimens; the specific cause of these events has not been determined.
Pregnancy
CAMPTOSAR may cause fetal harm when administered to a pregnant woman.
Radioactivity related to 14 C-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 postimplantation 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
C max 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 Injection 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, 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.
Immunosuppressant Effects/Increased Susceptibility to Infections: Administration of live
or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents
including CAMPTOSAR, may result in serious or fatal infections. Vaccination with a
live vaccine should be avoided in patients receiving irinotecan. Killed or inactivated
vaccines may be administered; however, the response to such vaccines may be
diminished.
Patients at Particular Risk: In patients receiving either irinotecan/5-FU/LV or 5-FU/LV
in the clinical trials, higher rates of hospitalization, neutropenic fever,
thromboembolism, first-cycle treatment discontinuation, and early deaths were observed
in patients with a baseline performance status of 2 than in patients with a baseline
performance status of 0 or 1. Patients who had previously received pelvic/abdominal
radiation and elderly patients with comorbid conditions should be closely monitored.
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. In clinical trials of the weekly dosage schedule, patients with modestly
elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) had a significantly
greater likelihood of experiencing first-cycle, grade 3 or 4 neutropenia than those
with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/226];
p<0.001). (Also see CLINICAL PHARMACOLOGY: Pharmacokinetics in Special
Populations: Hepatic Insufficiency). Patients with deficient glucuronidation of bilirubin,
such as those with Gilbert’s syndrome, may be at greater risk of myelosuppression when
receiving therapy with CAMPTOSAR.
Ketoconazole, enzyme-inducing anticonvulsants and St. John’s Wort are known to have
drug-drug interactions with irinotecan therapy. (See Drug-Drug Interactions sub-section
under CLINICAL PHARMACOLOGY)
Irinotecan commonly causes neutropenia, leucopenia, and anemia, any of which may be
severe and therefore should not be used in patients with severe bone marrow failure.
Patients must not be treated with irinotecan until resolution of the bowel obstruction.
Patients with hereditary fructose intolerance should not be given CAMPTOSAR, as this
product contains sorbitol.
Information for Patients
Patients and patients’ caregivers should be informed of the expected toxic effects of
CAMPTOSAR, particularly of its gastrointestinal complications, such as nausea,
vomiting, abdominal cramping, diarrhea, and infection. Each patient should be instructed
to have loperamide readily available and to begin treatment for late diarrhea (generally
occurring more than 24 hours after administration of CAMPTOSAR) at the first episode
of poorly formed or loose stools or the earliest onset of bowel movements more frequent
than normally expected for the patient. One dosage regimen for loperamide used in
clinical trials consisted of the following (Note: This dosage regimen exceeds the usual
dosage recommendations for loperamide.): 4 mg at the first onset of late diarrhea and
then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours.
Loperamide is not recommended to be used for more than 48 consecutive hours at these
doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg
of loperamide every 4 hours. Premedication with loperamide is not recommended. The
use of drugs with laxative properties should be avoided because of the potential for
exacerbation of diarrhea. Patients should be advised to contact their physician to discuss
any laxative use.
Patients should be instructed to contact their physician or nurse if any of the following
occur: diarrhea for the first time during treatment; black or bloody stools; symptoms of
dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by
mouth due to nausea or vomiting; inability to get diarrhea under control within 24 hours;
or fever or evidence of infection.
Patients should be warned about the potential for dizziness or visual disturbances which
may occur within 24 hours following the administration of CAMPTOSAR, and advised
not to drive or operate machinery if these symptoms occur.
Patients should be alerted to the possibility of alopecia.
Laboratory Tests
Careful monitoring of the white blood cell count with differential, hemoglobin, and
platelet count is recommended before each dose of CAMPTOSAR.
Drug Interactions
The adverse effects of CAMPTOSAR, such as myelosuppression and diarrhea, would
be expected to be exacerbated by other antineoplastic agents having similar adverse
effects.
Patients who have previously received pelvic/ abdominal irradiation are at increased
risk of severe myelosuppression following the administration of CAMPTOSAR. The
concurrent administration of CAMPTOSAR with irradiation has not been adequately
studied and is not recommended.
Lymphocytopenia has been reported in patients receiving CAMPTOSAR, and it is
possible that the administration of dexamethasone as antiemetic prophylaxis may have
enhanced the likelihood of this effect. However, serious opportunistic infections have not
been observed, and no complications have specifically been attributed to
lymphocytopenia.
Hyperglycemia has also been reported in patients receiving CAMPTOSAR. Usually,
this has been observed in patients with a history of diabetes mellitus or evidence of
glucose intolerance prior to administration of CAMPTOSAR. It is probable that
dexamethasone, given as antiemetic prophylaxis, contributed to hyperglycemia in some
patients.
The incidence of akathisia in clinical trials of the weekly dosage schedule was greater
(8.5%, 4/47 patients) when prochlorperazine was administered on the same day as
CAMPTOSAR than when these drugs were given on separate days (1.3%, 1/80 patients).
The 8.5% incidence of akathisia, however, is within the range reported for use of
prochlorperazine when given as a premedication for other chemotherapies.
It would be expected that laxative use during therapy with CAMPTOSAR would
worsen the incidence or severity of diarrhea, but this has not been studied.
In view of the potential risk of dehydration secondary to vomiting and/or diarrhea
induced by CAMPTOSAR, the physician may wish to withhold diuretics during dosing
with CAMPTOSAR and, certainly, during periods of active vomiting or diarrhea.
Drug-Laboratory Test Interactions
There are no known interactions between CAMPTOSAR and laboratory tests.
Carcinogenesis, Mutagenesis & Impairment of Fertility
Long-term carcinogenicity studies with irinotecan were not conducted. Rats were,
however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per
week for 13 weeks (in separate studies, the 25 mg/kg dose produced an irinotecan Cmax
and AUC that were about 7.0 times and 1.3 times the respective values in patients
administered 125 mg/m2 weekly) and were then allowed to recover for 91 weeks. Under
these conditions, there was a significant linear trend with dose for the incidence of
combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas.
Neither irinotecan nor SN-38 was mutagenic in the in vitro Ames assay. Irinotecan was
clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in
vivo (micronucleus test in mice). No significant adverse effects on fertility and general
reproductive performance were observed after intravenous administration of irinotecan in
doses of up to 6 mg/kg/day to rats and rabbits. However, atrophy of male reproductive
organs was observed after multiple daily irinotecan doses both in rodents at 20 mg/kg
(which in separate studies produced an irinotecan Cmax and AUC about 5 and 1 times,
respectively, the corresponding values in patients administered 125 mg/m2 weekly) and
dogs at 0.4 mg/kg (which in separate studies produced an irinotecan Cmax and AUC about
one-half and 1/15th, respectively, the corresponding values in patients administered 125
mg/m2 weekly).
Pregnancy
Pregnancy Category D—see WARNINGS.
Nursing Mothers
Radioactivity appeared in rat milk within 5 minutes of intravenous administration of
radiolabeled irinotecan and was concentrated up to 65-fold at 4 hours after administration
relative to plasma concentrations. Because many drugs are excreted in human milk and
because of the potential for serious adverse reactions in nursing infants, it is
recommended that nursing be discontinued when receiving therapy with
CAMPTOSAR.
Pediatric Use
The effectiveness of irinotecan in pediatric patients has not been established. Results
from two open-label, single arm studies were evaluated. One hundred and seventy
children with refractory solid tumors were enrolled in one phase 2 trial in which 50 mg/
m2 of irinotecan was infused for 5 consecutive days every 3 weeks. Grade 3-4
neutropenia was experienced by 54 (31.8%) patients. Neutropenia was complicated by
fever in 15 (8.8%) patients. Grade 3-4 diarrhea was observed in 35 (20.6%) patients.
This adverse event profile was comparable to that observed in adults. In the second
phase 2 trial of 21 children with previously untreated rhabdomyosarcoma, 20 mg/m2 of
irinotecan was infused for 5 consecutive days on weeks 0, 1, 3 and 4. This single agent
therapy was followed by multimodal therapy. Accrual to the single agent irinotecan
phase was halted due to the high rate (28.6%) of progressive disease and the early deaths
(14%). The adverse event profile was different in this study from that observed in adults;
the most significant grade 3 or 4 adverse events were dehydration experienced by 6
patients (28.6%) associated with severe hypokalemia in 5 patients (23.8%) and
hyponatremia in 3 patients (14.3%); in addition Grade 3-4 infection was reported in 5
patients (23.8%) (across all courses of therapy and irrespective of causal relationship).
Pharmacokinetic parameters for irinotecan and SN-38 were determined in 2 pediatric
solid-tumor trials at dose levels of 50 mg/m2 (60-min infusion, n=48) and 125 mg/m2
(90-min infusion, n=6). Irinotecan clearance (mean ± S.D.) was 17.3 ± 6.7 L/h/m2 for the
50mg/m2 dose and 16.2 ± 4.6 L/h/m2 for the 125 mg/m2 dose, which is comparable to that
in adults. Dose-normalized SN-38 AUC values were comparable between adults and
children. Minimal accumulation of irinotecan and SN-38 was observed in children on
daily dosing regimens [daily x 5 every 3 weeks or (daily x 5) x 2 weeks every 3 weeks].
Geriatric Use
Patients greater than 65 years of age should be closely monitored because of a greater
risk of late diarrhea in this population (see CLINICAL PHARMACOLOGY,
Pharmacokinetics in Special Populations and ADVERSE REACTIONS, Overview
of Adverse Events). The starting dose of CAMPT OS AR i n p at i en t s 7 0 years an d
o l d er fo r t h e o n ce-ev ery-3-week-dosage schedule should be 300 mg/m2 (see
DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Fi rst-L i n e Comb i n ati o n T h erap y
A total of 955 patients with metastatic colorectal cancer received the recommended
regimens of irinotecan in co m b i n at i o n wi t h 5 -FU/ LV, 5 -FU/ LV al o n e, o r
i ri not ecan al one. In t h e t wo phase 3 st udi es, 370 pat i ent s recei ved
irinotecan in combination with 5-FU/LV, 362 patients received 5-FU/LV alone, and 223
patients received irinotecan alone. (See Table 10 in DOSAGE AND
ADMINISTRATION for recommended combination-agent regimens.)
In Study 1, 49 (7.3%) patients died within 30 days of last study treatment: 21 (9.3%)
received irinotecan in combination with 5-FU/LV, 15 (6.8%) received 5-FU/LV alone,
and 13 (5.8%) received irinotecan alone. Deaths potentially related to treatment occurred
in 2 (0.9%) patients who received irinotecan in combination with 5-FU/LV (2
neutropenic fever/sepsis), 3 (1.4%) patients who received 5-FU/LV alone (1
neutropenic fever/sepsis, 1 CNS bleeding during thrombocytopenia, 1 unknown) and 2
(0.9%) patients who received irinotecan alone (2 neutropenic fever). Deaths from any
cause within 60 days of first study treatment were reported for 15 (6.7%) patients who
received irinotecan in combination with 5-FU/LV, 16 (7.3%) patients who received 5FU/LV alone, and 15 (6.7%) patients who received irinotecan alone. Discontinuations
due to adverse events were reported for 17 (7.6%) patients who received irinotecan in
combination with 5FU/LV, 14 (6.4%) patients who received 5-FU/LV alone, and 26
(11.7%) patients who received irinotecan alone.
In Study 2, 10 (3.5%) patients died within 30 days of last study treatment: 6 (4.1%)
received irinotecan in combination with 5-FU/LV and 4 (2.8%) received 5-FU/LV
alone. There was one potentially treatment-related death, which occurred in a patient
who received irinotecan in combination with 5-FU/LV (0.7%, neutropenic sepsis).
Deaths from any cause within 60 days of first study treatment were reported for 3 (2.1%)
patients who received irinotecan in combination with 5-FU/LV and 2 (1.4%) patients
who received 5-FU/LV alone. Discontinuations due to adverse events were reported for 9
(6.2%) patients who received irinotecan in combination with 5FU/LV and 1 (0.7%)
patient who received 5-FU/LV alone.
The most clinically significant adverse events for patients receiving irinotecan-based
therapy were diarrhea, nausea, vomiting, neutropenia, and alopecia. The most clinically
significant adverse events for patients receiving 5-FU/LV therapy were diarrhea,
neutropenia, neutropenic fever, and mucositis. In Study 1, grade 4 neutropenia,
neutropenic fever (defined as grade 2 fever and grade 4 neutropenia), and mucositis were
observed less often with weekly irinotecan/5-FU/LV than with monthly administration
of 5-FU/LV.
Tables 6 and 7 list the clinically relevant adverse events reported in Studies 1 and 2,
respectively.
Table 6. Study 1: Percent (%) of Patients Experiencing Clinically Relevant
Adverse Events in Combination Therapiesa
Study 1
Irinotecan +
Bolus 5-FU/LV
Bolus 5-FU/LV
Irinotecan
weekly x 4
daily x 5
weekly x 4
Adverse Event
q 6 weeks
q 4 weeks
q 6 weeks
N=225
N=219
N=223
Grade 1-4
Grade 3&4
Grade 1-4
Grade 3&4
Grade 1-4
Grade 3&4
TOTAL Adverse Events
100
53.3
100
45.7
99.6
45.7
GASTROINTESTINAL
Diarrhea
late
84.9
22.7
69.4
13.2
83.0
31.0
grade 3
-15.1
-5.9
-18.4
grade 4
-7.6
-7.3
-12.6
early
45.8
4.9
31.5
1.4
43.0
6.7
Nausea
79.1
15.6
67.6
8.2
81.6
16.1
Abdominal pain
63.1
14.6
50.2
11.5
67.7
13.0
Vomiting
60.4
9.7
46.1
4.1
62.8
12.1
Anorexia
34.2
5.8
42.0
3.7
43.9
7.2
Constipation
41.3
3.1
31.5
1.8
32.3
0.4
Mucositis
32.4
2.2
76.3
16.9
29.6
2.2
HEMATOLOGIC
Neutropenia
96.9
53.8
98.6
66.7
96.4
31.4
grade 3
-29.8
-23.7
-19.3
grade 4
-24.0
-42.5
-12.1
Leukopenia
96.9
37.8
98.6
23.3
96.4
21.5
Anemia
96.9
8.4
98.6
5.5
96.9
4.5
Neutropenic fever
-7.1
-14.6
-5.8
Thrombocytopenia
96.0
2.6
98.6
2.7
96.0
1.7
Neutropenic infection
-1.8
-0
-2.2
BODY AS A WHOLE
Asthenia
70.2
19.5
64.4
11.9
69.1
13.9
Pain
30.7
3.1
26.9
3.6
22.9
2.2
Fever
42.2
1.7
32.4
3.6
43.5
0.4
Infection
22.2
0
16.0
1.4
13.9
0.4
METABOLIC &
NUTRITIONAL
87.6
7.1
92.2
8.2
83.9
7.2
↑ Bilirubin
DERMATOLOGIC
Exfoliative dermatitis
0.9
0
3.2
0.5
0
0
Rash
19.1
0
26.5
0.9
14.3
0.4
Alopeciab
43.1
-26.5
-46.1
-RESPIRATORY
Dyspnea
27.6
6.3
16.0
0.5
22.0
2.2
Cough
26.7
1.3
18.3
0
20.2
0.4
Pneumonia
6.2
2.7
1.4
1.0
3.6
1.3
NEUROLOGIC
Dizziness
23.1
1.3
16.4
0
21.1
1.8
Somnolence
12.4
1.8
4.6
1.8
9.4
1.3
Confusion
7.1
1.8
4.1
0
2.7
0
CARDIOVASCULAR
Vasodilatation
9.3
0.9
5.0
0
9.0
0
Hypotension
5.8
1.3
2.3
0.5
5.8
1.7
Thromboembolic eventsc
9.3
-11.4
-5.4
-a
Severity of adverse events based on NCI CTC (version 1.0)
b
Complete hair loss = Grade 2
c
Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus
lower extremity, heart arrest, myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary embolus,
sudden death, thrombophlebitis, thrombosis, vascular disorder.
Table 7. Study 2: Percent (%) of Patients Experiencing Clinically Relevant
Adverse Events in Combination Therapiesa
Study 2
Irinotecan +
5-FU/LV
5-FU/LV
infusional d 1&2
infusional d 1&2
q 2 weeks
q 2 weeks
N= 145
N=143
Adverse Event
Grade 1-4
Grade 3&4
Grade 1-4
Grade 3&4
TOTAL Adverse Events
100
72.4
100
39.2
GASTROINTESTINAL
Diarrhea
late
72.4
14.4
44.8
6.3
grade 3
-10.3
-4.2
grade 4
-4.1
-2.1
Cholinergic syndromeb
28.3
1.4
0.7
0
Nausea
66.9
2.1
55.2
3.5
Abdominal pain
17.2
2.1
16.8
0.7
Vomiting
44.8
3.5
32.2
2.8
Anorexia
35.2
2.1
18.9
0.7
Constipation
30.3
0.7
25.2
1.4
Mucositis
40.0
4.1
28.7
2.8
HEMATOLOGIC
Neutropenia
82.5
46.2
47.9
13.4
grade 3
-36.4
-12.7
grade 4
-9.8
-0.7
Leukopenia
81.3
17.4
42.0
3.5
Anemia
97.2
2.1
90.9
2.1
Neutropenic fever
-3.4
-0.7
Thrombocytopenia
32.6
0
32.2
0
Neutropenic infection
-2.1
-0
BODY AS A WHOLE
Asthenia
57.9
9.0
48.3
4.2
Pain
64.1
9.7
61.5
8.4
Fever
22.1
0.7
25.9
0.7
Infection
35.9
7.6
33.6
3.5
METABOLIC & NUTRITIONAL
19.1
3.5
35.9
10.6
↑ Bilirubin
DERMATOLOGIC
Hand & foot syndrome
10.3
0.7
12.6
0.7
Cutaneous signs
17.2
0.7
20.3
0
Alopeciac
56.6
-16.8
-RESPIRATORY
Dyspnea
9.7
1.4
4.9
0
CARDIOVASCULAR
Hypotension
3.4
1.4
0.7
0
Thromboembolic eventsd
11.7
-5.6
-a
Severity of adverse events based on NCI CTC (version 1.0)
b
Includes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping or
diarrhea (occurring during or shortly after infusion of irinotecan)
c
Complete hair loss = Grade 2
d
Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep
thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischemia, peripheral
vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder.
Second-Line Single-Agent Therapy
Weekly Dosage Schedule
In three clinical studies evaluating the weekly dosage schedule, 304 patients with
metastatic carcinoma of the colon or rectum that had recurred or progressed following 5FU-based therapy were treated with CAMPTOSAR. Seventeen of the patients died within
30 days of the administration of CAMPTOSAR; in five cases (1.6%, 5/304), the
deaths were potentially drug-related. These five patients experienced a constellation of
medical events that included known effects of CAMPTOSAR. One of these patients
died of neutropenic sepsis without fever. Neutropenic fever occurred in nine (3.0%) other
patients; these patients recovered with supportive care.
One hundred nineteen (39.1%) of the 304 patients were hospitalized a total of 156 times
because of adverse events; 81 (26.6%) patients were hospitalized for events judged to be
related to administration of CAMPTOSAR. The primary reasons for drug-related
hospitalization were diarrhea, with or without nausea and/or vomiting (18.4%);
neutropenia/leukopenia, with or without diarrhea and/or fever (8.2%); and nausea and/or
vomiting (4.9%).
Adjustments in the dose of CAMPTOSAR were made during the cycle of treatment and
for subsequent cycles based on individual patient tolerance. The first dose of at least one
cycle of CAMPTOSAR was reduced for 67% of patients who began the studies at the
125-mg/m2 starting dose. Within-cycle dose reductions were required for 32% of the
cycles initiated at the 125-mg/m2 dose level. The most common reasons for dose
reduction were late diarrhea, neutropenia, and leukopenia. Thirteen (4.3%) patients
discontinued treatment with CAMPTOSAR because of adverse events. The adverse
events in Table 8 are based on the experience of the 304 patients enrolled in the three
studies described in the CLINICAL STUDIES, Studies Evaluating the Weekly Dosage
Schedule, section.
Table 8. Adverse Events Occurring in >10% of 304 Previously Treated Patients with
Metastatic Carcinoma of the Colon or Rectuma
Body System & Event
% of Patients Reporting
NCI Grades 1-4
NCI Grades 3 & 4
GASTROINTESTINAL
Diarrhea (late)b
88
7-9 stools/day (grade 3)

≥10 stools/day (grade 4)

Nausea
86
Vomiting
67
Anorexia
55
Diarrhea (early)c
51
Constipation
30
Flatulence
12
Stomatitis
12
Dyspepsia
10
HEMATOLOGIC
Leukopenia
63
Anemia
60
Neutropenia
54
500 to <1000/mm3 (grade 3)

<500/mm3 (grade 4)

BODY AS A WHOLE
Asthenia
76
Abdominal cramping/pain
57
Fever
45
Pain
24
Headache
17
Back pain
14
Chills
14
Minor infectiond
14
Edema
10
Abdominal enlargement
10
METABOLIC & NUTRITIONAL
30
↓ Body weight
Dehydration
15
13
↑ Alkaline phosphatase
10
↑ SGOT
DERMATOLOGIC
Alopecia
60
Sweating
16
Rash
13
RESPIRATORY
Dyspnea
22
17
↑ Coughing
Rhinitis
16
NEUROLOGIC
Insomnia
19
Dizziness
15
CARDIOVASCULAR
Vasodilation (flushing)
11
a
Severity of adverse events based on NCI CTC (version 1.0)
b
Occurring > 24 hours after administration of CAMPTOSAR
c
Occurring ≤24 hours after administration of CAMPTOSAR
d
Primarily upper respiratory infections
e
Not applicable; complete hair loss = NCI grade 2
31
(16)
(14)
17
12
6
8
2
0
1
0
28
7
26
(15)
(12)
12
16
1
2
1
2
0
0
1
0
1
4
4
1
NAe
0
1
4
0
0
0
0
0
Once-Every-3-Week Dosage Schedule
A total of 535 patients with metastatic colorectal cancer whose disease had recurred or
progressed following prior 5-FU therapy participated in the two phase 3 studies: 316
received irinotecan, 129 received 5-FU, and 90 received best supportive care. Eleven
(3.5%) patients treated with irinotecan died within 30 days of treatment. In three cases
(1%, 3/316), the deaths were potentially related to irinotecan treatment and were
attributed to neutropenic infection, grade 4 diarrhea, and asthenia, respectively. One
(0.8%, 1/129) patient treated with 5-FU died within 30 days of treatment; this death was
attributed to grade 4 diarrhea.
Hospitalizations due to serious adverse events (whether or not related to study
treatment) occurred at least once in 60% (188/316) of patients who received irinotecan,
63% (57/90) who received best supportive care, and 39% (50/129) who received 5-FUbased therapy. Eight percent of patients treated with irinotecan and 7% treated with 5FU-based therapy discontinued treatment due to adverse events.
Of the 316 patients treated with irinotecan, the most clinically significant adverse
events (all grades, 1-4) were diarrhea (84%), alopecia (72%), nausea (70%), vomiting
(62%), cholinergic symptoms (47%), and neutropenia (30%). Table 9 lists the grade 3
and 4 adverse events reported in the patients enrolled to all treatment arms of the two
studies described in the CLINICAL STUDIES, Studies Evaluating the Once-Every-3Week Dosage Schedule, section.
Table 9. Percent Of Patients Experiencing Grade 3 & 4 Adverse Events
In Comparative Studies Of Once-Every-3-Week Irinotecan Therapya
Study 1
Study 2
Irinotecan
Irinotecan
BSC b
N=90
N=127
N=189
Adverse Event
TOTAL Grade 3/4
Adverse Events
79
67
69
GASTROINTESTINAL
Diarrhea
22
6
22
Vomiting
14
8
14
Nausea
14
3
11
Abdominal pain
14
16
9
Constipation
10
8
8
Anorexia
5
7
6
Mucositis
2
1
2
HEMATOLOGIC
Leukopenia/Neutropenia
22
0
14
Anemia
7
6
6
Hemorrhage
5
3
1
Thrombocytopenia
1
0
4
Infection
without grade 3/4 neutropenia
8
3
1
with grade 3/4 neutropenia
1
0
2
Fever
without grade 3/4 neutropenia
2
1
2
with grade 3/4 neutropenia
2
0
4
BODY AS A WHOLE
Pain
19
22
17
Asthenia
15
19
13
METABOLIC &
NUTRITIONAL
Hepatic c
9
7
9
DERMATOLOGIC
Hand & foot syndrome
0
0
0
Cutaneous signs d
2
0
1
RESPIRATORY e
10
8
5
NEUROLOGIC f
12
13
9
CARDIOVASCULAR g
9
3
4
OTHER h
32
28
12
a
Severity of adverse events based on NCI CTC (version 1.0)
b
BSC = best supportive care
c
Hepatic includes events such as ascites and jaundice
d
Cutaneous signs include events such as rash
e
Respiratory includes events such as dyspnea and cough
f
Neurologic includes events such as somnolence
g
Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction
h
Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss
5-FU
N=129
54
11
5
4
8
6
4
5
2
3
3
2
4
0
0
2
13
12
6
5
3
7
4
2
14
Overview of Adverse Events
Gastrointestinal: Nausea, vomiting, and diarrhea are common adverse events following
treatment with CAMPTOSAR and can be severe. When observed, nausea and vomiting
usually occur during or shortly after infusion of CAMPTOSAR. In the clinical studies
testing the every 3-week-dosage schedule, the median time to the onset of late diarrhea
was 5 days after irinotecan infusion. In the clinical studies evaluating the weekly dosage
schedule, the median time to onset of late diarrhea was 11 days following
administration of CAMPTOSAR. For patients starting treatment at the 125-mg/m2
weekly dose, the median duration of any grade of late diarrhea was 3 days. Among those
patients treated at the 125-mg/m2 weekly dose who experienced grade 3 or 4 late
diarrhea, the median duration of the entire episode of diarrhea was 7 days. The frequency
of grade 3 or 4 late diarrhea was somewhat greater in patients starting treatment at 125
mg/m2 than in patients given a 100-mg/m2 weekly starting dose (34% [65/193] versus
23% [24/102]; p=0.08). The frequency of grade 3 and 4 late diarrhea by age was
significantly greater in patients ≥65 years than in patients <65 years (40% [53/133]
versus 23% [40/171]; p=0.002). In one study of the weekly dosage treatment, the
frequency of grade 3 and 4 late diarrhea was significantly greater in male than in female
patients (43% [25/58] versus 16% [5/32]; p=0.01), but there were no gender differences
in the frequency of grade 3 and 4 late diarrhea in the other two studies of the weekly
dosage treatment
schedule.
Colonic
ulceration,
sometimes
with
gastrointestinal bleeding, has been observed in association with
administration of CAMPTOSAR.
Hematology: CAMPTOSAR commonly causes neutropenia, leukopenia
(including lymphocytopenia), and anemia. Serious thrombocytopenia is
uncommon. When evaluated in the trials of weekly administration, the
frequency of grade 3 and 4 neutropenia was significantly higher in patients who
received previous pelvic/abdominal irradiation than in those who had not received
such irradiation (48% [13/27] versus 24% [67/277]; p=0.04). In these same
studies, patients with baseline serum total bilirubin levels of 1.0 mg/dL or
more also had a significantly greater likelihood of experiencing first-cycle
grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0
mg/dL (50% [19/38] versus 18% [47/266]; p<0.001). There were no
significant differences in the frequency of grade 3 and 4 neutropenia by age or
gender. In the clinical studies evaluating the weekly dosage schedule,
neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater)
occurred in 3% of the patients; 6% of patients received G-CSF for the treatment
of neutropenia. NCI grade 3 or 4 anemia was noted in 7% of the patients
receiving weekly treatment; blood transfusions were given to 10% of the patients in these
trials.
Body as a Whole: Asthenia, fever, and abdominal pain are generally the most
common events of this type.
Cholinergic Symptoms: Patients may have cholinergic symptoms of rhinitis,
increased salivation, miosis, lacrimation, diaphoresis, flushing, and
intestinal hyperperistalsis that can cause abdominal cramping and early
diarrhea. If these symptoms occur, they manifest during or shortly after drug
infusion. They are thought to be related to the anticholinesterase activity of
the irinotecan parent compound and are expected to occur more frequently with
higher irinotecan doses.
Hepatic: In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4
liver enzyme abnormalities were observed in fewer than 10% of patients. These events
typically occur in patients with known hepatic metastases.
Dermatologic: Alopecia has been reported during treatment with CAMPTOSAR.
Rashes have also been reported but did not result in discontinuation of treatment.
Respiratory: Severe pulmonary events are infrequent. In the clinical studies
evaluating the weekly dosage schedule, NCI grade 3 or 4 dyspnea was reported in
4% of patients. Over half the patients with dyspnea had lung metastases; the extent to
which malignant pulmonary involvement or other preexisting lung disease may have
contributed to dyspnea in these patients is unknown.
Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during
irinotecan therapy. Interstitial pulmonary disease can be fatal. Risk factors possibly
associated with the development of interstitial pulmonary disease include pre-existing
lung disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating factors.
Patients with risk factors should be closely monitored for respiratory symptoms before
and during irinotecan therapy.
Neurologic: Insomnia and dizziness can occur, but are not usually considered to be
directly related to the administration of CAMPTOSAR. Dizziness may sometimes
represent symptomatic evidence of orthostatic hypotension in patients with
dehydration.
Cardiovascular: Vasodilation (flushing) may occur during administration of
CAMPTOSAR. Bradycardia may also occur, but has not required intervention.
These effects have been attributed to the cholinergic syndrome sometimes
observed during or shortly after infusion of CAMPTOSAR. Thromboembolic events
have been observed in patients receiving CAMPTOSAR; the specific cause of
these events has not been determined.
Other Non-U.S. Clinical Trials
Irinotecan has been studied in over 1100 patients in Japan. Patients in these
studies had a variety of tumor types, including cancer of the colon or rectum,
and were treated with several different doses and schedules. In general, the
types of toxicities observed were similar to those seen in U.S. trials with
CAMPTOSAR. There is some information from Japanese trials that patients
with considerable ascites or pleural effusions were at increased risk for
neutropenia or diarrhea. A potentially life-threatening pulmonary syndrome,
consisting of dyspnea, fever, and a reticulonodular pattern on chest x-ray, was
observed in a small percentage of patients in early Japanese studies. The
contribution of irinotecan to these preliminary events was difficult to assess
because these patients also had lung tumors and some had preexisting
nonmalignant pulmonary disease. As a result of these observations, however,
clinical studies in the United States have enrolled few patients with
compromised pulmonary function, significant ascites, or pleural effusions.
Post-Marketing Experience
The following events have been identified during postmarketing use of
CAMPTOSAR in clinical practice. Myocardial ischemic events have been observed
following irinotecan therapy predominantly in patients with underlying cardiac disease,
other known risk factors for cardiac disease or previous cytotoxic chemotherapy (See also
Table 7, thromboembolic events). Infrequent cases of ulcerative and ischemic colitis have
been observed. This can be complicated by ulceration, bleeding, ileus, obstruction, and
infection, including typhlitis. Patients experiencing ileus should receive prompt antibiotic
support (see PRECAUTIONS). Rare cases of megacolon and intestinal perforation
have been reported. Rare cases of symptomatic pancreatitis or asymptomatic elevated
pancreatic enzymes have been observed.
Hypersensitivity reactions including severe anaphylactic or anaphylactoid
reactions have also been observed (see WARNINGS).
Rare cases of hyponatremia mostly related with diarrhea and vomiting have been
reported. Increases in serum levels of transaminases (i.e., AST and ALT) in the absence
of progressive liver metastasis; transient increase of amylase and occasionally transient
increase of lipase have been very rarely reported.
Infrequent cases of renal insufficiency including acute renal failure, hypotension or
circulatory failure have been observed in patients who experienced episodes of
dehydration associated with diarrhea and/or vomiting, or sepsis (see WARNINGS).
Early effects such as muscular contraction or cramps and paresthesia have been
reported.
Hiccups have been reported.
OVERDOSAGE
In U.S. phase 1 trials, single doses of up to 345 mg/m 2 of irinotecan were
administered to patients with various cancers. Single doses of up to 750
mg/m 2 of irinotecan have been given in non-U.S. trials. The adverse events in
these patients were similar to those reported with the recommended dosage
and regimen. There have been reports of overdosage at doses up to approximately twice
the recommended therapeutic dose, which may be fatal. The most significant adverse
reactions reported were severe neutropenia and severe diarrhea. There is no known
antidote for overdosage of CAMPTOSAR. Maximum supportive care should
be instituted to prevent dehydration due to diarrhea and to treat any infectious
complications.
DOSAGE AND ADMINISTRATION
Dosage in Patients with Reduced UGT1A1 Activity
When administered in combination with other agents, or as a single-agent, a reduction in
the starting dose by at least one level of CAMPTOSAR should be considered for patients
known to be homozygous for the UGT1A1*28 allele (see CLINICAL
PHARMACOLOGY and WARNINGS). However, the precise dose reduction in this
patient population is not known and subsequent dose modifications should be considered
based on individual patient tolerance to treatment (see Tables 10-13).
Combination-Agent Dosage
Dosage Regimens
CAMPTOSAR Injection in Combination with 5-Fluorouracil (5-FU) and Leucovorin (LV)
C A M P T O S A R s h o u l d b e a d m i n i s t e r e d a s a n i n t r a v e n o u s infusion over
90 minutes (see Preparation of Infusion Solution). For all regimens, the dose of LV
should be administered immediately after CAMPTOSAR, with the a d m i n i s t r a t i o n o f
5-FU to occur immediately after receipt of LV. CAMPTOSAR should
be used as recommended; the currently recommended regimens are
shown in Table 10.
Regimen 1
6-wk cycle with
bolus 5-FU/LV
(next cycle begins
on day 43)
Table 10. Combination-Agent Dosage Regimens & Dose Modificationsa
125 mg/m2 IV over 90 min, d 1,8,15,22
CAMPTOSAR
20 mg/m2 IV bolus, d 1,8,15,22
LV
500 mg/m2 IV bolus, d 1,8,15,22
5-FU
Starting Dose & Modified Dose Levels (mg/m2)
Dose Level -1
Starting Dose
Dose Level -2
Regimen 2
6-wk cycle with
infusional
5-FU/LV
(next cycle begins
on day 43)
CAMPTOSAR
125
100
75
LV
20
20
20
5-FU
500
400
300
CAMPTOSAR
LV
5-FU
Bolus
5-FU
Infusionb
2
180 mg/m IV over 90 min, d 1,15,29
200 mg/m2 IV over 2 h, d 1,2,15,16,29,30
400 mg/m2 IV bolus, d 1,2,15,16,29,30
600 mg/m2 IV over 22 h, d 1,2,15,16,29,30
Starting Dose & Modified Dose Levels (mg/m2)
Starting Dose
Dose Level -1
Dose Level -2
CAMPTOSAR
180
150
120
LV
200
200
200
5-FU
Bolus
400
320
240
5-FU
Infusionb
600
480
360
a
Dose reductions beyond dose level –2 by decrements of ≈20% may be warranted for patients continuing to experience
toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as
long as patients continue to experience clinical benefit.
b
Infusion follows bolus administration.
Dosing for patients with bilirubin >2 mg/dL cannot be recommended b e c a u s e t h e r e
is insufficient information to recommend a dose in these patients. It
i s r e c o m m e n d e d t h a t p a t i e n t s r e c e i v e premedication with antiemetic agents.
Prophylactic or t h e r a p e u t i c a d m i n i s t r a t i o n o f a t r o p i n e s h o u l d b e
consi dered i n pat i ent s ex peri enci ng chol i nergi c sym pt om s . S ee
PRECAUTIONS, General.
Dose Modifications
Patients should be carefully monitored for toxicity and assessed prior to each treatment.
Doses of CAMPTOSAR and 5-FU should be modified as necessary to accommod a t e
i n d i v i d u a l p a t i e n t t o l e r a n c e t o t r e a t m e n t . B a s e d o n the recommended
dose-levels described in Table 10, C o m b i n a t i o n - A g e n t D o s a g e R e g i m e n s &
Dose Modifications, subsequent doses should be adjusted as
s u g g e s t e d in Table 11, Recommended Dose Modifications for C o m b i n a t i o n
S c h e d u l e s . A l l d o s e m o d i f i c a t i o n s s h o u l d b e based on the worst preceding
toxicity. After the first t r e a t m e n t , p a t i e n t s w i t h a c t i v e d i a r r h e a s h o u l d
r e t u r n t o pre-treatment bowel function without requiring anti-diarrhea medications for
at least 24 hours before the n e x t c h e m o t h e r a p y a d m i n i s t r a t i o n .
A new cycle of therapy should not begi n until the tox i city has
recovered to NCI grade 1 or less. Treatment maybe delayed 1 to 2
w e e k s t o a l l o w f o r r e c o v e r y f r o m t r e a t m en t -rel at ed t o x i ci t y. If t h e
p at i en t h as n o t reco v ered , c o n s i d e r a t i o n s h o u l d b e g i v e n t o
discontinuing therapy. Provided intolerable tox i city does not
d e v e l o p , t r e a t m e n t with additional cycles of CAMPTOSAR/5-FU/LV may
be continued indefinitely as long as patients continue to e x p e r i e n c e c l i n i c a l
benefit.
Table 11. Recommended Dose Modifications for
CAMPTOSAR/5-Fluorouracil (5-FU)/Leucovorin (LV) Combination Schedules
Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before
the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to
≥1500/mm3, and the platelet count has recovered to ≥100,000/mm3, and treatment-related diarrhea is fully resolved. Treatment
should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2week delay, consideration should be given to discontinuing therapy
Toxicity
During a Cycle of Therapy
At the Start of Subsequent Cycles
NCI CTC Gradea (Value)
of Therapyb
No toxicity
Maintain dose level
Maintain dose level
Neutropenia
1 (1500 to 1999/mm3)
Maintain dose level
Maintain dose level
Maintain dose level
2 (1000 to 1499/mm3)
↓ 1 dose level
3 (500 to 999/mm3)
↓ 1 dose level
Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level
3
4 (<500/mm )
↓ 2 dose levels
Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels
Neutropenic fever
Omit dose until resolved, then ↓ 2 dose levels
Dose modifications for leukopenia or thrombocytopenia during a cycle of therapy and at the start of
Other hematologic toxicities
subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as
recommended for neutropenia above.
Diarrhea
Delay dose until resolved to baseline, then give same dose
Maintain dose level
1 (2-3 stools/day > pretxc)
Maintain dose level
2 (4-6 stools/day > pretx)
Omit dose until resolved to baseline, then ↓ 1 dose level
3 (7-9 stools/day > pretx)
↓ 1 dose level
Omit dose until resolved to baseline, then ↓ 1 dose level
4 (≥10 stools/day > pretx)
↓ 2 dose levels
Omit dose until resolved to baseline, then ↓ 2 dose levels
Other nonhematologic toxicitiesd
Maintain dose level
Maintain dose level
1
Maintain dose level
2
Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level
3
↓ 1 dose level
Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level
4
↓ 2 dose levels
Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels
For mucositis/stomatitis decrease
only 5-FU, not CAMPTOSAR.
For mucositis/stomatitis decrease only 5-FU, not
CAMPTOSAR
National Cancer Institute Common Toxicity Criteria (version 1.0)
b
Relative to the starting dose used in the previous cycle
c
Pretreatment
d
Excludes alopecia, anorexia, asthenia
a
Single-Agent Dosage Schedules
Dosage Regimens
CAMPTOSAR should be administered as an intravenous infusion
o v e r 9 0 m i n u t e s f o r b o t h t h e w e e k l y a n d o n c e - every-3-week dosage
schedules (see Preparation of Infusion Solution). Single-agent dosage regimens are
shown in Table 12.
Weekly Regimena
Table 12. Single-Agent Regimens of CAMPTOSAR and Dose Modifications
125 mg/m2 IV over 90 min, d 1,8,15,22 then 2-wk rest
Starting Dose & Modified Dose Levelsc (mg/m2)
b
Once-Every-3-Week Regimen
Starting Dose
Dose Level -1
125
100
2
Dose Level -2
75
c
350 mg/m IV over 90 min, once every 3 wks
Starting Dose & Modified Dose Levels (mg/m2)
Starting Dose
Dose Level -1
Dose Level -2
350
300
250
a
Subsequent doses may be adjusted as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg/m2 decrements
depending upon individual patient tolerance.
b
Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient
tolerance.
c
Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long
as patients continue to experience clinical benefit.
A reduction in the starting dose by one dose level of C A M P T O S A R m a y b e
c o n s i d e r e d f o r p a t i e n t s w i t h a n y o f the following conditions: age ≥65 years,
prior pelvic/abdominal radiotherapy, performance status of 2, o r i n creas ed b i l i ru b i n
l ev el s . Do s i n g fo r p at i en t s wi t h bilirubin >2 mg/dL cannot be recommended
because there is insufficient information to recommend a dose in these patients.
It is recommended that patients receive premedication with antiemetic agents.
Prophylactic or therapeutic administration of atropine should be considered in p at i en t s
ex peri enci ng chol i n ergi c sym p t o m s . S ee P R ECAUTIONS, General.
Dose Modifications
Patients should be carefully monitored for toxicity and doses of CAMPTOSAR should
be modified as necessary to accom m odat e i n di vi dual pat i ent t o l erance t o
t r e a t m e n t . Bas e d o n r e c o m m e n d e d d o s e- l e v e l s d e s c r i b e d i n T a b l e 1 2 ,
S i n gl e - A gen t R e gi m e n s o f C A M P T OS AR an d Do s e Modifications,
subsequent doses should be adjusted as suggested in Table 13, Recommended Dose
Modifications for Single-Agent Schedules. All dose modifications should be based on the
worst preceding toxicity.
A new cycle of therapy should not begin until the toxicity has recovered to NCI grade 1
or less. Treatment may be delayed 1 to 2 weeks to allow for recovery from treatm en t rel at ed t o x i ci t y. If t h e p at i en t h as n o t reco v ered , consideration should be
given to discontinuing this combination therapy. Provided intolerable toxicity does not
develop, treatment with additional cycles of CAMPTOSAR may be continued
indefinitely as long as patients continue to experience clinical benefit.
Table 13. Recommended Dose Modifications For Single-Agent Schedulesa
A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm3, and the platelet count has recovered to
≥100,000/mm3, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatmentrelated toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing CAMPTOSAR.
At the Start of the Next Cycles of Therapy
During a Cycle of Therapy
(After Adequate Recovery), Compared with
Worst Toxicity
b
the Starting Dose in the Previous Cyclea
NCI Grade (Value)
Weekly
Weekly
Once Every 3 Weeks
No toxicity
Maintain dose level
Maintain dose level
↑ 25 mg/m2 up to a
maximum dose of
150 mg/m2
Neutropenia
1 (1500 to 1999/mm3)
Maintain dose level
Maintain dose level
Maintain dose level
Maintain dose level
Maintain dose level
2 (1000 to 1499/mm3)
↓ 25 mg/m2
3
3 (500 to 999/mm )
↓ 25 mg/m2
↓ 50 mg/m2
Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2
4 (<500/mm3)
↓ 50 mg/m2
↓ 50 mg/m2
Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2
Neutropenic fever
↓ 50 mg/m2
↓ 50 mg/m2
Omit dose until resolved, then ↓ 50 mg/m2 when resolved
Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent
Other hematologic
cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.
toxicities
Diarrhea
Maintain dose level
1 (2-3 stools/day > pretxc)
Maintain dose level
Maintain dose level
Maintain dose level
Maintain dose level
2 (4-6 stools/day > pretx)
↓ 25 mg/m2
3 (7-9 stools/day > pretx)
↓ 25 mg/m2
↓ 50 mg/m2
Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2
4 (≥10 stools/day > pretx)
↓ 50 mg/m2
↓ 50 mg/m2
Omit dose until resolved to ≤ grade 2 then ↓ 50 mg/m2
Other nonhematologicd
toxicities
Maintain dose level
1
Maintain dose level
Maintain dose level
2
↓ 25 mg/m2
↓ 25 mg/m2
↓ 50 mg/m2
3
↓ 25 mg/m2
↓ 50 mg/m2
Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2
4
Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2
↓ 50 mg/m2
↓ 50 mg/m2
a
All dose modifications should be based on the worst preceding toxicity
b
National Cancer Institute Common Toxicity Criteria (version 1.0)
c
Pretreatment
d
Excludes alopecia, anorexia, asthenia
Prep arati o n & Ad mi n i strati on Precau ti o n s
As with other potentially toxic anticancer agents, care should be exercised in the
handling and preparation of infusion solutions prepared from CAMPTOSAR Injection.
The use of gloves is recommended. If a solution of CAMPTOSAR contacts the skin,
wash the skin immediately and t h o r o u gh l y w i t h s o a p a n d w a t e r . If
C AM P TOS AR co n t act s the mucous membranes, flush thoroughly with water.
Several published guidelines for handling and disposal of anticancer agents are
available.1-7
Preparation of Infusion Solution
Inspect vial contents for particulate matter and repeat inspection when drug product is
withdrawn from vial into syringe.
CAMPTOSAR Injection must be diluted prior to infusion. CAMPTOSAR should be
diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection,
USP, to a final concentration range of 0.12 to 2.8 mg/mL. In most clinical trials,
CAMPTOSAR was administered in 2 5 0 m L t o 5 0 0 m L o f 5 % D e x t r o s e
In j e c t i o n , U S P .
T h e s o l u t i o n i s p h ys i c a l l y a n d c h e m i c a l l y s t a b l e f o r u p to 24 hours at
room temperature (approximately 25°C) a n d i n a m b i e n t f l u o r e s c e n t l i g h t i n g .
S o l u t i o n s d i l u t e d i n 5% Dextrose Injection, USP, and stored at refrigerated
temperatures (approximately 2° to 8°C), and protected from light are physically and
chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium
C h l o r i d e In j e c t i o n , U S P , i s n o t r e c o m m e n d e d d u e t o a l o w and sporadic
incidence of visible particulates. Freezing CAMPTOSAR and admixtures of
CAMPTOSAR may result in p r e c i p i t a t i o n o f t h e d r u g a n d s h o u l d b e
avoided. Because of possible microbial contamination during
d i l u t i o n , i t i s advisable to use the admixture prepared with 5%Dex trose
Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the
case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride
Injection, USP, the solutions should be used within 6 hours if kept at room temperature
(15° to 30°C, 5 9 ° t o 8 6 ° F ) .
Other drugs should not be added to the infusion solution. Parenteral drug
products should be inspected visually for particulate matter and discoloration prior
to administration whenever solution and container permit.
HOW SUPPLIED
Each mL of CAMPTOSAR Injection contains 20 mg irinotecan (on the
basis of the trihydrate salt); 45 mg sorbitol; and 0.9 mg lactic acid. When
necessary, pH has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or
hydrochloric acid.
CAMPTOSAR Injection is available in single-dose amber glass vials in the
following package sizes:
2 mL
NDC 0009-7529-02
5 mL
NDC 0009-7529-01
The vial should be inspected for damage and visible signs of leaks before
removing from the carton. If damaged, incinerate the unopened package.
Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from
light. It is recommended that the vial should remain in the carton until the time of use.
Rx only
REFERENCES
1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and
Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:3241.
2. Recommendations for the safe handling of parenteral antineoplastic drugs.
Washington, DC: Division of Safety, National Institutes of Health; 1983. US Dept of
Health and Human Services, Public Health Service publication NIH 83-2621.
3. AMA Council on Scientific Affairs. Guidelines for handling parenteral
antineoplastics. JAMA. 1985;253:1590-1592.
4. National Study Commission on Cytotoxic Exposure. Recommendations for handling
cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study
Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied
Health Sciences, 179 Longwood Avenue, Boston, MA 02115.
5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe
handling of antineoplastic agents. Med J Australia. 1983;1:426-428.
6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from
the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263.
7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on
handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.
8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice
Guidelines). Am J Health-SystPharm. 1996;53;1669-1685.
Licensed from Yakult Honsha Co., LTD, Japan, and Daiichi Pharmaceutical
Co., LTD, Japan
Revised July 2008
LAB-0134-13.0
© 2007 Current Medicine Group LLC
CQ278602A