Irinotecan Hydrochloride (Page 3 of 7)

5.3 Patients With Reduced UGT1A1 Activity

Individuals who are homozygous for the UGT1A1^* 28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of Irinotecan hydrochloride treatment.

In a study of 66 patients who received single-agent Irinotecan hydrochloride (350 mg/m² once-every-3-weeks), the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1^* 28 allele was 50%, and in patients heterozygous for this allele (UGT1A1 6/7 genotype) the incidence was 12.5%. No grade 4 neutropenia was observed in patients homozygous for the wild-type allele (UGT1A1 6/6 genotype).

When administered as a single-agent, a reduction in the starting dose by at least one level of Irinotecan hydrochloride should be considered for patients known to be homozygous for the UGT1A1^* 28 allele. However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment [see Dosage and Administration (2)].

UGT1A1 Testing

A laboratory test is available to determine the UGT1A1 status of patients. Testing can detect the UGT1A1 6/6, 6/7 and 7/7 genotypes.

5.4 Hypersensitivity

Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue Irinotecan hydrochloride if anaphylactic reaction occurs.

5.5 Renal Impairment/Renal Failure

Renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhea.

5.6 Pulmonary Toxicity

Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred in patients receiving irinotecan (in combination and as monotherapy). Risk factors include pre-existing lung disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during Irinotecan hydrochloride therapy. In Japanese studies, a reticulonodular pattern on chest x-ray was observed in a small percentage of patients. New or progressive, dyspnea, cough, and fever should prompt interruption of chemotherapy, pending diagnostic evaluation. If IPD is diagnosed, Irinotecan hydrochloride and other chemotherapy should be discontinued and appropriate treatment instituted as needed [see Adverse Reactions (6.1)].

5.7 Toxicity of the 5 Day Regimen

Outside of a well-designed clinical study, irinotecan hydrochloride injection should not be used in combination with a regimen of 5-FU/LV administered for 4-5 consecutive days every 4 weeks because of reports of increased toxicity, including toxic deaths. [see Dosage and Administration (2)].

5.8 Increased Toxicity in Patients with Performance Status 2

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.

5.9 Embryofetal Toxicity

Irinotecan hydrochloride can cause fetal harm when administered to a pregnant woman. Irinotecan was embryotoxic in rats and rabbits at doses significantly lower than those administered to humans on a mg/m² basis. In rats, at exposures approximately 0.2 times those achieved in humans at the 125 mg/m² dose, irinotecan was embryotoxic and resulted in decreased learning ability and female fetal body weight in surviving pups; the drug was teratogenic at lower exposures (approximately 0.025 times the AUC in humans at the 125 mg/m² dose).There are no adequate and well-controlled studies of irinotecan in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Irinotecan hydrochloride.

5.10 Patients with Hepatic Impairment

The use of Irinotecan hydrochloride in patients with significant hepatic impairment 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) [see Dosage and Administration (2), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

6 ADVERSE REACTIONS

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 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.

Serious opportunistic infections have not been observed, and no complications have specifically been attributed to lymphocytopenia.

Second-Line Single-Agent Therapy

Weekly Dosage Schedule

In three clinical studies evaluating the weekly dosage schedule, 304 patients with metastatic carcinoma of the colon or rectum that had recurred or progressed following 5-FU-based therapy were treated with Irinotecan hydrochloride. Seventeen of the patients died within 30 days of the administration of Irinotecan hydrochloride; in five cases (1.6%, 5/304), the deaths were potentially drug-related. One of the patients died of neutropenic sepsis without fever. Neutropenic fever occurred in nine (3.0%) other patients; these patients recovered with supportive care.

One hundred nineteen (39.1%) of the 304 patients were hospitalized because of adverse events; 81 (26.6%) patients were hospitalized for events judged to be related to administration of Irinotecan hydrochloride. The primary reasons for drug-related hospitalization were diarrhea, with or without nausea and/or vomiting (18.4%); neutropenia/leukopenia, with or without diarrhea and/or fever (8.2%); and nausea and/or vomiting (4.9%).

The first dose of at least one cycle of Irinotecan hydrochloride was reduced for 67% of patients who began the studies at the 125-mg/m² starting dose. Within-cycle dose reductions were required for 32% of the cycles initiated at the 125-mg/m² dose level. The most common reasons for dose reduction were late diarrhea, neutropenia, and leukopenia. Thirteen (4.3%) patients discontinued treatment with Irinotecan hydrochloride because of adverse events. The adverse events in Table 7 are based on the experience of the 304 patients enrolled in the three studies described in Clinical Studies (14.1).

Table 7. Adverse Events Occurring in >10% of 304 Previously Treated Patients with Metastatic Carcinoma of the Colon or Rectum^a

a  Severity of adverse events based on NCI CTC (version 1.0)
b Occurring >24 hours after administration of Irinotecan hydrochloride
c Occurring ≤24 hours after administration of Irinotecan hydrochloride
d Primarily upper respiratory infections
e Not applicable; complete hair loss = NCI grade 2
Body System & Event	% of Patients Reporting
	NCI Grades 1-4	NCI Grades 3 & 4
GASTROINTESTINAL
Diarrhea (late)b	88	31
7–9 stools/day (grade 3)	—	(16)
≥10 stools/day (grade 4)	—	(14)
Nausea	86	17
Vomiting	67	12
Anorexia	55	6
Diarrhea (early)c	51	8
Constipation	30	2
Flatulence	12	0
Stomatitis	12	1
Dyspepsia	10	0
HEMATOLOGIC
Leukopenia	63	28
Anemia	60	7
Neutropenia	54	26
500 to <1000/mm3 (grade 3)	—	(15)
<500/mm3 (grade 4)	—	(12)
BODY AS A WHOLE
Asthenia	76	12
Abdominal cramping/pain	57	16
Fever	45	1
Pain	24	2
Headache	17	1
Back pain	14	2
Chills	14	0
Minor infectiond	14	0
Edema	10	1
Abdominal enlargement	10	0
METABOLIC AND NUTRITIONAL
↓ Body weight	30	1
Dehydration	15	4
↑ Alkaline phosphatase	13	4
↑ SGOT	10	1
DERMATOLOGIC
Alopecia	60	NAe
Sweating	16	0
Rash	13	1
RESPIRATORY
Dyspnea	22	4
↑ Coughing	17	0
Rhinitis	16	0
NEUROLOGIC
Insomnia	19	0
Dizziness	15	0
CARDIOVASCULAR
Vasodilation (flushing)	11	0

Once-Every-3-Week Dosage Schedule

A total of 535 patients with metastatic colorectal cancer whose disease had recurred or progressed following prior 5-FU therapy participated in the two phase 3 studies: 316 received irinotecan, 129 received 5-FU, and 90 received best supportive care. Eleven (3.5%) patients treated with irinotecan died within 30 days of treatment. In three cases (1%, 3/316), the deaths were potentially related to irinotecan treatment and were attributed to neutropenic infection, grade 4 diarrhea, and asthenia, respectively. One (0.8%, 1/129) patient treated with 5-FU died within 30 days of treatment; this death was attributed to grade 4 diarrhea.

Hospitalizations due to serious adverse events occurred at least once in 60% (188/316) of patients who received irinotecan, 63% (57/90) who received best supportive care, and 39% (50/129) who received 5-FU-based therapy. Eight percent of patients treated with irinotecan and 7% treated with 5-FU-based therapy discontinued treatment due to adverse events.

Of the 316 patients treated with irinotecan, the most clinically significant adverse events (all grades, 1-4) were diarrhea (84%), alopecia (72%), nausea (70%), vomiting (62%), cholinergic symptoms (47%), and neutropenia (30%). Table 8 lists the grade 3 and 4 adverse events reported in the patients enrolled to all treatment arms of the two studies described in Clinical Studies (14.1).

Table 8: Percent of Patients Experiencing Grade 3 & 4 Adverse Events in Comparative Studies of Once-Every-3-Week Irinotecan Therapy^a

a  Severity of adverse events based on NCI CTC (version 1.0)
b BSC = best supportive care
c Hepatic includes events such as ascites and jaundice
d Cutaneous signs include events such as rash
e Respiratory includes events such as dyspnea and cough
f Neurologic includes events such as somnolence
g Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction
h Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss
Adverse Event	Study 1		Study 2
	Irinotecan N=189	BSCb N=90	Irinotecan N=127	5-FU N=129
TOTAL Grade 3/4Adverse Events	79	67	69	54
GASTROINTESTINAL
Diarrhea	22	6	22	11
Vomiting	14	8	14	5
Nausea	14	3	11	4
Abdominal pain	14	16	9	8
Constipation	10	8	8	6
Anorexia	5	7	6	4
Mucositis	2	1	2	5
HEMATOLOGIC
Leukopenia/Neutropenia	22	0	14	2
Anemia	7	6	6	3
Hemorrhage	5	3	1	3
Thrombocytopenia	1	0	4	2
Infection
without grade 3/4 neutropenia	8	3	1	4
with grade 3/4 neutropenia	1	0	2	0
Fever
without grade 3/4 neutropenia	2	1	2	0
with grade 3/4 neutropenia	2	0	4	2
BODY AS A WHOLE
Pain	19	22	17	13
Asthenia	15	19	13	12
METABOLIC AND NUTRITIONAL
Hepatic c	9	7	9	6
DERMATOLOGIC
Hand and foot syndrome	0	0	0	5
Cutaneous signs d	2	0	1	3
RESPIRATORY e	10	8	5	7
NEUROLOGIC f	12	13	9	4
CARDIOVASCULAR g	9	3	4	2
OTHER h	32	28	12	14

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 Irinotecan hydrochloride 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.