A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Camptosar Warnings, Precautions, Pregnancy, Nursing, Abuse - Irinotecan Hcl
Camptosar Warnings, Precautions, Pregnancy, Nursing, Abuse - Irinotecan Hcl
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 12).
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.
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 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. However in clinical
trials of the weekly dosage schedule, it has been noted that patients with modestly
elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) have had a
significantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia
than those with bilirubin levels that were less than 1.0 mg/dL (50.0% [19/38]
versus 17.7% [47/226]; p<0.001). Patients with abnormal glucuronidation of
bilirubin, such as those with Gilbert’s syndrome, may also be at greater risk
of myelosuppression when receiving therapy with CAMPTOSAR. An association between
baseline bilirubin elevations and an increased risk of late diarrhea has not
been observed in studies of the weekly dosage schedule.
INFORMATION FOR PATIENTS
Patients and 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. 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 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.
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 hypokalaemia 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).
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