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 anti-diarrhea 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 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.
