Irinotecan Hydrochloride

• CAMPTOSAR is indicated as a component of first-line therapy in combination with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic carcinoma of the colon or rectum.
• CAMPTOSAR is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. CAMPTOSAR is a topoisomerase inhibitor indicated for:
• First-line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum. ( 1 )
• Patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. ( 1 )

Injection: 40 mg/2 mL (20 mg/mL), 100 mg/5 mL (20 mg/mL), and 300 mg/15 mL (20 mg/mL) sterile, pale yellow, clear, aqueous solution in a single-dose vial. Injection: 40 mg/2 mL (20 mg/mL), 100 mg/5 mL (20 mg/mL), and 300 mg/15 mL (20 mg/mL) solution in a single-dose vial. ( 3 )

• CAMPTOSAR Injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.
• Hypersensitivity to CAMPTOSAR or its excipients ( 4 )

• Diarrhea and Cholinergic Reactions : Early diarrhea (occurring during or shortly after infusion of CAMPTOSAR) is usually transient and may be accompanied by cholinergic symptoms. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). Late diarrhea (generally occurring more than 24 hours after administration of CAMPTOSAR) can occur. Monitor and replace fluid and electrolytes. Treat with loperamide. Use antibiotic support for ileus and fever. Interrupt CAMPTOSAR and reduce subsequent doses if severe diarrhea occurs. ( 5.1 )
• Myelosuppression : Manage promptly with antibiotic support. Interrupt CAMPTOSAR and reduce subsequent doses if necessary. ( 5.2 )
• Increased Risk of Neutropenia in Patients With Reduced UGT1A1 Activity: Individuals with UGT1A1*28/*28, or *6/*6, or *6/*28 genotypes are at increased risk for severe neutropenia during CAMPTOSAR treatment. ( 5.3 )
• Hypersensitivity: Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue CAMPTOSAR if this occurs. ( 5.4 )
• 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. ( 5.5 )
• Pulmonary Toxicity: Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred. Interrupt for new or progressive dyspnea, cough, and fever pending evaluation. If IPD diagnosed, discontinue and institute appropriate treatment as needed. ( 5.6 )
• Toxicity of the 5 Day Regimen: CAMPTOSAR should not be used in combination with a regimen of 5-FU/LV administered for 4–5 consecutive days every 4 weeks outside of a clinical study. ( 5.7 )
• Embryo-Fetal Toxicity: CAMPTOSAR can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. Advise male patients with female partners of reproductive potential to use condoms. ( 5.9 , 8.1 , 8.3 )
• Patients With Hepatic Impairment: In clinical trials, CAMPTOSAR has not been administered to patients with serum bilirubin > 2.0 mg/dL, or transaminases > 3 times ULN if no liver metastases, or transaminases > 5 times ULN if liver metastases. With the weekly dosage schedule, patients with total bilirubin levels 1.0–2.0 mg/dL had greater likelihood of grade 3–4 neutropenia. ( 5.10 )

5.1 Diarrhea and Cholinergic Reactions Early diarrhea (occurring during or shortly after infusion of CAMPTOSAR) is usually transient and infrequently severe. It may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Bradycardia may also occur. Early diarrhea and other cholinergic symptoms may be prevented or treated. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). These symptoms are expected to occur more frequently with higher irinotecan doses. 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. Grade 3–4 late diarrhea occurred in 23–31% of patients receiving weekly dosing. In the clinical studies, the median time to the onset of late diarrhea was 5 days with 3-week dosing and 11 days with weekly dosing. Late diarrhea can be complicated by colitis, ulceration, bleeding, ileus, obstruction, and infection. Cases of megacolon and intestinal perforation have been reported. Patients should have loperamide readily available to begin treatment for late diarrhea. Begin loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normal. One dosage regimen for loperamide is 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. Monitor and replace fluid and electrolytes. Use antibiotic support for ileus, fever, or severe neutropenia. Subsequent weekly chemotherapy treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without anti-diarrhea medication. Patients must not be treated with CAMPTOSAR until resolution of the bowel obstruction. If grade 2, 3, or 4 late diarrhea recurs, subsequent doses of CAMPTOSAR should be decreased [see Dosage and Administration (2) ] . Avoid diuretics or laxatives in patients with diarrhea.

5.2 Myelosuppression CAMPTOSAR can cause severe myelosuppression. Bacterial, viral, and fungal infections have occurred in patients treated with CAMPTOSAR. Deaths due to sepsis following severe neutropenia have been reported in patients treated with CAMPTOSAR. 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. Manage febrile neutropenia promptly with antibiotic support [see Warnings and Precautions (5.2) ] . Hold CAMPTOSAR if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm 3 . After recovery to an absolute neutrophil count ≥1000/mm 3 , subsequent doses of CAMPTOSAR should be reduced [see Dosage and Administration (2) ] . When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was 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). Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of CAMPTOSAR. Based on sparse available data, the concurrent administration of CAMPTOSAR with irradiation is not recommended. Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a 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). 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 [see Warnings and Precautions (5.3) ] .

5.3 Increased Risk of Neutropenia in Patients With Reduced UGT1A1 Activity Published studies have shown that individuals who are homozygous for either the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or who are compound or double heterozygous for the UGT1A1*28 and *6 alleles (*6/*28) are at increased risk for severe or life-threatening neutropenia during treatment with CAMPTOSAR. These individuals are UGT1A1 poor metabolizers and experience increased systemic exposure to SN-38, an active metabolite of irinotecan. Individuals who are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*28, *1/*6) are intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia [see Dosage and Administration (2) and Clinical Pharmacology (12.3 , 12.5) ] . Consider UGT1A1 genotype testing for the *28 and *6 alleles to determine UGT1A1 metabolizer status [see Clinical Pharmacology (12.5) ] . When administering CAMPTOSAR, consider a reduction in the CAMPTOSAR starting dose by at least one level for patients known to be homozygous or compound heterozygous for the UGT1A1*28 and/or *6 alleles (*28/*28, *6/*6, *6/*28). […]

Common adverse reactions (≥30%) observed in combination therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, alopecia. ( 6.1 ) Common adverse reactions (≥30%) observed in single agent therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, alopecia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc, at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Common adverse reactions (≥30%) observed in combination therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, and alopecia. Common adverse reactions (≥30%) observed in single agent therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and alopecia. 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 Dosage and Administration (2) ] . 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 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 5 and 6 list the clinically relevant adverse events reported in Studies 1 and 2, respectively. Table 5. Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies Severity of adverse events based on NCI CTC (version 1.0) Adverse Event Study 1 Irinotecan + Bolus 5-FU/LV weekly × 4 every 6 weeks N=225 Bolus 5-FU/LV daily × 5 every 4 weeks N=219 Irinotecan weekly × 4 every 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 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 Bilirubin 87.6 7.1 92.2 8.2 83.9 7.2 DERMATOLOGIC Exfoliative dermatitis 0.9 0 3.2 0.5 0 0 Rash 19.1 0 26.5 0.9 14.3

0.4 Alopecia Complete hair loss = Grade 2 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 events 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. 9.3 — 11.4 — 5.4 — Table 6. […]

• Strong CYP3A4 Inducers: Do not administer strong CYP3A4 inducers with CAMPTOSAR. ( 7.2 )
• Strong CYP3A4 Inhibitors: Do not administer strong CYP3A4 inhibitors with CAMPTOSAR. ( 7.3 ) 7.1 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 C max and AUC 0–24 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 (2) ] . 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.

7.2 Strong CYP3A4 Inducers Exposure to irinotecan or its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital, carbamazepine, or St. John's wort. The appropriate starting dose for patients taking these or other strong inducers such as rifampin and rifabutin has not been defined. Consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of CAMPTOSAR therapy. Do not administer strong CYP3A4 inducers with CAMPTOSAR unless there are no therapeutic alternatives.

7.3 Strong CYP3A4 or UGT1A1 Inhibitors Irinotecan and its active metabolite, SN-38, are metabolized via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), respectively, [see Clinical Pharmacology (12.3) ] . Patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Coadministration of CAMPTOSAR with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, indinavir) may increase systemic exposure to irinotecan or SN-38. Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting CAMPTOSAR therapy. Do not administer strong CYP3A4 or UGT1A1 inhibitors with CAMPTOSAR unless there are no therapeutic alternatives.

• Lactation: Advise not to breastfeed. ( 8.2 )
• Geriatric Use: Closely monitor patients greater than 65 years of age because of a greater risk of early and late diarrhea in this population. ( 8.5 )
• Patients With Renal Impairment: Use caution and do not use in patients on dialysis. ( 8.6 )
• Patients With Hepatic Impairment: Use caution. ( 2.1 , 5.10 , 8.7 , 12.3 )

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/m 2 ( 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 14 C-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/m 2 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/m 2 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/m 2 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/ m 2 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/m 2 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/m 2 (60-min infusion, n=48) and 125 mg/m 2 (90-min infusion, n=6). Irinotecan clearance (mean ± S.D.) was 17.3 ± 6.7 L/h/m 2 for the 50mg/m 2 dose and 16.2 ± 4.6 L/h/m 2 for the 125 mg/m 2 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/m 2 [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) ] .

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.