Irinotecan Product Monograph

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TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES .................................................................................................. 2

TABLE OF CONTENTS ..................................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION .......................................................................... 4

• 1 INDICATIONS ..................................................................................................................... 4

  • 1.1 Pediatrics .................................................................................................................. 4
  • 1.2 Geriatrics .................................................................................................................. 4

2 CONTRAINDICATIONS ....................................................................................................... 4

• 3 SERIOUS WARNINGS AND PRECAUTIONS BOX ................................................................ 4

4 DOSAGE AND ADMINISTRATION ...................................................................................... 5

• 4.1 Dosing Considerations ............................................................................................. 5
• 4.2 Recommended Dose and Dosage Adjustment ........................................................ 6
• 4.3 Reconstitution ........................................................................................................ 11
• 4.4 Administration ....................................................................................................... 12

5 OVERDOSAGE .................................................................................................................. 12

• 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 12

7 WARNINGS AND PRECAUTIONS ..................................................................................... 12

• 7.1 Special Populations ................................................................................................ 17
• 7.1.1 Pregnant Women ............................................................................................. 17
• 7.1.2 Breast-feeding .................................................................................................. 18
• 7.1.3 Pediatrics .......................................................................................................... 18
• 7.1.4 Geriatrics .......................................................................................................... 18

8 ADVERSE REACTIONS ...................................................................................................... 18

• 8.1 Adverse Reaction Overview ................................................................................... 18
• 8.2 Clinical Trial Adverse Reactions ............................................................................. 21
• 8.2.1 Clinical Trial Adverse Reactions – Pediatrics .................................................... 32
• 8.3 Less Common Clinical Trial Adverse Reactions ...................................................... 32
• 8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics ............................ 32
• 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................. 32
• 8.5 Post-Market Adverse Reactions ............................................................................. 33

9 DRUG INTERACTIONS ...................................................................................................... 33

• 9.2 Drug Interactions Overview ................................................................................... 33
• 9.3 Drug-Behavioural Interactions ............................................................................... 34
• 9.4 Drug-Drug Interactions .......................................................................................... 34
• 9.5 Drug-Food Interactions .......................................................................................... 36
• 9.6 Drug-Herb Interactions .......................................................................................... 36
• 9.7 Drug-Laboratory Test Interactions ......................................................................... 37

10 CLINICAL PHARMACOLOGY ............................................................................................. 37

• 10.1 Mechanism of Action ....................................................................................... 37
• 10.2 Pharmacodynamics .......................................................................................... 37
• 10.3 Pharmacokinetics ............................................................................................. 37

11 STORAGE, STABILITY AND DISPOSAL .............................................................................. 40

• 12 SPECIAL HANDLING INSTRUCTIONS ................................................................................ 40

PART II: SCIENTIFIC INFORMATION ............................................................................................ 41

• 13 PHARMACEUTICAL INFORMATION ................................................................................. 41

14 CLINICAL TRIALS............................................................................................................... 42

• 14.1 Trial Design and Study Demographics.............................................................. 42
• 14.2 Study Results .................................................................................................... 45

15 MICROBIOLOGY ............................................................................................................... 52

• 16 NON-CLINICAL TOXICOLOGY ........................................................................................... 53

PATIENT MEDICATION INFORMATION ....................................................................................... 59

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

IRINOTECAN (irinotecan hydrochloride for injection) is indicated as:

• a component of first-line therapy for patients with metastatic carcinoma of the colon or rectum.
• a single agent for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following 5-fluorouracil-based therapy.

IRINOTECAN (irinotecan hydrochloride for injection) should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

• 1.1 Pediatrics

Pediatrics: The safety and effectiveness of IRINOTECAN in the pediatric population have not been established (see 7 WARNINGS AND PRECAUTIONS).

1.2 Geriatrics

Geriatrics: Evidence from clinical and pharmacokinetic studies suggests that patients 65 years of age or older should be closely monitored because of a greater risk of late diarrhea in this population. Specific dosing recommendations may apply to this population depending upon the regimen used (see 7 WARNINGS AND PRECAUTIONS, General, Geriatrics; 4 DOSAGE AND ADMINISTRATION and 14 CLINICAL TRIALS).

2 CONTRAINDICATIONS

IRINOTECAN (irinotecan hydrochloride for injection) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

Co-administration of IRINOTECAN with azole antifungals (ketoconazole, fluconazole, itraconazole), known CYP3A4 inhibitors, is contraindicated because this can lead to an increase in the relative exposure to the active metabolite SN-38 and can therefore possibly lead to increased toxicity.

In patients receiving concomitant IRINOTECAN and ketoconazole, exposure to SN-38 was increased by approximately 110%. Patients should discontinue ketoconazole at least 1 week prior to starting irinotecan therapy. See 7 WARNINGS AND PRECAUTIONS regarding potential drug-drug interactions with other CYP3A4 inhibitors and inducers.

Patients with hereditary fructose intolerance should not be given IRINOTECAN, as this product contains sorbitol, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

• IRINOTECAN (irinotecan hydrochloride for injection) should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.
• Severe early and late forms of diarrhea leading to dehydration and electrolyte imbalance (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS).

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Recommendations common to combination and single agent IRINOTECAN (irinotecan hydrochloride for injection) schedules

• Dosing of patients is not recommended with (see 7 WARNINGS AND PRECAUTIONS)

  • serum bilirubin > 35 µmol/L, transaminase > 3 times ULN if no liver metastases, or transaminase > 5 times ULN with liver metastases
  • ECOG performance status 3 or 4

• Recommended laboratory tests (see 7 WARNINGS AND PRECAUTIONS) before/during therapy

  • white blood cell count with differential, hemoglobin and platelet count before each dose
  • liver function before initiation of treatment and monthly or as clinically indicated

• Dose reduction may be considered for patients (see 7 WARNINGS AND PRECAUTIONS)

  • aged ≥ 70 years
  • with prior pelvic/abdominal radiotherapy
  • with performance status of 2
  • with moderately elevated bilirubin levels (17-35 µmol/L)
  • with Gilbert’s syndrome

• Dose schedules, dose modifications and dose delay

  • patients should be carefully monitored for toxicity and assessed prior to each treatment

  • dosage schedule and dose modifications for combination therapy are summarized in Tables 1

    and 2 and for single agent therapy in Tables 3 and 4

  • dose modifications should be based on the worst preceding toxicity. Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. Patients experiencing clinically significant (defined as grade ≥2) diarrhea, abdominal cramping, or neutropenia on the day of treatment administration should have treatment delayed until they recover and subsequent doses should be decreased.

  • a new cycle of therapy should not begin until the toxicity has recovered to NCI grade 1 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicity. If the patient has not recovered, consideration should be given to discontinuing therapy.

    • Typhlitis, ulcerative and ischemic colitis, ileus and intestinal perforation (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse Reactions).

    • Severe myelosuppression with grade 3-4 neutropenia (see 7 WARNINGS AND PRECAUTIONS

      and 8 ADVERSE REACTIONS).

    • Cases of bacterial, fungal and viral infections, sometimes fatal and/or life-threatening, have been reported with the use of IRINOTECAN (see 8 ADVERSE REACTIONS).
  • provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.

It is recommended that patients receive premedication with antiemetic agents. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms. Besides the dosage modification, prompt use of oral loperamide is recommended in order to control and treat the diarrhea (see 7 WARNINGS AND PRECAUTIONS, Gastrointestinal).

4.2 Recommended Dose and Dosage Adjustment Dosage in Patients with Reduced UGT1A1 Activity

When administered in combination with other agents, or as a single-agent, a reduction in the starting dose should be considered for patients known to be homozygous for UGT1A1*28 or *6 allele, as well as for those who have experienced prior hematologic toxicity with previous treatment. The exact reduction in starting dose in this patient population has not been established and any subsequent dose modifications should be based on individual patient tolerance to treatment (see 7 WARNINGS AND PRECAUTIONS, Hematologic).

IRINOTECAN Combination-Agent Therapy - Dosage Schedules:

IRINOTECAN should be administered as an intravenous infusion over 90 minutes. For all regimens, the dose of Leucovorin (LV) should be administered immediately after IRINOTECAN, with the administration of 5-Fluorouracil (5-FU) to occur immediately after receipt of LV. The recommended regimens are shown in Table 1.

Table 1. Combination-Agent Dosage Schedules & Dose Modifications^a

^a Dose reductions beyond dose level –2 by decrements of ~20% may be warranted for patients continuing to experience toxicity.

^b Infusion follows bolus administration.

IRINOTECAN Combination-Agent Therapy - Dose Modifications:

Patients should be carefully monitored for toxicity and assessed prior to each treatment, especially during the first cycle of therapy. Doses of IRINOTECAN and 5-FU should be modified as necessary to accommodate individual patient tolerance to treatment. Based on the recommended dose-levels described in Table 1, subsequent doses should be adjusted as suggested in Table 2.

Table 2. Recommended Dose Modifications for IRINOTECAN/5-Fluorouracil(5-FU)/Leucovorin (LV) Combination Schedule

• 2 Omit dose, then ↓ 1 dose level when resolved to < grade 1
• 3 Omit dose, then ↓ 1 dose level when resolved to < grade 2

• 4 Omit dose, then ↓ 2 dose levels when resolved to < grade 2

  For mucositis/stomatitis decrease only 5-FU, not IRINOTECAN

^a National Cancer Institute Common Toxicity Criteria

^b Relative to the starting dose used in the previous cycle.

^c Pretreatment

^d Excludes alopecia, anorexia, asthenia

Maintain dose level

↓ 1 dose level

↓ 2 dose levels

For mucositis/stomatitis decrease only 5-FU, not IRINOTECAN.

IRINOTECAN Single-Agent Therapy - Dosage Schedules:

IRINOTECAN should be administered as an intravenous infusion over 90 minutes for both the weekly and once-every-3-week dosage schedules. Single-agent dosage regimens are shown in Table 3.

Table 3. Single-Agent Regimens of IRINOTECAN and Dose Modifications

^a Subsequent doses may be adjusted as high as 150 mg/m² or to as low as 50 mg/m² in 25 to 50 mg/m² decrements depending upon individual patient tolerance.

^b Subsequent doses may be adjusted as low as 200 mg/m² in 50 mg/m² decrements depending upon individual patient tolerance.

IRINOTECAN Single-Agent Therapy - Dose Modifications:

Patients should be carefully monitored for toxicity and doses of IRINOTECAN should be modified as necessary to accommodate individual patient tolerance to treatment. Based on recommended dose- levels described in Table 3, subsequent doses should be adjusted as suggested in Table 4. The 350 mg/m² dose has not been evaluated in patients who are 70 years and older (see 14 CLINICAL TRIALS) and the recommended starting dose is therefore 300 mg/m².

Table 4. Recommended Dose Modifications for Single-Agent Schedules ^a

^a National Cancer Institute Common Toxicity Criteria

^b All dose modifications should be based on the worst preceding toxicity

^c Pretreatment

^d Excludes alopecia, anorexia, asthenia

4.3 Reconstitution Parenteral Products:

The IRINOTECAN vial is for single use only. Unused portions must be discarded. IRINOTECAN must be diluted prior to infusion, using 5% Dextrose Injection (preferred) or 0.9% Sodium Chloride Injection to a final concentration range of 0.12 to 3.0 mg/mL. Other drugs should not be added to the infusion solution.

The infusion solutions, when packaged in low-density polyethylene (LDPE) or polyvinyl chloride (PVC) containers, are physically and chemically stable for up to 28 days at controlled room temperature (15 to 30^oºC) or at refrigerated temperatures (2 to 8^oºC), if protected from light. If stored at room temperature (15 to 30^oºC) but exposed to light, the infusion solutions are physically and chemically stable for 72 hours (3 days). Freezing IRINOTECAN and admixtures of IRINOTECAN may result in precipitation of the drug and should be avoided. See 11 STORAGE, STABILITY AND DISPOSAL.

4.4 Administration

Because of possible microbial contamination during dilution, it is recommended that the admixture be prepared immediately prior to use and infusion commenced as soon as practicable after preparation. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8^oC, or 6 hours at 15 to 30^oC, unless reconstitution /dilution has taken place in controlled and validated aseptic conditions.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.

5 OVERDOSAGE

Single doses of up to 750 mg/m² of IRINOTECAN (irinotecan hydrochloride for injection) have been given in some trials and there have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhea. There is no known antidote for overdosage of IRINOTECAN. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications. Complete blood count (CBC), platelets, electrolytes, liver and renal function should be monitored in cases of overdosage and patients should be monitored for signs and symptoms of respiratory distress.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 5 – Dosage Forms, Strengths, Composition and Packaging

IRINOTECAN (irinotecan hydrochloride for injection) is supplied as a sterile, clear, light yellow, aqueous solution. IRINOTECAN is available as single use vials in the following package size: 300 mg in 15 mL of solution.

Each mL of IRINOTECAN contains 20 mg irinotecan hydrochloride trihydrate, 45 mg sorbitol, 0.9 mg lactic acid and water for injection. Sodium hydroxide and/or hydrochloric acid may be used to adjust the pH to 3.0 - 3.8.

7 WARNINGS AND PRECAUTIONS

General

Patients at Particular Risk:

Physicians should exercise particular caution in monitoring the effects of IRINOTECAN in patients with poor performance status. Patients with performance status of 3 or 4 should not receive IRINOTECAN. In patients receiving either IRINOTECAN /5-FU/LV or 5-FU/LV in clinical trials comparing these agents, higher rates of hospitalisation, 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. Close monitoring is recommended in patients who have previously received pelvic/abdominal irradiation and in the elderly as these patients may be less tolerant of the toxic effects of the drug. The use of IRINOTECAN has not been established in patients with significant hepatic dysfunction (see 7 WARNINGS AND PRECAUTIONS, Hepatic). There are known and suspected drug-drug interactions (see 2 CONTRAINDICATIONS, Drug interactions below and 9 DRUG INTERACTIONS).

Patients with reduced UGT1A1 activity

Patients with UGT1A1*28 or *6 variants (especially if homozygous) are at increased risk of experiencing adverse events such as neutropenia and diarrhea. A reduced irinotecan starting dose should be considered for homozygous patients (see 4 DOSAGE AND ADMINISTRATION, 4.2 Recommended Dose and Dosage Adjustment). In addition, *28 and *6 homozygous and heterozygous patients should be closely monitored for neutropenia and diarrhea. In order to identify patients at increased risk of experiencing neutropenia and diarrhea, UGT1A1 genotyping can be useful (see 7 WARNINGS AND PRECAUTIONS, Hematologic). More in detail, UGT1A1*28 genotyping can be useful in Caucasians, Africans and Latinos, UGT1A1*6 in East-Asians and combined UGT1A1*28 and *6 in Chinese and Japanese, since these are the populations in which these variants are more prevalent.

Drug Interactions:

CYP3A4 Inhibitors

• Co-administration of IRINOTECAN with azole antifungals (ketoconazole, fluconazole, itraconazole) is contraindicated (see 2 CONTRAINDICATIONS).
• Co-administration of IRINOTECAN with other CYP3A4 inhibitors (e.g., cimetidine, fluoroquinolone antibiotics [ciprofloxacin and norfloxacin in patients with compromised renal function], macrolide antibiotics (azithromycin, clarithromycin, erythromycin), atazanavir sulfate, grapefruit juice, and CYP3A4-inhibitory calcium channel blockers (verapamil, diltiazem, and nifedipine) could lead to an increase in the relative exposure to the active metabolite SN-38 and therefore possibly increased toxicity (see 9 DRUG INTERACTIONS and 4 DOSAGE AND ADMINISTRATION).

The appropriate starting dose of IRINOTECAN when co-administered with CYP3A4 inhibitors has not been determined.

CYP3A4 Inducers

• The co-administration of IRINOTECAN with CYP3A4 inducers (e.g. St. John’s Wort, phenytoin, phenobarbital, carbamazepine, glucocorticoids, rifampin) leads to a reduction in the plasma concentration of the active metabolite SN-38, which could potentially lead to a reduction of efficacy (see 9 DRUG INTERACTIONS).

The appropriate starting dose of IRINOTECAN when co-administered with CYP3A4 inducers has not been determined.

UGT1A1 Inhibitors

• The co-administration of atazanavir sulfate, a UGT1A1 inhibitor, has the potential to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should take this into consideration when coadministering irinotecan with a UGT1A1 inhibitor.

Irradiation Therapy:

The concurrent administration of IRINOTECAN with irradiation is not recommended.

Extravasation:

IRINOTECAN is administered by intravenous infusion. Care should be taken to avoid extravasation. The infusion site should be monitored for signs of inflammation or other adverse effects. If extravasation occurs, flushing the site with sterile water and/or applying ice to the area are recommended.

Carcinogenesis and Mutagenesis

Carcinogenicity studies have not been conducted. Rats administered 2 mg/kg or 25 mg/kg irinotecan intravenously once weekly for 13 weeks and allowed to recover for 91 weeks had a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Irinotecan and SN-38 were not mutagenic in bacterial in vitro assays (Ames assay). Irinotecan was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice) (see 16 NON CLINICAL TOXICOLOGY). Therefore, irinotecan may be able to induce chromosomal damage in human spermatozoa. For this reason, males undergoing IRINOTECAN treatment should discuss effective contraceptive methods with their doctors.

Cardiovascular

All 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 and vascular disorder) when considered together have been commonly observed in patients receiving IRINOTECAN. The specific cause of these events has not been determined. See also 8 ADVERSE REACTIONS, 8.2 Clinical Trial Adverse Drug Reactions.

Myocardial ischemic events have been uncommonly observed in patients receiving IRINOTECAN. In some cases, a causal association with administration of IRINOTECAN could not be excluded. See 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse Drug Reactions.

Driving and Operating Machinery

Patients should be warned about the potential for fatigue, dizziness or visual disturbances which may occur following the administration of irinotecan and advised not to drive or operate machinery if these symptoms occur.

Endocrine and Metabolism

Hyperglycemia has been reported in patients receiving IRINOTECAN. This has usually been observed in patients with a history of diabetes or evidence of glucose intolerance prior to administration of IRINOTECAN (see also 9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions, Dexamethasone).

Gastrointestinal Diarrhea:

IRINOTECAN can induce both an early (occurring during or shortly after infusion of IRINOTECAN) and a late (generally occurring more than 24 hours after IRINOTECAN administration) form of diarrhea that appear to be mediated by different mechanisms.

Early onset diarrhea 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 may be alleviated by the use of atropine. Prophylactic or therapeutic administration of 0.25 to 1.0 mg of intravenous or subcutaneous atropine should be considered (unless contraindicated) (see 4 DOSAGE AND ADMINISTRATION).

Late onset diarrhea can be prolonged, may lead to dehydration, electrolyte imbalance, or infection, and can be life-threatening. The mechanism of action of late onset diarrhea is unknown. All grade late onset diarrhea occurred in 80% of patients and late diarrhea should be treated promptly with loperamide.

Patients with diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Patients should be given antibiotic support (see 9 DRUG INTERACTIONS) if they develop ileus, fever, or severe neutropenia. After the first treatment, subsequent chemotherapy should be delayed until patients return to pre-treatment bowel function for at least 24 hours without need for antidiarrhea medication. Patients experiencing clinically significant (grade ≥ 2) late diarrhea, should have subsequent doses of IRINOTECAN decreased (see 4 DOSAGE AND ADMINISTRATION).

Management of late onset diarrhea: At the initiation of chemotherapy, patients should be given a sufficient supply of loperamide and instructed on its appropriate use. The prompt use of oral loperamide for controlling and treating the diarrhea is recommended and is higher than the usual dosage recommendation. Pre-treatment with loperamide before the onset of late diarrhea is not recommended. Instead, at the first episode of late-onset diarrhea (i.e. poorly formed stools or more frequent bowel movement), patients are to take 4 mg loperamide, followed by 2 mg loperamide every two hours until they are free of diarrhea for at least 12 hours. During the night, the dose of loperamide may be 4 mg administered every 4 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus.

Inflammatory-Bowel Disease and/or Bowel Obstruction:

Cases of colitis complicated by ulceration, bleeding, ileus, and infection have been observed. Cases of ileus without preceding colitis have also been reported. Patients experiencing ileus should receive prompt antibiotic support (see 9 DRUG INTERACTIONS) and must not be treated with irinotecan until resolution of the bowel obstruction.

Nausea and Vomiting:

IRINOTECAN is emetogenic (see 8 ADVERSE REACTIONS). Pre-medication with anti-emetic agents is recommended for patients receiving IRINOTECAN. In clinical studies with the weekly dosage schedule, this pre-medication has mostly consisted of 10 mg dexamethasone given in conjunction with another type of anti-emetic agent. Anti-emetic agents should be given on the day of treatment, starting at least 30 minutes before administration of IRINOTECAN. Physicians should also consider providing patients with an anti-emetic regimen for subsequent use as needed.

Hematologic

IRINOTECAN commonly causes neutropenia, leukopenia, and anemia, any of which may be severe and therefore should not be used in patients with severe bone marrow failure. Therapy with IRINOTECAN should be temporarily omitted if neutropenic fever occurs or if the absolute neutrophil count drops below 1.5 x 10⁹/L. After the patient recovers to an absolute neutrophil count >1.5 x 10⁹/L, subsequent doses of IRINOTECAN should be reduced depending upon the level of neutropenia observed (see 4 DOSAGE AND ADMINISTRATION). Severe neutropenia resulting in deaths due to sepsis have been reported in patients treated with IRINOTECAN. Neutropenic complications should be managed promptly with antibiotic support (see 9 DRUG INTERACTIONS). Routine administration of colony stimulating factor is not necessary; however, physicians should consider the use of colony-stimulating factors in patients experiencing clinically significant neutropenia (>grade 2).

In one study an increased risk of neutropenia was observed in patients homozygous for the UGT1A1*28 allele, who received single-agent IRINOTECAN at a dose of 350 mg/m². Individuals with certain genetic polymorphisms in the UGT1A1 gene (e.g. UGT1A1 *28/*28 genotype) have reduced UGT1A1 activity, which in turn increases the concentration of SN-38, the active metabolite of irinotecan (see 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics).

Patients with the UGT1A1*28 allele, treated with combination regimens that deliver doses of IRINOTECAN in the range of 100-180 mg/m², in combination with 5-FU/LV, the risk of grade 4 neutropenia was lower than in studies where IRINOTECAN was administered at doses of 300-350 mg/m² as a single agent (see 8 ADVERSE REACTIONS, Hematology).

Another specific polymorphism of UGT1A1 gene (that reduces the activity of this enzyme) is a missense mutation known as UGT1A1*6 variant.

A reduced irinotecan starting dose should be considered for patients known to be homozygous for UGT1A1*28 or *6 allele, as well as for those who have experienced prior hematologic toxicity with previous treatment. The exact reduction in starting dose in this patient population has not been established and any subsequent dose modifications should be based on individual patient tolerance to treatment (see 4 DOSAGE AND ADMINISTRATION).

Hepatic/Biliary/Pancreatic

Increases in serum levels of liver enzymes and bilirubin have been reported in clinical trials and in the post-market period (see 8 ADVERSE REACTIONS).

The use of IRINOTECAN in patients with significant hepatic dysfunction has not been established. IRINOTECAN was not administered to patients with serum bilirubin > 35μmol/L, or transaminase > 3 times the upper limit of normal if no liver metastases, or transaminase > 5 times the upper limit of normal with liver metastases (see 4 DOSAGE AND ADMINISTRATION).

In clinical trials of weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (17-35 μmol/L) had a significantly greater likelihood of experiencing first-cycle grade 3 or 4 hematologic toxicities including neutropenia than those with bilirubin levels that were less than 17

μmol/L. Patients with deficient glucuronidation of bilirubin, such as those with Gilbert’s syndrome, may also be at greater risk of myelosuppression when receiving therapy with IRINOTECAN. An association between baseline bilirubin elevations and an increased risk of late diarrhea has not been observed in studies of the weekly dosage schedule (see 4 DOSAGE AND ADMINISTRATION).

Immune

Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been reported (see 8 ADVERSE REACTIONS).

Administration of live or live attenuated vaccines in patients immunocompromised by chemotherapeutic agents including irinotecan, 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.

Monitoring and Laboratory Tests

Careful monitoring of white blood cell count with differential, hemoglobin and platelet count is recommended before each dose of IRINOTECAN. Liver function should be monitored before initiation of treatment and monthly, or as clinically indicated (see 8 ADVERSE REACTIONS).

Neurologic Speech disorders

There have been post-market reports of speech disorders (e.g. dysarthria, stuttering, change in voice, garbled or slurred speech, difficulty speaking) in patients treated with irinotecan. In some cases, the speech disorder occurred in the context of other symptoms such as numbness or tingling of the tongue or mouth or symptoms attributed to cholinergic syndrome, hypersensitivity/allergy, cerebrovascular events, or intracranial neoplasia. In some cases, however, the speech disorder occurred in the absence of other symptoms and recurred with subsequent infusions of irinotecan. In most of these cases, the speech disorders occurred during or shortly after infusion of irinotecan and resolved spontaneously within minutes to hours following discontinuation of the irinotecan infusion. The cause of speech disorders in patients treated with irinotecan has not been determined.

Renal

Increases in serum creatinine or blood urea nitrogen have been observed. Rare cases of renal impairment and acute renal failure have been identified. These events have generally been attributed to complications of infection or to dehydration related to nausea, vomiting and/or diarrhea, which are common and sometimes severe adverse events following IRINOTECAN treatment. Rare instances of renal dysfunction due to tumour lysis syndrome have also been reported.

The influence of renal insufficiency on the pharmacokinetics of IRINOTECAN has not been evaluated.

Respiratory

Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during IRINOTECAN therapy (see 8 ADVERSE REACTIONS). Interstitial pulmonary disease can be fatal. Risk factors possibly associated with the development of interstitial pulmonary disease 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 therapy.

7.1 Special Populations

• 7.1.1 Pregnant Women

There are no adequate and well-controlled studies of irinotecan in pregnant women. IRINOTECAN has been shown to be embryotoxic in rats and rabbits at a dose of 6 mg/kg/day. It is teratogenic in rats at doses greater than 1.2 mg/kg/day, and in rabbits at 6 mg/kg/day. Treatment-related changes in the fetuses included external and visceral abnormalities, skeletal variations and abnormalities. IRINOTECAN may cause fetal harm when administered to a pregnant woman.

Women of childbearing potential should not be started on irinotecan until pregnancy is excluded. Women should undergo pregnancy tests before, during and one month after the last irinotecan dose. Pregnancy should be avoided if either partner is receiving irinotecan.

Due to the potential for genotoxicity, advise female patients of reproductive potential to use highly effective contraception during treatment and for 6 months after the last dose of irinotecan.

Due to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of irinotecan.

7.1.2 Breast-feeding

Irinotecan and its active metabolite SN-38 are present in human breast milk. Because of the potential for serious adverse reactions in nursing infants, it is recommended not to breastfeed when receiving therapy with irinotecan and for 7 days after the final dose.

In rats, radioactivity appeared in the 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.

7.1.3 Pediatrics

The safety and effectiveness of IRINOTECAN in the pediatric population have not been established.

7.1.4 Geriatrics

Patients greater than 65 years of age should be closely monitored because of a greater risk of late diarrhea in this population (see 14 CLINICAL TRIALS and 8 ADVERSE REACTIONS). The starting dose of IRINOTECAN in patients 70 years and older for the once-every-3-week-dosage schedule should be 300 mg/m² (see 4 DOSAGE AND ADMINISTRATION).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview Gastrointestinal

Nausea, vomiting and diarrhea are common adverse events following treatment with IRINOTECAN (irinotecan hydrochloride for injection) and can be severe. When observed, nausea and vomiting usually occur during or shortly after infusion of IRINOTECAN. In the clinical studies testing the every 3-week- dosage schedule, the median time to the onset of late diarrhea was 5 days after IRINOTECAN infusion. In the clinical studies evaluating the weekly dosage schedule, the median time to onset of late diarrhea was 11 days following administration of IRINOTECAN. All grade late diarrhea occurred in approximately 80% in this patient population. For patients on the 125 mg/m² weekly dose, the median duration of any grade late diarrhea was 3 days. The median duration was 7 days for those patients reporting grades 3 or 4 late diarrhea on this same weekly dose.

Results from a retrospective analysis have shown that the frequency of grade 3 and 4 late diarrhea by age was significantly greater in patients ≥ 65 years than in patients < 65 years of age. However, results from a prospective study treating patients with metastatic colorectal cancer refractory to one 5-FU- based chemotherapeutic regimen, on a 125 mg/m² weekly dosage schedule (4 weeks on, 2 weeks off) did not demonstrate any statistically significant difference in the rate of treatment-emergent grade 3-4 late diarrhea in patients >65 years of age versus patients <65 years of age. It should be noted however, that a statistically significant increase in the incidence of treatment-emergent early diarrhea in patients

>65 years of age versus patients <65 years of age was found. Furthermore, a 10% reduction in median relative weekly dose intensity was required in patients >65 years versus patients <65 years in order to achieve tolerability. In the early Japanese trials, there is some information that patients with considerable ascites or pleural effusions were at increased risk for neutropenia or diarrhea.

Hematology

Typical adverse hematologic events of IRINOTECAN included neutropenia, leukopenia (including lymphocytopenia), and anemia. Serious thrombocytopenia is uncommon. When evaluated in the trials of weekly administration, the frequency of grade 3 or 4 neutropenia was significantly increased in patients who had prior pelvic or abdominal irradiation. 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 3.0% of the patients. Only 5.6% of patients received G-CSF for the treatment of neutropenia. NCI grade 3 or 4 anemia was noted in 6.9% of the patients. Blood transfusions were given to 9.9% of the patients. There were no significant differences in the frequency of grade 3 and 4 neutropenia by age or gender (see 7 WARNINGS AND PRECAUTIONS, and 4 DOSAGE AND ADMINISTRATION, 4.2 Recommended Dose and Dosage Adjustment for Single-agent and Combination Dosage Schedules). In the early Japanese trials, there is some information that patients with considerable ascites or pleural effusions were at increased risk for neutropenia or diarrhea.

Individuals with certain polymorphs of UGT1A1, such as UGT1A1*28, may have reduced activity of this enzyme. Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele (also referred to as UGT1A1 7/7 genotype).

In a single arm study of 66 patients with solid tumors or lymphomas who received IRINOTECAN as a single-agent at a dose of 350 mg/m² on a once every 3 weeks schedule, 3 out of 6 patients with UGT1A1

*28/*28 genotype had grade 4 neutropenia versus 3 out of 24 patients with the UGT1A1 *1/*28 genotype, and 0 out of 29 patients with the UGT1A1 *1/*1 genotype (see 7 WARNINGS AND PRECAUTIONS).

In a study which compared IRINOTECAN (100-125 mg/m2) in combination with bolus 5-FU/LV (IFL regimen), oxaliplatin (85 mg/m2) in combination with infusional 5-FU/LV (FOLFOX4 regimen) and a combination of oxaliplatin (85 mg/m²) plus IRINOTECAN (200 mg/m²) (IROX regimen), the incidence of grade 4 neutropenia is shown in the table below.

Rates of Grade 4 Neutropenia for UGT1A1*28 Genotype by Treatment

^a IFL: irinotecan 100-125 mg/m² followed by leucovorin 20 mg/m² and 5-FU 400 mg/m² given as a bolus on days 1, 8, 15, and 22 followed by a 2-week rest in repeated 6-week cycles.

^b FOLFOX4: oxaliplatin 85 mg/m² on day 1, leucovorin 200 mg/m² on days 1 and 2, and 5-FU 400 mg/m² given as a bolus followed by 600 mg/m² given as a 22 hr continuous infusion on days 1 and 2 administered in repeated 2-week cycles.

^c oxaliplatin 85 mg/m² followed by irinotecan 200 mg/m² administered on day 1 of repeated 3-week cycles.

In a study to investigate the role of UGT1A1*28 polymorphism in the development of toxicity in patients treated with IRINOTECAN and infusional 5-FU/LV at doses of 180 mg/m², 1 out of 22 patients with the UGT1A1 *28/*28 genotype had grade 4 neutropenia, versus 6 out of 114 patients with the UGT1A1

*1/*28 and 2 out of 114 for patients with the UGT1A1 *1/*1 genotype.

Whole Body

Asthenia, fever, and abdominal pain are generally the most common events of this type.

Cholinergic Symptoms

Patients may have cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping and early diarrhea. If these symptoms occur, they manifest during or shortly after drug infusion. They are thought to be related to the anticholinesterase activity of the irinotecan parent compound and are more likely to occur at higher irinotecan dose levels. The timing of the symptoms is most consistent with the occurrence of peak irinotecan serum levels during parenteral administration.

Hepatic

In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4 liver enzyme abnormalities were observed in less than 10% of patients. These events typically occur in patients with known hepatic metastases.

Dermatologic

Alopecia has been reported during treatment with IRINOTECAN. Rashes have also been reported but did not result in discontinuation of treatment.

Respiratory

Severe pulmonary events are infrequent. Early effects such as dyspnea have been reported (see 7 WARNINGS AND PRECAUTIONS). In the clinical studies evaluating the weekly dosage schedule, over half the patients with dyspnea had lung metastases. The extent to which malignant pulmonary involvement or other pre-existing lung disease may have contributed to dyspnea in these patients is unknown.

Potentially life-threatening interstitial disease presenting with dyspnea, fever and pulmonary infiltrates (reticulonodular pattern on chest x-ray) is uncommon during IRINOTECAN therapy. Usually seen in Japanese studies the contribution of IRINOTECAN to these events was difficult to assess because these patients also had lung tumours and some had pre-existing non-malignant pulmonary disease.

Neurologic

Insomnia and dizziness can occur but are not usually considered to be directly related to the administration of IRINOTECAN. Dizziness may sometimes represent symptomatic evidence of orthostatic hypotension in patients with dehydration (see 7 WARNINGS AND PRECAUTIONS).

Cardiovascular

Vasodilation (flushing) may occur during administration of IRINOTECAN. Bradycardia may also occur but has not required intervention. These effects have been attributed to the cholinergic syndrome sometimes observed during or shortly after infusion of IRINOTECAN. All thromboembolic events, when considered together, have commonly been observed in patients receiving IRINOTECAN (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular). The specific cause of these events has not been determined.

Hypersensitivity

Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed (see 7 WARNINGS AND PRECAUTIONS).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Combination-Agent (Irinotecan/5-FU/LV) Therapy:

A total of 955 patients with metastatic colorectal cancer received 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 Table 1 in 4 DOSAGE AND ADMINISTRATION for recommended combination regimens).

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 5FU/LV, 16 (7.3%) patients who received 5FU/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 5-FU/LV, 14 (6.4%) patients who received 5- FU/LV alone, and 26 (11.7%) patients who received IRINOTECAN alone.

In Study 1, data on hospitalization included hospitalization required as a consequence of chemotherapy- induced adverse events and hospitalizations that may have resulted from complications due to cancer or intercurrent illnesses. One hundred and thirteen (50.2%) patients of 225 who received IRINOTECAN in combination with 5FU/LV were hospitalized. Sixty-eight (30.2%) patients were hospitalized once, 28 (12.4%) patients were hospitalized twice and 17 (7.6%) patients were hospitalized more than two times. Ninety-nine (44.4%) patients of 223 treated with IRINOTECAN alone were hospitalized. Seventy-one (31.8%) patients were hospitalized once, 21 (9.4%) were hospitalized twice and 7 (3.1%) were hospitalized more than two times. Eighty-six (39.3%) patients of 219 treated with 5 FU/LV were hospitalized. Sixty (27.4%) patients were hospitalized once, 20 (9.1%) patients were hospitalized twice and 6 (2.7%) were hospitalized more than two times.

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 5FU/LV and 2 (1.4%) patients who received 5FU/LV alone. Discontinuations due to adverse events were reported for 9 (6.2%) patients who received IRINOTECAN in combination with 5-FU/LV and 1 (0.7%) patients who received 5-FU/LV alone.

In Study 2, data on hospitalization included hospitalization required as a consequence of chemotherapy- induced adverse events. Fifty (34.5%) patients of 145 who received IRINOTECAN in combination with 5FU/LV were hospitalized. Thirty-five (24.1%) patients were hospitalized once, 8 (5.5%) patients were hospitalized twice and 7 (4.8%) patients were hospitalized more than two times. Twenty-nine (20.3%) patients of 143 treated with 5FU/LV were hospitalized. Twenty-one (14.7%) patients were hospitalized once, 6 (4.2%) patients were hospitalized twice and 2 (1.4%) patients were hospitalized more than two times.

The most clinically significant adverse events (all grades 1-4) 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.

Table 6 and Table 7 list the clinically relevant adverse events reported in Studies 1 and 2, respectively.

Table 6. Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies^a

^a Severity of adverse events based on NCI CTC (version 1.0)

^b Complete hair loss = Grade 2

^c 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

Note: Combination toxicities (gastrointestinal and cardiovascular syndromes) may occur simultaneously and both contribute to the toxicity profile

Table 7. Study 2: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies^a

^a Severity of adverse events based on NCI CTC (version 1.0)

^b Includes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping or diarrhea (occurring during or shortly after infusion of irinotecan)

^c Complete hair loss = Grade 2

^d 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

Note: Combination toxicities (gastrointestinal and cardiovascular syndromes) may occur simultaneously and both contribute to the toxicity profile

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.

Seventeen of the patients died within 30 days of the administration of IRINOTECAN. In five cases (1.6%, 5/304), the deaths were potentially drug-related. These five patients experienced a constellation of medical events that included known effects of IRINOTECAN. One of these patients died of neutropenic sepsis without fever. Neutropenic fever, defined as NCI grade 4 neutropenia and grade 2 or greater fever, occurred in nine (3.0%) other patients. These patients recovered with supportive care. Thirteen (4.3%) patients discontinued IRINOTECAN treatment because of medical events.

One hundred and nineteen (39.1%) of the 304 patients were hospitalized a total of 156 times because of adverse events; 81 (26.6%) patients were hospitalized for events judged to be related to administration of IRINOTECAN. 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%).

Adjustments in the dose of IRINOTECAN were made during the cycle of treatment and for subsequent cycles based on individual patient tolerance. The first dose of at least one cycle of IRINOTECAN 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 leucopenia.

The adverse events in Table 8 are based on the experience of the 304 patients enrolled in the three studies.

Once-Every-3-Week Dosage Schedule

A total of 535 patients with metastatic colorectal cancer whose disease had 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.

Fifty-five percent (295/535) of patients were hospitalized at least once due to serious adverse events: 60% (188/316) of patients received IRINOTECAN, 63% (57/90) received best supportive care, and 39% (50/129) received 5-FU- based therapy. Eight percent (25/316) of patients treated with IRINOTECAN and 7% (9/129) treated with 5-FU-based therapy discontinued treatment due to adverse events.

Table 9 lists the grade 3 and 4 adverse events reported in the 535 patients enrolled in the two studies (V301 and V302) evaluating the once-every-3-week dosage schedule.

^a Severity of adverse events based on NCI CTC (version 1.0)

*Occurring > 24 hours after administration of IRINOTECAN

Occurring <24 hours after administration of IRINOTECAN

^‡ Primarily upper respiratory infections

^§ Not applicable; complete hair loss = NCI grade 2

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

The clinical trial adverse reaction pediatric data is not available.

8.3 Less Common Clinical Trial Adverse Reactions

The less common clinical trial adverse reaction data is not available.

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics

The less common clinical trial adverse reaction pediatric data is not available.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings

The clinical trial abnormal laboratory findings data is not available.

Post-Market Findings

The post-market abnormal laboratory findings data is not available.

8.5 Post-Market Adverse Reactions

The following events have been identified during postmarketing use of IRINOTECAN in clinical practice.

Infrequent cases of colitis, including typhlitis, ulcerative and ischemic colitis, have been observed. This can be complicated by ileus or what was described as toxic megacolon, ulceration, bleeding, obstruction, and infection. Rare cases of intestinal perforation have been reported. Cases of ileus without preceding colitis have also been observed. Patients experiencing ileus should receive prompt antibiotic support (see 7 WARNINGS AND PRECAUTIONS). Hiccups have also been reported.

Rare cases of hyponatremia mostly related to diarrhea and vomiting have been reported.

Increases in serum levels of transaminases (i.e., AST and ALT), GGT and bilirubin in the absence of progressive liver metastasis have been observed; rare cases of symptomatic pancreatitis or asymptomatic elevated pancreatic enzymes have been observed.

Infrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhea and/or vomiting, or sepsis (see 7 WARNINGS AND PRECAUTIONS).

Early effects such as muscular contraction or cramps and paresthesia have been reported.

Severe pulmonary events are infrequent. Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Early effects such as dyspnea have been reported (see 7 WARNINGS AND PRECAUTIONS).

Myocardial ischemic events, with some cases resulting in fatality, have been observed in patients treated with IRINOTECAN, the majority of whom had underlying cardiac disease, other known risk factors for cardiac disease and/or were treated with other concomitant cytotoxic chemotherapy (see 7 WARNINGS AND PRECAUTIONS).

Speech disorders have been reported in patients treated with irinotecan (see 7 WARNINGS AND PRECAUTIONS, Neurologic).

Cases of bacterial, fungal and viral infections, sometimes fatal and/or life-threatening, have been reported with the use of IRINOTECAN, mostly in combination with other chemotherapeutic and/or immunosuppressant agents.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

Irinotecan hydrochloride trihydrate is metabolized by carboxyl esterase to an active metabolite, SN-38, and oxidized by CYP3A4 to two relatively inactive metabolites (APC and NPC). SN-38 is glucuronidated to an inactive conjugate (see 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics). Pharmacokinetic drug-drug and drug-herbal interactions have been shown (Table 10). These have most often been attributed to inhibition or induction of CYP3A4, though multiple mechanisms have been suggested to contribute to the interactions (induction/inhibition of carboxyl esterase, UDP-glucuronyl transferase 1A1, and drug transporters).

In vitro drug interaction studies reveal that the metabolism of irinotecan to its active metabolite SN-38 by carboxylesterase enzymes is not inhibited by 5-fluorouracil (5-FU). Data from a phase 1 clinical study involving IRINOTECAN, 5-FU, and leucovorin (LV) in 26 patients with solid tumours indicate that the disposition of irinotecan and its active metabolite SN-38 are not substantially altered when the drugs are co-administered. 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.

Irinotecan and active metabolite SN-38 are metabolized via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1).

Coadministration of irinotecan with inhibitors of CYP3A4 (e.g. cimetidine, macrolide antibiotics [azithromycin, clarithromycin, erythromycin], azole antifungals [fluconazole, ketoconazole, itraconazole], grapefruit juice, CYP3A4-inhibitory calcium channel blockers such as verapamil, diltiazem, and nifedipine) and/or UGT1A1 may result in significantly increased systemic exposure to irinotecan and the active metabolite SN-38 and potential toxicity.

This interaction has been documented in cancer patients with the co-administration of IRINOTECAN and ketoconazole, a potent enzyme inhibitor, where the relative exposure to the CYP3A4-mediated metabolite APC was reduced by 87%, whereas the relative exposure to the active metabolite SN-38 increased by 100%.

Physicians should take this into consideration when administering irinotecan with these drugs.

Exposure to fluoroquinolones such as ciprofloxacin or norfloxacin may be increased in patients with compromised renal function due to dehydration or colorectal cancer complications. In these circumstances, co-administration of IRINOTECAN and CYP3A4-inhibitory fluoroquinolone antibiotics could potentially lead to increased SN-38 exposure and enhanced toxicity.

Similarly, co-administration of IRINOTECAN with CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, glucocorticoids, St. John’s Wort) leads to reduction in plasma levels of the active metabolite SN-38, which may have a deleterious impact on treatment outcome. This interaction has been documented in cancer patients with the co-administration of IRINOTECAN with St. John’s Wort and with the co-administration of IRINOTECAN with phenytoin.

The prescribing information of concomitant medications should also be consulted to identify potential interactions.

9.3 Drug-Behavioural Interactions

Drug-Behavioural interactions have not been established.

9.4 Drug-Drug Interactions

Table 10 - Established or Potential Drug-Drug Interactions

PRECAUTIONS

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Appropriate starting dose for patients taking drugs shown or anticipated to alter the kinetics of IRINOTECAN has not been formally defined. Co-administration of azole antifungals and irinotecan is contraindicated and patients should discontinue ketoconazole at least 1 week prior to starting IRINOTECAN therapy (see 2 CONTRAINDICATIONS). Patients should not drink grapefruit juice during treatment. Consideration should be given to starting or substituting to non-enzyme-inducing anticonvulsants at least one week prior to initiation of IRINOTECAN therapy in patients requiring anticonvulsant treatment. Coadministration of atazanavir sulfate, a CYP3A4 and UGT1A1 inhibitor has the potential to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should take this into consideration when co-administering these drugs (see 7 WARNINGS AND PRECAUTIONS).

Pharmacodynamic Interactions

Antineoplastic agents: Adverse events due to IRINOTECAN, such as myelosuppression and diarrhea, would be expected to be enhanced by combination with other anti-neoplastic agents having similar adverse effects.

Laxatives: It would be expected that laxative use during IRINOTECAN therapy may worsen the incidence or severity of diarrhea.

Diuretics: The use of diuretics should be carefully monitored because of the potential risk of dehydration secondary to vomiting and/or diarrhea induced by IRINOTECAN. The physician may wish to withhold diuretics during IRINOTECAN dosing, and certainly during periods of active vomiting or diarrhea.

Dexamethasone: Lymphocytopenia has been reported in patients receiving IRINOTECAN. It is possible that the administration of dexamethasone as an anti-emetic prophylaxis may have enhanced the likelihood of this effect. However, in these reports, serious opportunistic infections were not observed and no complications were specifically attributed to lymphocytopenia.

Hyperglycemia has been reported in patients receiving IRINOTECAN. This has usually been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of IRINOTECAN. It is probable that dexamethasone, given as anti-emetic prophylaxis, contributed to hyperglycemia in some patients.

Prochlorperazine: The incidence of akathisia in clinical trials of the weekly dosage schedule was greater (8.5%, 4 of 47 patients) when prochlorperazine was administered on the same day as IRINOTECAN than when these drugs were given on separate days (1.3%, 1 of 80 patients). However, the 8.5% incidence of akathisia is within the range reported for use of prochlorperazine when given as premedication for other chemotherapies.

Neuromuscular blocking agents: Interaction between IRINOTECAN and neuromuscular blocking agents cannot be ruled out, since irinotecan has anticholinesterase activity. Drugs with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarizing drugs may be antagonized.

Bevacizumab: Results from a dedicated drug-drug interaction trial demonstrated no significant effect of bevacizumab on the AUC_0-last of irinotecan and its active metabolite SN-38. Results from a phase III clinical trial reported a small increase in diarrhea and leukopenia adverse events in the patients treated with IFL + AVASTIN when compared to patients treated with IFL alone. Patients who develop severe diarrhea, leukopenia or neutropenia with AVASTIN and irinotecan combination therapy should have irinotecan dose modifications as specified.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

St. John’s Wort: Exposure to the active metabolite SN-38 is reduced by approximately 40% in patients taking concomitant St. John’s Wort and IRINOTECAN. St. John’s Wort should be discontinued at least 1 week prior to the first cycle of IRINOTECAN (see 7 WARNINGS AND PRECAUTIONS).

9.7 Drug-Laboratory Test Interactions

There are no known interactions between IRINOTECAN and laboratory tests.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Irinotecan hydrochloride trihydrate is an antineoplastic agent of the topoisomerase I inhibitor class. Irinotecan is a semi-synthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata. 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 relegation of these single- strand breaks.

Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38, which is formed from irinotecan primarily by liver carboxylesterase enzymes. The SN-38 metabolite is approximately 1000 times more potent than irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumour cell lines. The precise contribution of SN-38 to the activity of IRINOTECAN in humans has not been completely defined. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. An acidic pH promotes the formation of the lactone whereas a basic pH favours the hydroxy acid anion form.

10.2 Pharmacodynamics

This information is not available.

10.3 Pharmacokinetics

After intravenous infusion of IRINOTECAN in humans, irinotecan plasma levels decline in a multiexponential manner. A summary of mean irinotecan and SN-38 pharmacokinetic parameters in patients with metastatic carcinoma of the colon and rectum (dosed at 125 or 340 mg/m²) is shown in Table 11.

C_max : Maximum plasma concentration

AUC_0-24: Area under plasma concentration-time curve from 0 to 24 hours after end of infusion t_1/2 : Terminal elimination half-life

V_area: Volume of distribution of terminal elimination phase CL: Total systemic clearance

*: Plasma specimens collected for 24 hours following the end of the 90-minute infusion

†: Plasma specimens collected for 48 hours following the end of the 90-minute infusion. Because of the longer collection period, these values provide a more accurate reflection of the terminal elimination half-lives of irinotecan and SN-38.

Over the recommended dose range of 50 to 350 mg/m², the AUC of irinotecan increases linearly with dose. The AUC of SN-38 increases less than proportionally with dose. Irinotecan exhibits moderate plasma protein binding (30 to 68% bound). SN-38 is approximately 95% bound to human plasma proteins, mainly albumin.

The complete disposition of irinotecan in humans has not been fully elucidated. Irinotecan (CPT-11) is subject to extensive metabolic conversion by various enzyme systems, including esterases to form the active metabolite SN-38, and UGT1A1 mediating glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G. Irinotecan (CPT-11) can also undergo CYP3A4-mediated oxidative metabolism to several pharmacologically inactive oxidation products, one of which can be hydrolyzed by carboxylesterase to release SN-38. UGT1A1 enzyme activity is reduced in individuals with certain genetic polymorphisms, such as UGT1A1*28. Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele (also known as UGT1A1 7/7).

In a prospective study, in which irinotecan was administered as a single-agent (350 mg/m²) on a once every 3 week schedule, patients homozygous for the UGT1A1*28 allele (UGT1A1 7/7) had higher systemic exposures to SN-38 than those who were homozygous for the wild-type UGT1A1 allele (UGT1A1 *1/*1) (see 7 WARNINGS AND PRECAUTIONS – Hematologic and 8 ADVERSE REACTIONS –

Hematology). The urinary excretion of irinotecan (11 to 20%), SN-38 (< 1%), and SN-38 glucuronide (3%) is low.

Irinotecan is oxidized by cytochrome P450 isozyme 3A4 (CYP3A4) to yield two relatively inactive metabolites, APC (7-ethyl-l0-[4-N-(5-aminopentanoic acid)-l-piperidino]carbonyloxycamptothecin) and the minor metabolite, NPC (7-ethyl-l0-(4 amino-1-piperidino)carbonyloxycamptothecin). See diagram below.

In one pharmacokinetic study of patients administered a starting dose of irinotecan 125mg/m², the terminal half-life of irinotecan was statistically significantly longer in patients who were 65 years or older compared to patients younger than 65 years (6.0 hours versus 5.5 hours, respectively). Dose-normalized AUC_0-24 was 14.8% higher, C_max was 11.3% higher and clearance was 17.5% lower in patients 65 years and older compared with patients younger than 65 years. Also, dose normalized AUC_0-24 of SN-38 was 11.2% higher in subjects age 65 years and over compared to subjects less than 65 years, but this result was not statistically significant.

In a different pharmacokinetic study that was prospectively designed to investigate the effect of age on irinotecan toxicity, no statistically significant differences in irinotecan pharmacokinetics were seen in patients >65 years compared to those <65 years administered a single 125 mg/m² irinotecan dose.

Irinotecan C_max and AUC_0-24 were, respectively, 0.7% and 0.3% lower in patients >65 years compared to patients who were <65 years. Values for SN-38 C_max and AUC_0-24 were, respectively, 1.8% lower and 0.8% higher in patients >65 years compared to patients <65 years and values for SN-38 glucuronide C_max and AUC_0-24 were, respectively, 1.0% and 3.1% lower in patients >65 years compared to patients who were

<65 years.

The reason for the conflicting results between the two pharmacokinetic results is not known. Clinically, however, particular caution should be exercised when administering irinotecan to elderly patients as these patients may be less tolerant of the toxic effects of the drug (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS).

Special Populations and Conditions

• Sex: There is no clinically important gender influence on the pharmacokinetics of irinotecan.
• Ethnic Origin: The influence of race has not been studied.

• Hepatic Insufficiency: Irinotecan clearance is diminished in patients with hepatic dysfunction while relative exposure to the active metabolite SN-38 is increased. The magnitude of these

  effects is proportional to the degree of liver impairment as measured by elevations in serum total bilirubin and transaminase concentrations (see 4 DOSAGE AND ADMINISTRATION and 7 WARNINGS AND PRECAUTIONS).

• Renal Insufficiency: The influence of renal insufficiency on the pharmacokinetics of irinotecan has not been formally studied.

11 STORAGE, STABILITY AND DISPOSAL

Store at controlled room temperature (15 to 30^oC). Protect from light and freezing. IRINOTECAN (irinotecan hydrochloride for injection) is available in an amber-coloured polypropylene vial that is packaged in plastic blister to protect from breakage. It is recommended that the vial remain in the carton until time of use.

12 SPECIAL HANDLING INSTRUCTIONS

As with other potentially toxic anti-cancer agents, care should be exercised in the handling and preparation of infusion solutions containing IRINOTECAN (irinotecan hydrochloride for injection). Preparation of IRINOTECAN should be done in a vertical laminar flow hood. The use of gloves, safety glasses and protective clothing is recommended. If IRINOTECAN solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If IRINOTECAN contacts the mucous membranes, flush thoroughly with water. All waste material that has come in contact with IRINOTECAN should be properly segregated, sealed and incinerated.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Irinotecan hydrochloride

Chemical name: [1,4'-Bipiperidine]-1'-carboxylic acid, 4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14- dioxo-1H-pyrano[3',4:6,7]-indolizino[1,2-b]quinolin-9-yl ester, monohydrochloride, trihydrate, (S)-

Molecular formula and molecular mass: C₃₃H₃₈N₄O₆⋅HCl⋅3H₂O; 677.19 g /mol Structural formula:

Physicochemical properties:

Description: Pale yellow to yellow crystalline powder which melts at 256.5^oC with decomposition. The partition coefficient in an acidic medium (pH < 6) was 0.03; in a basic medium (pH > 9) was 0.05.

Solubility: It is soluble in water but sparingly soluble in organic solvents.

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

IRINOTECAN (irinotecan hydrochloride for injection) has been studied in clinical trials as a combination therapy with 5-FU and LV and as a single agent (see 4 DOSAGE and ADMINISTRATION). Weekly and once-every-2-week dosage schedules were used for the combination-agent treatment. Weekly and once-every-3-week dosage schedules were used for the single-agent studies. Clinical studies of combination and single-agent uses are described below.

First-line Treatment of Metastatic Colorectal Cancer:

Two phase 3, randomized, controlled, multicentre, multinational clinical trials support the use of IRINOTECAN (irinotecan hydrochloride for injection) in combination with 5-FU/LV as a first-line treatment for patients with metastatic carcinoma of the colon or rectum. In both studies, these combinations of IRINOTECAN with 5-FU and LV were compared with 5-FU/LV alone.

• Study 1 compared combination IRINOTECAN /bolus 5-FU/LV therapy given weekly with a standard bolus regimen of 5-FU/LV alone given daily for 5 days every 4 weeks; a IRINOTECAN - alone treatment arm given on a weekly schedule was also included.
• Study 2 evaluated two different methods of administering infusional 5-FU/LV, with or without IRINOTECAN. A 7-day course of fluoroquinolone antibiotic prophylaxis was given in patients whose diarrhea persisted for greater than 24 hours despite loperamide or if they developed a fever in addition to diarrhea. Treatment with oral fluoroquinolone was also initiated in patients who developed an absolute neutrophil count (ANC) < 500/mm³, even in the absence of fever or diarrhea.

In both studies, concomitant medications such as antiemetics, atropine, and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. Patients in both studies also received treatment with intravenous antibiotics if they had persistent diarrhea or fever, or if ileus developed.

Table 12 - Summary of patient demographics for clinical trials in First-line Treatment of Metastatic Colorectal Cancer

Recurrent or Progressive Metastatic Colorectal Cancer:

Weekly Dosage Schedule:

Data from three single-agent studies, involving a total of 304 patients support the use of IRINOTECAN in the treatment of patients with metastatic cancer of the colon or rectum that has recurred or progressed following treatment with 5-FU-based therapy. In each study, IRINOTECAN was administered in repeated 6-week cycles as a once weekly dose for 4 weeks, followed by a 2-week rest period. In these trials, the starting doses of IRINOTECAN were 100, 125 or 150 mg/m².

Across all three studies, 193 of the 304 patients began therapy at the recommended starting dose of 125 mg/m². Among these 193 patients, 2 complete and 27 partial responses were observed for an overall response rate of 15.0% (95% confidence interval (CI), 10.0 to 20.1%).

Table 13 - Summary of patient demographics for clinical trials in Recurrent or Progressive Metastatic Colorectal Cancer - Weekly Dosage Schedule

¹ Total subjects across all three studies: 304

Once-Every-3-Week Dosage Schedule:

Two phase 3, multicentre, randomized, clinical studies support the use of IRINOTECAN in patients with metastatic colorectal cancer whose disease has progressed following prior 5-FU therapy. Second-line IRINOTECAN plus best supportive care was compared with best supportive care alone in the first study (V301) and with infusional 5-FU-based therapy in the second study (V302). The primary endpoint in both studies was survival. A total of 535 patients were randomized in 94 centres in Europe, the Middle East, and South Africa. IRINOTECAN was administered intravenously at a starting dose of 350 mg/m² over 90 minutes once every 3 weeks. The starting dose was 300 mg/m² for patients who were 70 years and older, or who had a WHO performance status of 2. The highest total dose permitted was 700 mg.

Dose reductions and/or administration delays were permitted in the event of severe hematologic and/or nonhematologic toxicities while on treatment. Antiemetics, atropine, and loperamide were provided as needed. If late diarrhea persisted for greater than 24 hours despite loperamide, a 7-day course of fluoroquinolone antibiotic prophylaxis was given. Patients were to be followed every 3 to 6 weeks for 1 year.

Table 14 - Summary of patient demographics for clinical trials in Recurrent or Progressive Metastatic Colorectal Cancer - Once-Every-3-Week Dosage Schedule

• 14.2 Study Results

First-line Treatment of Metastatic Colorectal Cancer

In both studies, the combination of IRINOTECAN /5-FU/LV therapy resulted in significant improvement in objective tumour response rates, time to tumour progression (TTP) and survival when compared with 5-FU/LV alone. These differences in survival were observed in spite of second-line therapy in a majority of patients on both arms, including crossover to IRINOTECAN -containing regimens in the control arms. Fifty six percent (56%) of patients in Study 1 who received 5FU/LV therapy were treated with IRINOTECAN as second-line therapy and thirty four percent (34%) of patients in Study 2 who received 5FU/LV were treated with IRINOTECAN as second-line therapy. Patient characteristics and major efficacy results are shown in Table 15.

Table 15. Combination Dosage Schedule: Study Results

^a Study 1: N=225 (IRINOTECAN/5-FU/LV), N=219 (5-FU/LV), N=223 (IRINOTECAN) Study 2: N=199 (IRINOTECAN/5-FU/LV), N=186 (5-FU/LV)

^b Confirmed > 4 to 6 weeks after first evidence of objective response

^c Chi-square test

^d Log-rank test

Improvement was noted with IRINOTECAN-based combination therapy relative to 5-FU/LV when response rates and time to tumour progression were examined across the following demographic and disease-related subgroups (age, gender, ethnic origin, performance status, extent of organ involvement with cancer, time from diagnosis of cancer, prior adjuvant therapy, and baseline laboratory abnormalities).

Figure 1 and Figure 2 illustrate the Kaplan-Meier survival curves for the comparison of IRINOTECAN /5- FU/LV versus 5-FU/LV in Studies 1 and 2, respectively.

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Figure 1. Survival

First-Line Irinotecan/5-FU/LV vs 5-FU/LV Study 1

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Months

*log-rank test

P_roba b_il^ity

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Figure 2. Survival

First-Line Irinotecan/5-FU/LV vs 5-FU/LV Study 2

0 3 6 9 12 15 18 21 24 27 30

Months

*log-rank test

Figure 3 and Figure 4 illustrate the Kaplan-Meier Time to Tumour Progression curves for comparison of IRINOTECAN /5-FU/LV versus 5-FU/LV in Studies 1 and 2, respectively.

Figure 3 Time to Tumour Progression (Study 1)

Pro b ab i^l i ty

Figure 4 Time to Tumour Progression (Study 2)

Cox regression modeling was used to evaluate the effect of treatment with IRINOTECAN /5-FU/LV versus 5-FU/LV alone on time to tumour progression and survival in the context of prespecified patient baseline characteristics. The most predictive factors for improved survival with the IRINOTECAN

/5FU/LV combination therapy were : normal serum lactate dehydrogenase (LDH) and better performance status.

In Study 1, treatment with combination IRINOTECAN /5-FU/LV was associated with a 36% lower risk of tumour progression and a 20% lower risk of death relative to treatment with 5-FU/LV. In Study 2, treatment with IRINOTECAN /5-FU/LV was associated with 42% lower risk of tumour progression and a 23% lower risk of death relative to treatment with 5-FU/LV.

The European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was used in both first line therapy studies. At the beginning of the treatment in Study 1, there was close to one hundred percent (99%) return of the filled questionnaires. Over the first 30-32 weeks of treatment, the return of questionnaire at the scheduled assessments was 76-82% for IRINOTECAN /5-FU/LV, and 77-97% for those treated with 5-FU/LV alone. In Study 2, there was an 83% return of the questionnaires at baseline whereas during the first 28 weeks the return was 46-61% for IRINOTECAN /5-FU/LV and 46-60% for 5-FU/LV alone.

In Study 1, the pain, role functioning, and global health status/QOL scales were prospectively selected to test treatment effect by the analysis of variance for repeated measurements. Data imputation method as suggested by Zwinderman was adopted in the presence of missing data during follow-up, which was due to withdrawal of patients. On the basis of the performed analysis, there were no significant differences between the group treated with IRINOTECAN / 5-FU/LV and the group given

5-FU/LV in any of the three items analyzed. However, when analyzing worst scores, mean changes in pain and role functioning were significantly better for patients receiving IRINOTECAN /5-FU/LV than those treated with 5-FU/LV. It was also observed that increases in mean scores for appetite loss were less prominent with IRINOTECAN /5-FU/LV relative to 5-FU/LV alone. Similar findings were apparent in Study 2.

The repeated - measurement analysis conducted on global health status/QOL showed no statistically significant treatment effect although the evolution of the global health status scale tended to be better with irinotecan- containing combination treatment. In the presence of missing data due to patient withdrawal, both last observations carried forward (LOCF) and the mean of the worst scores of progressive patients were used as imputation methods.

A difference was found in favour of IRINOTECAN /5-FU/LV therapy in assessment of time to definitive deterioration of global health status scale from baseline. In this analysis, times to either 5% or a 20% decrement in global health status were statistically improved with IRINOTECAN /5-FU/LV (log rank p=

0.03 and 0.04, respectively). When similarly analyzing the time to 10% or 30% declines in global health status, the differences were close to significant (log rank p=0.06 in both cases). The median time to performance status deterioration was significantly longer with patients treated with IRINOTECAN

/5-FU/LV than those treated with 5-FU/LV alone (11.2 months versus 9.9 months; log rank p=.046). The impact of the side effects of IRINOTECAN with/without in combination of 5-FU/LV on the quality of life of patients were not addressed in this questionnaire.

Recurrent or Progressive Metastatic Colorectal Cancer:

Weekly Dosage Schedule:

All of the patients had a performance status (PS) of 0 to 2, with the majority at 0 or 1. The majority of responses were observed within the first two cycles of therapy. The median duration of response for patients beginning therapy at 125 mg/m² was 5.8 months (range, 2.6 to 15.1 months). An additional 53.4% (103/193) of the patients treated at a starting dose of 125 mg/m² achieved a best response of stable disease by formal response criteria.

Response to IRINOTECAN was seen in both males and females of all ages. These patients responded to IRINOTECAN regardless of whether prior 5-FU had been given as adjuvant therapy or for metastatic disease. Patients with cancer of the colon or rectum responded to the drug, and these responses occurred both in patients with single and multiple metastatic sites.

The Kaplan-Meier estimate of median survival time for patients on the 125 mg/m² starting dose was

8.9 months (range, 0.3 to 33.4 months). The majority of patients treated with IRINOTECAN had an increase in, or stabilization of body weight, and an improvement or maintenance of performance status. Among responding patients with tumour-related symptoms, the majority experienced amelioration of these symptoms during IRINOTECAN treatment.

Once-Every-3-Week Dosage Schedule:

The data indicate a statistically significant survival advantage for IRINOTECAN over best supportive care or infusional 5-FU-based therapy (p = 0.001 and p = 0.035, respectively). The benefit appears early and is sustained during follow up. One-year survivals are 36% vs 14% (IRINOTECAN vs supportive care) and 45% vs 32% (IRINOTECAN vs infusional 5-FU). Median survivals are 9.2 months vs 6.5 months (IRINOTECAN vs supportive care) and 10.8 months vs 8.5 months (IRINOTECAN vs infusional 5-FU).

Median survival and 1-year survival for the patients receiving the once-every-3-week dosage regimen of IRINOTECAN in these phase 3 studies were similar to those seen in phase 2 studies of patients on the weekly regimen of second-line IRINOTECAN therapy developed in North America.

Multiple regression analyses were performed to assess the influence of baseline patient characteristics (e.g. performance status) on survival. When adjusted for these characteristics, survival among patients treated with IRINOTECAN remained significantly longer than in the control populations (p=0.001 for V301 and p = 0.017 for V302).

Surrogate efficacy endpoints are summarized in Table 16 below:

Table 16: Once- Every 3- Week Dosage Schedule Study Results

¹ p = 0.0001; ² p = 0.018; ³ p = 0.003 ⁴ p = 0.03; ⁵ p = 0.002

PS: performance status; CR: complete response; PR: partial responses; SD: stable diseases; PD: progressive diseases

All surrogate endpoints show an advantage for IRINOTECAN groups. In Study V301, these differences were statistically significant for: survival without PS deterioration, survival without weight loss, and pain-free survival. In Study V302, these differences were significant for progression free survival and tumour response.

In the two randomized studies of second line therapy for metastatic colorectal cancer, the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C-30) instrument was utilized. At each visit, patients completed a questionnaire consisting of 30 questions, such as "Did pain interfere with daily activities?" ( 1 = Not at All, to 4 = Very Much) and "Do you have trouble taking a long walk?" (Yes or No). The answers from 30 questions were converted into 15 subscales, that were scored 0 to 100. The global health status was derived from two questions about the patient's sense of general well being in the past week. The results are summarized in Table 17 based on patients' worst post-baseline scores.

Table 17: EORTC QLQ-C30: Mean Worst Post-Baseline Score* (Data from Two Randomized Studies for Second Line Therapy)

Best supportive care

* For the five functional subscales and global health status subscale, higher scores imply better functioning, whereas, on the nine symptom subscales, higher scores imply more severe symptoms. The subscale scores of each patient were collected at each visit until the patient dropped out of the study.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Acute Toxicity

Acute toxicity in rodents consists of tremors, convulsions, respiratory distress, and death. The acute toxicity of irinotecan after a single oral dose was 8- to 10-fold less than for a single intravenous dose.

Repeated-dose toxicity studies showed that irinotecan caused vomiting, anorexia, alopecia, diarrhea, soft stools, anemia, leukopenia, and thrombocytopenia. Irinotecan has an effect on tissues with high proliferative activity such as bone marrow, thymus gland, spleen, lymph nodes and testes.

Long-Term Toxicity

Long-Term Toxicity

Long-Term Toxicity

Long-Term Toxicity

Carcinogenicity: Long-term carcinogenicity studies with irinotecan were not conducted. However, rats were administered intravenous doses of 2 mg/kg or 25 mg/kg once per week for 13 weeks, followed by a 91-week observation period. There was a significant linear dose-related incidence in combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas.

Genotoxicity:

Mutagenicity

Reproductive and Developmental Toxicology:

Reproduction and Teratology

Local Tolerance: Local tolerance of irinotecan was satisfactory when given to rabbits by the intramuscular route, instilled in the eye, or applied to intact and abraded skin. The intramuscular irritation of irinotecan in the rabbit at a dose of 20 mg/site was less than that for 5 mg/site of doxorubicin.

Antigenicity Potential: Irinotecan did not demonstrate antigenicity in mice but had antigenic potential in guinea pigs and rabbits. SN-38 did not demonstrate antigenicity in either mice or guinea pigs. The active systemic anaphylactic assay (ASA), enzyme-linked immunosorbent assay (ELISA) and passive cutaneous anaphylaxis (PCA) showed positive reactions to the piperidinopiperidine side-chain.