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CAMPTOSAR® (irinotecan HCl) Use in Specific Populations

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action, CAMPTOSAR can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Available postmarketing and published data reporting the use of CAMPTOSAR in pregnant women, are insufficient and confounded by the concomitant use of other cytotoxic drugs, to evaluate for any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, intravenous administration of irinotecan to rats and rabbits during the period of organogenesis resulted in embryofetal mortality and teratogenicity in pregnant animals at exposures lower than the human exposure based on AUC at the clinical dose of 125 mg/m2 (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Radioactivity related to 14C-irinotecan crosses the placenta of rats following intravenous administration. Intravenous administration of irinotecan to rats at a dose of 6 mg/kg/day (approximately 0.2 times the clinical exposure (AUC) at the 125 mg/m2 dose based on exposure data from a separate rat study) during the period of organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses; at doses ≥ 1.2 mg/kg/day (approximately 0.03 times the clinical exposure (AUC) at the 125 mg/m2 dose based on exposure data from a separate rat study) there were increases in a variety of external, visceral, and skeletal abnormalities. Administration of irinotecan to pregnant rabbits at a dose of 6 mg/kg (approximately half of the clinical dose of 125 mg/m2 based on BSA) resulted in similar findings to those in rats, with increased post-implantation loss, decreased live fetuses, and increased 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.

8.2 Lactation

Risk Summary

Irinotecan and its metabolites are present in human milk. There is no information regarding the effects of irinotecan on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from CAMPTOSAR in the breastfed child, advise lactating women not to breastfeed during treatment with CAMPTOSAR and for 7 days after the final dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status in female patients of reproductive potential prior to initiating CAMPTOSAR.

Contraception

CAMPTOSAR can cause fetal harm when administered to a pregnant woman.

Females

Advise female patients of reproductive potential to use effective contraception during treatment and for 6 months after the final dose of CAMPTOSAR [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].

Males

Due to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use condoms during treatment and for 3 months after the final dose of CAMPTOSAR [see Nonclinical Toxicology (13.1)].

Infertility

Females

Based on postmarketing reports, female fertility may be impaired by treatment with CAMPTOSAR. Menstrual dysfunction has been reported following CAMPTOSAR administration.

Males

Based on findings from animal studies, male fertility may be impaired by treatment with CAMPTOSAR [see Nonclinical Toxicology (13.1)].

8.4 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 × 5 every 3 weeks or (daily × 5) × 2 weeks every 3 weeks].

8.5 Geriatric Use

Patients greater than 65 years of age should be closely monitored because of a greater risk of early and late diarrhea in this population [see Clinical Pharmacology (12.3) and Adverse Reactions (6.1)]. 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 Clinical Pharmacology (12.3) and Dosage and Administration (2)].

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 another study of 183 patients treated on the weekly schedule, the frequency of grade 3 or 4 late diarrhea in patients ≥65 years of age was 28.6% [26/91] and in patients <65 years of age was 23.9% [22/92].

8.6 Renal Impairment

The influence of renal impairment on the pharmacokinetics of irinotecan has not been evaluated. Therefore, use caution in patients with impaired renal function. CAMPTOSAR is not recommended for use in patients on dialysis.

8.7 Hepatic Impairment

Irinotecan clearance is diminished in patients with hepatic impairment 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. Therefore, use caution when administering CAMPTOSAR to patients with hepatic impairment. 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 (2.1), Warnings and Precautions (5.10) and Clinical Pharmacology (12.3)].

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