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 CAMPTOSAR in patients 70 years and older for the once-every-3-week-dosage
schedule should be 300 mg/m2 (see DOSAGE AND ADMINISTRATION).