Camptosar Injection

Camptosar Injection information, interactions and side effects, CAMPTOSAR (irinotecan hydrochloride) Injection is an antineoplastic agent of the topoisomerase I inhibitor class.

CAMPTOSAR is supplied as a sterile, pale yellow, clear, aqueous solution. Each milliliter of solution contains 20 mg of irinotecan hydrochloride (on the basis of the trihydrate salt), 45 mg of sorbitol, NF, and 0.9 mg of lactic acid, USP. The pH of the solution has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. CAMPTOSAR is intended for dilution with 5% Dextrose Injection, USP (D5W), or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion. The preferred diluent is 5% Dextrose Injection, USP.

Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata or is chemically synthesized.

The chemical name is (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1Hpyrano[3′,4′:6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4’bipiperidine]-1′-carboxylate, monohydrochloride, trihydrate. Its empirical formula is C33H38N4O6•HCl•3H2O and molecular weight is 677.19. It is slightly soluble in water and organic solvents. Its structural formula is as follows:

camptosar1

INDICATIONS

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

DOSAGE AND ADMINISTRATION

Colorectal Cancer Combination Regimens 1 and 2

Administer CAMPTOSAR as a 90-minute intravenous infusion followed by LV and 5-FU. The currently recommended regimens are shown in Table 1.

A reduction in the starting dose by one dose level of CAMPTOSAR may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin > 2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients.

Table 1: Combination-Agent Dosage Regimens and Dose Modificationsa

Regimen 1
6-wk cycle with bolus 5-FU/LV (next cycle begins on day 43)
CAMPTOSAR LV 5-FU 125 mg/m² intravenous infusion over 90 minutes, days 1,8,15,22 20 mg/m² intravenous injection bolus, days 1,8,15,22 500 mg/m² intravenous injection bolus, days 1,8,15,22
Starting Dose & Modified Dose Levels (mg/m²)
Starting Dose Dose Level -1 Dose Level -2
CAMPTOSAR 125 100 75
LV 20 20 20
5-FU 500 400 300
Regimen 2
6-wk cycle with infusional 5-FU/LV (next cycle begins on day 43)
CAMPTOSAR LV 5-FU Bolus 5-FU Infusionb 180 mg/m² intravenous infusion over 90 minutes, days 1,15,29 200 mg/m² intravenous infusion over 2 hours, days 1,2,15,16,29,30 400 mg/m² intravenous injection bolus, days 1,2,15,16,29,30 600 mg/m² intravenous infusion over 22 hours, days 1,2,15,16,29,30
Starting Dose & Modified Dose Levels (mg/m²)
Starting Dose Dose Level -1 Dose Level -2
CAMPTOSAR 180 150 120
LV 200 200 200
5-FU Bolus 400 600 320
5-FU Infusionb 480 240 360
aDose reductions beyond Dose Level –2 by decrements of ≈ 20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
bInfusion follows bolus administration.

Dosing for patients with bilirubin > 2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients [see WARNINGS AND PRECAUTIONS, Use in Specific Populations and CLINICAL PHARMACOLOGY].

Dose Modifications

Based on recommended dose levels described in Table 1, Combination Regimens of CAMPTOSAR and Dose Modifications, subsequent doses should be adjusted as suggested in Table 2, Recommended Dose Modifications for Combination Regimens. All dose modifications should be based on the worst preceding toxicity.

Table 2: Recommended Dose Modifications for CAMPTOSAR/5-Fluorouracil (5-FU)/Leucovorin (LV) Combination Schedules

Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥ 1500/mm³, and the platelet count has recovered to ≥ 100,000/mm³, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing therapy.
Toxicity NCI CTC Gradea (Value) During a Cycle of Therapy At the Start of Subsequent Cycles of Therapyb
No toxicity Maintain dose level Maintain dose level
Neutropenia
1 (1500 to 1999/mm³) Maintain dose level Maintain dose level
2 (1000 to 1499/mm³) ↓1 dose level Maintain dose level
3 (500 to 999/mm³) Omit dose until resolved to ≤ grade 2, then ↓ 1 ↓1 dose level
4 (<500/mm³) dose level Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels ↓ 2 dose levels
Neutropenic fever Omit dose until resolved, then ↓2 dose levels
Other hematologic toxicities Dose modifications for leukopenia or thrombocytopenia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.
Diarrhea
1 (2-3 stools/day > pretxc) Delay dose until resolved to baseline, then give same dose Maintain dose level
2 (4-6 stools/day > pretx) Omit dose until resolved to baseline, then ↓1 dose level Maintain dose level
3 (7-9 stools/day > pretx) Omit dose until resolved to baseline, then ↓1 dose level ↓ 1 dose level
4 ( ≥ 10 stools/day > pretx) Omit dose until resolved to baseline, then ↓2 dose levels ↓ 2 dose levels
Other nonhematologic toxicitiesd
1 Maintain dose level Maintain dose level
2 Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level Maintain dose level
3 Omit dose until resolved to ≤ grade 2, then ↓1 dose level ↓1 dose level
4 Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels ↓ 2 dose levels
For mucositis/stomatitis decrease only 5-FU, not CAMPTOSAR For mucositis/stomatitis decrease only 5-FU, not CAMPTOSAR.
aNational Cancer Institute Common Toxicity Criteria (version 1.0)
bRelative to the starting dose used in the previous cycle
cPretreatment
dExcludes alopecia, anorexia, asthenia

Colorectal Single Agent Regimens 1 and 2

Administer CAMPTOSAR as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 3.

A reduction in the starting dose by one dose level of CAMPTOSAR may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin > 2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients.

Table 3: Single-Agent Regimens of CAMPTOSAR and Dose Modifications

Regimen 1 (weekly)a 125 mg/m² intravenous infusion over 90 minutes, days 1,8,15,22 then 2-week rest
Starting Dose and Modified Dose Levelsc (mg/m²)
Starting Dose Dose Level -1 Dose Level -2
125 100 75
Regimen 2 (every 3 weeks)b 350 mg/m² intravenous infusion over 90 minutes, once every 3 weeksc
Starting Dose and Modified Dose Levels (mg/m²)
Starting Dose Dose Level -1 Dose Level -2
350 300 250
aSubsequent 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.
bSubsequent doses may be adjusted as low as 200 mg/m² in 50 mg/m² decrements depending upon individual patient tolerance.
cProvided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.

Dose Modifications

Based on recommended dose-levels described in Table 3, Single-Agent Regimens of CAMPTOSAR and Dose Modifications, subsequent doses should be adjusted as suggested in Table 4, Recommended Dose Modifications for Single-Agent Schedules. All dose modifications should be based on the worst preceding toxicity.

Table 4: Recommended Dose Modifications For Single-Agent Schedulesa

A new cycle of therapy should not begin until the granulocyte count has recovered to ≥ 1500/mm³, and the platelet count has recovered to ≥ 100,000/mm³, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing CAMPTOSAR.
Worst Toxicity NCI Gradeb (Value) During a Cycle of Therapy At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cyclea
Weekly Weekly Once Every 3 Weeks
No toxicity Maintain dose level ↑25 mg/m² up to a maximum dose of 150 mg/m² Maintain dose level
Neutropenia
1 (1500 to 1999/mm³) Maintain dose level ↓25 mg/m² Maintain dose level Maintain dose level
2 (1000 to 1499/mm³) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m² Maintain dose level Maintain dose level
3 (500 to 999/mm³) Omit dose until resolved to ≤ grade 2, then ↓50 mg/m² ↓ 25 mg/m² ↓50 mg/m²
4 ( < 500/mm³) ↓50 mg/m² ↓50 mg/m²
Neutropenic fever Omit dose until resolved, then ? 50 mg/m² when resolved ↓50 mg/m² ↓50 mg/m²
Other hematologic toxicities Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.
Diarrhea
1 (2-3 stools/day > pretxc) Maintain dose level ↓ 25 mg/m² Maintain dose level Maintain dose level
2 (4-6 stools/day > pretx) Omit dose until resolved to ≤ grade 2, then ↓25 mg/m² Maintain dose level Maintain dose level
3 (7-9 stools/day > pretx) Omit dose until resolved to ≤ grade 2 then ↓ 50 mg/m² ↓25 mg/m² ↓ 50 mg/m²
4 ( ≥ 10 stools/day > pretx) ↓ 50 mg/m² ↓50 mg/m²
Other nonhematologicd toxicities
1 Maintain dose level ↓ 25 mg/m² Maintain dose level Maintain dose level
2 Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m² ↓25 mg/m² ↓50 mg/m²
3 Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m² ↓25 mg/m² ↓ 50 mg/m²
4 ↓50 mg/m² ↓ 50 mg/m²
aAll dose modifications should be based on the worst preceding toxicity
bNational Cancer Institute Common Toxicity Criteria (version 1.0)
cPretreatment
dExcludes alopecia, anorexia, asthenia

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 by at least one level of CAMPTOSAR should be considered for patients known to be homozygous for the UGT1A1*28 allele [see WARNINGS AND PRECAUTIONS]. 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 Tables 1-4).

Premedication

It is recommended that patients receive premedication with antiemetic agents. In clinical studies of the weekly dosage schedule, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HT3 blocker (e.g., ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of CAMPTOSAR. Physicians should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed. A similar antiemetic regimen should be used with Camptosar in combination therapy.

Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms.

Preparation of Infusion Solution

Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe.

CAMPTOSAR Injection 20 mg/mL is intended for single use only and any unused portion should be discarded.

CAMPTOSAR Injection must be diluted prior to infusion. CAMPTOSAR should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 mg/mL to 2.8 mg/mL. Other drugs should not be added to the infusion solution.

The solution is physically and chemically stable for up to 24 hours at room temperature and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C, 36° to 46°F), and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates. Freezing CAMPTOSAR and admixtures of CAMPTOSAR may result in precipitation of the drug and should be avoided.

The CAMPTOSAR Injection solution should be used immediately after reconstitution as it contains no antibacterial preservative. Because of possible microbial contamination during dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should be used within 4 hours if kept at room temperature. If reconstitution and dilution are performed under strict aseptic conditions (e.g. on Laminar Air Flow bench), CAMPTOSAR Injection solution should be used (infusion completed) within 12 hours at room temperature or 24 hours if refrigerated (2° to 8°C, 36° to 46°F).

Safe Handling

Care should be exercised in the handling and preparation of infusion solutions prepared from CAMPTOSAR Injection. The use of gloves is recommended. If a solution of CAMPTOSAR contacts the skin, wash the skin immediately and thoroughly with soap and water. If CAMPTOSAR contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available.

Extravasation

Care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site with sterile water and applications of ice are recommended.

HOW SUPPLIED

Dosage Forms And Strengths

CAMPTOSAR Injection is available in three single-dose sizes:

  • 2 mL-fill vial containing 40 mg irinotecan hydrochloride
  • 5 mL-fill vial containing 100 mg irinotecan hydrochloride
  • 15 mL-fill vial containing 300 mg irinotecan hydrochloride

Storage And Handling

CAMPTOSAR Injection is available in single-dose brown glass vials in the following package sizes:

2 mL NDC 0009-7529-02
5 mL NDC 0009-7529-01

CAMPTOSAR Injection is available in single-dose amber colored polypropylene CYTOSAFE® vials in the following package sizes:

2 mL NDC 0009-7529-04
5 mL NDC 0009-7529-03
15 mL NDC 0009-7529-05

Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from light. Keep the vial in the carton until the time of use.

Inspect the vial for damage and visible signs of leaks before removing from the carton. If damaged, incinerate the unopened package.

SIDE EFFECTS

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Common adverse reactions ( > 30%) observed in combination therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, and alopecia.

Common adverse reactions ( > 30%) observed in single agent therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and alopecia.

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

First-Line Combination Therapy

A total of 955 patients with metastatic colorectal cancer received the recommended regimens of irinotecan in combination with 5-FU/LV, 5-FU/LV alone, or irinotecan alone. In the two phase 3 studies, 370 patients received irinotecan in combination with 5-FU/LV, 362 patients received 5-FU/LV alone, and 223 patients received irinotecan alone [see DOSAGE AND ADMINISTRATION].

In Study 1, 49 (7.3%) patients died within 30 days of last study treatment: 21 (9.3%) received irinotecan in combination with 5-FU/LV, 15 (6.8%) received 5-FU/LV alone, and 13 (5.8%) received irinotecan alone. Deaths potentially related to treatment occurred in 2 (0.9%) patients who received irinotecan in combination with 5-FU/LV (2 neutropenic fever/sepsis), 3 (1.4%) patients who received 5-FU/LV alone (1 neutropenic fever/sepsis, 1 CNS bleeding during thrombocytopenia, 1 unknown) and 2 (0.9%) patients who received irinotecan alone (2 neutropenic fever). Deaths from any cause within 60 days of first study treatment were reported for 15 (6.7%) patients who received irinotecan in combination with 5-FU/LV, 16 (7.3%) patients who received 5-FU/LV alone, and 15 (6.7%) patients who received irinotecan alone. Discontinuations due to adverse events were reported for 17 (7.6%) patients who received irinotecan in combination with 5FU/LV, 14 (6.4%) patients who received 5FU/LV alone, and 26 (11.7%) patients who received irinotecan alone.

In Study 2, 10 (3.5%) patients died within 30 days of last study treatment: 6 (4.1%) received irinotecan in combination with 5-FU/LV and 4 (2.8%) received 5-FU/LV alone. There was one potentially treatment-related death, which occurred in a patient who received irinotecan in combination with 5-FU/LV (0.7%, neutropenic sepsis). Deaths from any cause within 60 days of first study treatment were reported for 3 (2.1%) patients who received irinotecan in combination with 5-FU/LV and 2 (1.4%) patients who received 5-FU/LV alone. Discontinuations due to adverse events were reported for 9 (6.2%) patients who received irinotecan in combination with 5FU/LV and 1 (0.7%) patient who received 5-FU/LV alone.

The most clinically significant adverse events for patients receiving irinotecan-based therapy were diarrhea, nausea, vomiting, neutropenia, and alopecia. The most clinically significant adverse events for patients receiving 5-FU/LV therapy were diarrhea, neutropenia, neutropenic fever, and mucositis. In Study 1, grade 4 neutropenia, neutropenic fever (defined as grade 2 fever and grade 4 neutropenia), and mucositis were observed less often with weekly irinotecan/5-FU/LV than with monthly administration of 5-FU/LV.

Tables 5 and 6 list the clinically relevant adverse events reported in Studies 1 and 2, respectively.

Table 5: Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapiesa

Adverse Event Study 1
Irinotecan + Bolus 5-FU/LV weekly x 4 every 6 weeks
N=225
Bolus 5-FU/LV daily x 5 every 4 weeks
N=219
Irinotecan weekly x 4 every 6 weeks
N=223
Grade 1-4 Grade 3&4 Grade 1-4 Grade 3&4 Grade 1-4 Grade 3&4
TOTAL Adverse Events 100 53.3 100 45.7 99.6 45.7
GASTROINTESTINAL
  Diarrhea 84.9 22.7 69.4 13.2 83 31
   late 15.1 5.9 18.4
    grade 3 7.6 7.3 12.6
    grade 4 45.8 4.9 31.5 1.4 43 6.7
   early
Nausea 79.1 15.6 67.6 8.2 81.6 16.1
Abdominal pain 63.1 14.6 50.2 11.5 67.7 13
Vomiting 60.4 9.7 46.1 4.1 62.8 12.1
Anorexia 34.2 5.8 42 3.7 43.9 7.2
Constipation 41.3 3.1 31.5 1.8 32.3 0.4
Mucositis 32.4 2.2 76.3 16.9 29.6 2.2
HEMATOLOGIC
  Neutropenia 96.9 53.8 98.6 66.7 96.4 31.4
    grade 3 29.8 23.7 19.3
    grade 4 24 42.5 12.1
  Leukopenia 96.9 37.8 98.6 23.3 96.4 21.5
  Anemia 96.9 8.4 98.6 5.5 96.9 4.5
  Neutropenic fever 7.1 14.6 5.8
  Thrombocytopenia 96 2.6 98.6 2.7 96 1.7
  Neutropenic infection 1.8 0 2.2
BODY AS A WHOLE
  Asthenia 70.2 19.5 64.4 11.9 69.1 13.9
  Pain 30.7 3.1 26.9 3.6 22.9 2.2
  Fever 42.2 1.7 32.4 3.6 43.5 0.4
  Infection 22.2 0 16 1.4 13.9 0.4
METABOLIC & NUTRITIONAL
  Bilirubin 87.6 7.1 92.2 8.2 83.9 7.2
DERMATOLOGIC
  Exfoliative dermatitis 0.9 0 3.2 0.5 0 0
  Rash 19.1 0 26.5 0.9 14.3 0.4
  Alopeciab 43.1 26.5 46.1
RESPIRATORY
  Dyspnea 27.6 6.3 16.0 0.5 22.0 2.2
  Cough 26.7 1.3 18.3 0 20.2 0.4
  Pneumonia 6.2 2.7 1.4 1.0 3.6 1.3
NEUROLOGIC
  Dizziness 23.1 1.3 16.4 0 21.1 1.8
  Somnolence 12.4 1.8 4.6 1.8 9.4 1.3
  Confusion 7.1 1.8 4.1 0 2.7 0
CARDIOVASCULAR
  Vasodilatation 9.3 0.9 5.0 0 9.0 0
  Hypotension 5.8 1.3 2.3 0.5 5.8 1.7
  Thromboembolic eventsc 9.3 11.4 5.4
aSeverity of adverse events based on NCI CTC (version 1.0)
bComplete hair loss = Grade 2
cIncludes 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.

Table 6: Study 2: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapiesa

Adverse Event Study 2
Irinotecan + 5-FU/LV infusional days 1&2 every 2 weeks
N= 145
5-FU/LV infusional days 1&2 every 2 weeks
N=143
Grades 1-4 Grades 3&4 Grades 1-4 Grades 3&4
TOTAL Adverse Events 100 72.4 100 39.2
GASTROINTESTINAL
  Diarrhea 72.4 14.4 44.8 6.3
    late 10.3 4.2
    grade 3 4.1 2.1
    grade 4 28.3 1.4 0.7 0
  Cholinergic syndromeb
  Nausea 66.9 2.1 55.2 3.5
  Abdominal pain 17.2 2.1 16.8 0.7
  Vomiting 44.8 3.5 32.2 2.8
  Anorexia 35.2 2.1 18.9 0.7
  Constipation 30.3 0.7 25.2 1.4
  Mucositis 40 4.1 28.7 2.8
HEMATOLOGIC
  Neutropenia 82.5 46.2 47.9 13.4
    grade 3 36.4 12.7
    grade 4 9.8 0.7
  Leukopenia 81.3 17.4 42 3.5
  Anemia 97.2 2.1 90.9 2.1
  Neutropenic fever 3.4 0.7
  Thrombocytopenia 32.6 0 32.2 0
  Neutropenic infection 2.1 0
BODY AS A WHOLE
  Asthenia 57.9 9 48.3 4.2
  Pain 64.1 9.7 61.5 8.4
  Fever 22.1 0.7 25.9 0.7
  Infection 35.9 7.6 33.6 3.5
METABOLIC AND NUTRITIONAL
  Bilirubin 19.1 3.5 35.9 10.6
DERMATOLOGIC
  Hand and foot syndrome 10.3 0.7 12.6 0.7
  Cutaneous signs 17.2 0.7 20.3 0
  Alopeciac 56.6 16.8
RESPIRATORY
  Dyspnea 9.7 1.4 4.9 0
CARDIOVASCULAR
  Hypotension 3.4 1.4 0.7 0
  Thromboembolic eventsd 11.7 5.6
aSeverity of adverse events based on NCI CTC (version 1.0)
bIncludes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping or diarrhea (occurring during or shortly after infusion of irinotecan)
cComplete hair loss = Grade 2
dIncludes 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.

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 CAMPTOSAR. Seventeen of the patients died within 30 days of the administration of CAMPTOSAR; 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 CAMPTOSAR. 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 CAMPTOSAR 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 CAMPTOSAR 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 Rectuma

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
aSeverity of adverse events based on NCI CTC (version 1.0)
bOccurring > 24 hours after administration of CAMPTOSAR
cOccurring ≤ 24 hours after administration of CAMPTOSAR
dPrimarily upper respiratory infections
eNot applicable; complete hair loss = NCI grade 2

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.

Table 8: Percent Of Patients Experiencing Grade 3 & 4 Adverse Events In Comparative Studies Of Once-Every-3-Week Irinotecan Therapya

Adverse Event Study 1 Study 2
Irinotecan
N=189
BSCb
N=90
Irinotecan
N=127
5-FU
N=129
TOTAL Grade 3/4 Adverse 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 8 3 1 4
  neutropenia with grade 3/4 neutropenia 1 0 2 0
Fever
  without grade 3/4 2 1 2 0
  neutropenia 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
  Hepaticc 9 7 9 6
DERMATOLOGIC
  Hand and foot syndrome 0 0 0 5
  Cutaneous signsd 2 0 1 3
RESPIRATORYe 10 8 5 7
NEUROLOGICf 12 13 9 4
CARDIOVASCULARg 9 3 4 2
OTHERh 32 28 12 14
aSeverity of adverse events based on NCI CTC (version 1.0)
bBSC = best supportive care
cHepatic includes events such as ascites and jaundice
dCutaneous signs include events such as rash
eRespiratory includes events such as dyspnea and cough
fNeurologic includes events such as somnolence
gCardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction
hOther includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss

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

Postmarketing Experience

The following adverse reactions have been identified during post approval use of CAMPTOSAR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Myocardial ischemic events have been observed following irinotecan therapy. Thromboembolic events have been observed in patients receiving CAMPTOSAR.

Symptomatic pancreatitis, asymptomatic pancreatic enzyme elevation have been reported. Increases in serum levels of transaminases (i.e., AST and ALT) in the absence of progressive liver metastasis have been observed.

Hyponatremia, mostly with diarrhea and vomiting, has been reported.

Transient dysarthria has been reported in patients treated with CAMPTOSAR; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan.

Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarizing drugs may be antagonized.

DRUG INTERACTIONS

5-Fluorouracil (5-FU) and Leucovorin (LV)

In a phase 1 clinical study involving irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) in 26 patients with solid tumors, the disposition of irinotecan was not substantially altered when the drugs were co-administered. Although the Cmax and AUC0-24 of SN-38, the active metabolite, were reduced (by 14% and 8%, respectively) when irinotecan was followed by 5FU and LV administration compared with when irinotecan was given alone, this sequence of administration was used in the combination trials and is recommended [see DOSAGE AND ADMINISTRATION]. Formal in vivo or in vitro drug interaction studies to evaluate the influence of irinotecan on the disposition of 5-FU and LV have not been conducted.

Strong CYP 3A4 Inducers

Anticonvulsants and other strong inducers: Exposure to irinotecan and its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital or carbamazepine. The appropriate starting dose for patients taking these anticonvulsants or other strong inducers such as rifampin and rifabutin has not been defined. Consideration should be given to substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan therapy.

St. John’s wort: Exposure to the active metabolite SN-38 is reduced in patients receiving concomitant St. John’s wort. St. John’s wort should be discontinued at least 2 weeks prior to the first cycle of irinotecan, and St. John’s wort is contraindicated during irinotecan therapy.

Dexamethasone, a moderate CYP3A4 inducer, does not appear to alter the pharmacokinetics of irinotecan.

Strong CYP 3A4 Inhibitors

Ketoconazole is a strong inhibitor of CYP3A4 enzymes. Patients receiving concomitant ketoconazole have increased exposure to irinotecan and its active metabolite SN-38. Patients should discontinue ketoconazole at least 1 week prior to starting irinotecan therapy and ketoconazole is contraindicated during irinotecan therapy.

Atazanavir Sulfate

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.

Drug-Laboratory Test Interactions

There are no known interactions between CAMPTOSAR and laboratory tests.

PRECAUTIONS

Diarrhea and Cholinergic Reactions

Early diarrhea (occurring during or shortly after infusion of CAMPTOSAR) is usually transient and infrequently severe. It may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Bradycardia may also occur. Early diarrhea and other cholinergic symptoms may be prevented or treated. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). These symptoms are expected to occur more frequently with higher irinotecan doses.

Late diarrhea (generally occurring more than 24 hours after administration of CAMPTOSAR) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Grade 3-4 late diarrhea occurred in 23-31% of patients receiving weekly dosing. In the clinical studies, the median time to the onset of late diarrhea was 5 days with 3-week dosing and 11 days with weekly dosing. Late diarrhea can be complicated by colitis, ulceration, bleeding, ileus, obstruction, and infection. Cases of megacolon and intestinal perforation have been reported. Patients should have loperamide readily available to begin treatment for late diarrhea. Begin loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normal. One dosage regimen for loperamide is 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg of loperamide every 4 hours. Monitor and replace fluid and electrolytes. Use antibiotic support for ileus, fever, or severe neutropenia. Subsequent weekly chemotherapy treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without anti-diarrhea medication. Patients must not be treated with irinotecan until resolution of the bowel obstruction. If grade 2, 3, or 4 late diarrhea recurs, subsequent doses of CAMPTOSAR should be decreased [see DOSAGE AND ADMINISTRATION].

Avoid diuretics or laxatives in patients with diarrhea.

Myelosuppression

Deaths due to sepsis following severe neutropenia have been reported in patients treated with CAMPTOSAR. In the clinical studies evaluating the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3% of the patients; 6% of patients received G-CSF for the treatment of neutropenia. Manage febrile neutropenia promptly with antibiotic support. Hold CAMPTOSAR if neutropenic fever occurs or if the absolute neutrophil count drops < 1000/mm³. After recovery to an absolute neutrophil count ≥ 1000/mm³, subsequent doses of CAMPTOSAR should be reduced [see DOSAGE AND ADMINISTRATION].

When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation (48% [13/27] versus 24% [67/277]; p=0.04). Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of CAMPTOSAR. Based on sparse available data, the concurrent administration of CAMPTOSAR with irradiation is not recommended.

Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/266]; p < 0.001). Patients with deficient glucuronidation of bilirubin, such as those with Gilbert’s syndrome, may be at greater risk of myelosuppression when receiving therapy with CAMPTOSAR.

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 CAMPTOSAR treatment.

In a study of 66 patients who received single-agent CAMPTOSAR (350 mg/m² once-every3-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).

In a prospective study (n=250) to investigate the role of UGT1A1*28 polymorphism in the development of toxicity in patients treated with CAMPTOSAR (180 mg/m²) in combination with infusional 5-FU/LV, the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 4.5%, and in patients heterozygous for this allele the incidence was 5.3%. Grade 4 neutropenia was observed in 1.8% of patients homozygous for the wild-type allele.

In another study in which 109 patients were treated with CAMPTOSAR (100-125 mg/m²) in combination with bolus 5-FU/LV, the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 18.2%, and in patients heterozygous for this allele the incidence was 11.1%. Grade 4 neutropenia was observed in 6.8% of patients homozygous for the wild-type allele.

When administered in combination with other agents or as a single-agent, a reduction in the starting dose by at least one level of CAMPTOSAR 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].

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.

Hypersensitivity

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

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.

Pulmonary Toxicity

Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred in patients receiving irinotecan (in combination and as monotherapy). Risk factors include preexisting 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. 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 and other chemotherapy should be discontinued and appropriate treatment instituted as needed [see ADVERSE REACTIONS].

Toxicity of the 5 Day Regimen

Outside of a well-designed clinical study, CAMPTOSAR 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. CAMPTOSAR should be used as recommended in Table 2 [see DOSAGE AND ADMINISTRATION].

Increased Toxicity in Patients with Performance Status 2

In patients receiving either irinotecan/5-FU/LV or 5-FU/LV in the clinical trials, higher rates of hospitalization, neutropenic fever, thromboembolism, first-cycle treatment discontinuation, and early deaths were observed in patients with a baseline performance status of 2 than in patients with a baseline performance status of 0 or 1.

Pregnancy

CAMPTOSAR 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 CAMPTOSAR.

Patients with Hepatic Impairment

The use of CAMPTOSAR 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, Use In Specific Populations and CLINICAL PHARMACOLOGY].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies with irinotecan were not conducted. Rats were, however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per week for 13 weeks (in separate studies, the 25 mg/kg dose produced an irinotecan Cmax and AUC that were about 7.0 times and 1.3 times the respective values in patients administered 125 mg/m² weekly) and were then allowed to recover for 91 weeks. Under these conditions, there was a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Irinotecan was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). Neither irinotecan nor its active metabolite SN-38 was mutagenic in the in vitro Ames assay.

No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan in doses of up to 6 mg/kg/day to rats and rabbits; however, atrophy of male reproductive organs was observed after multiple daily irinotecan doses both in rodents at 20 mg/kg and in dogs at 0.4 mg/kg. In separate studies in rodents, this dose produced an irinotecan Cmax and AUC about 5 and 1 times, respectively, of the corresponding values in patients administered 125 mg/m² weekly. In dogs this dose produced an irinotecan Cmax and AUC about one-half and 1/15th, respectively, of the corresponding values in patients administered 125 mg/m² weekly.

Use In Specific Populations

Pregnancy

Pregnancy Category D [see WARNINGS AND PRECAUTIONS]

CAMPTOSAR can cause fetal harm when administered to a pregnant woman. Radioactivity related to 14C-irinotecan crosses the placenta of rats following intravenous administration of 10 mg/kg (which in separate studies produced an irinotecan Cmax and AUC about 3 and 0.5 times, respectively, the corresponding values in patients administered 125 mg/m²). Intravenous administration of irinotecan 6 mg/kg/day to rats and rabbits during the period of organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses. In separate studies in rats, this dose produced an irinotecan Cmax and AUC of about 2 and 0.2 times, respectively, the corresponding values in patients administered 125 mg/m². In rabbits, the embryotoxic dose was about one-half the recommended human weekly starting dose on a mg/m² basis. Irinotecan was teratogenic in rats at doses greater than 1.2 mg/kg/day and in rabbits at 6.0 mg/kg/day. In separate studies in rats, this dose produced an irinotecan Cmax and AUC about 2/3 and 1/40th, respectively, of the corresponding values in patients administered 125 mg/m². In rabbits, the teratogenic dose was about one-half the recommended human weekly starting dose on a mg/m² basis. Teratogenic effects included a variety of external, visceral, and skeletal abnormalities. Irinotecan administered to rat dams for the period following organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring. 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 CAMPTOSAR.

Nursing Mothers

Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CAMPTOSAR, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The effectiveness of irinotecan in pediatric patients has not been established. Results from two open-label, single arm studies were evaluated. One hundred and seventy children with refractory solid tumors were enrolled in one phase 2 trial in which 50 mg/ m² of irinotecan was infused for 5 consecutive days every 3 weeks. Grade 3-4 neutropenia was experienced by 54 (31.8%) patients. Neutropenia was complicated by fever in 15 (8.8%) patients. Grade 3-4 diarrhea was observed in 35 (20.6%) patients. This adverse event profile was comparable to that observed in adults. In the second phase 2 trial of 21 children with previously untreated rhabdomyosarcoma, 20 mg/m² of irinotecan was infused for 5 consecutive days on weeks 0, 1, 3 and 4. This single agent therapy was followed by multimodal therapy. Accrual to the single agent irinotecan phase was halted due to the high rate (28.6%) of progressive disease and the early deaths (14%). The adverse event profile was different in this study from that observed in adults; the most significant grade 3 or 4 adverse events were dehydration experienced by 6 patients (28.6%) associated with severe hypokalemia in 5 patients (23.8%) and hyponatremia in 3 patients (14.3%); in addition Grade 3-4 infection was reported in 5 patients (23.8%) (across all courses of therapy and irrespective of causal relationship).

Pharmacokinetic parameters for irinotecan and SN-38 were determined in 2 pediatric solid-tumor trials at dose levels of 50 mg/m² (60-min infusion, n=48) and 125 mg/m² (90-min infusion, n=6). Irinotecan clearance (mean ± S.D.) was 17.3 ± 6.7 L/h/m² for the 50mg/m² dose and 16.2 ± 4.6 L/h/m² for the 125 mg/m² dose, which is comparable to that in adults. Dose-normalized SN-38 AUC values were comparable between adults and children. Minimal accumulation of irinotecan and SN-38 was observed in children on daily dosing regimens [daily x 5 every 3 weeks or (daily x 5) x 2 weeks every 3 weeks].

Geriatric Use

Patients greater than 65 years of age should be closely monitored because of a greater risk of early and late diarrhea in this population [see CLINICAL PHARMACOLOGY and ADVERSE REACTIONS]. The starting dose of CAMPTOSAR in patients 70 years and older for the once-every-3-week-dosage schedule should be 300 mg/m² [see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION].

The frequency of grade 3 and 4 late diarrhea by age was significantly greater in patients ≥ 65 years than in patients < 65 years (40% [53/133] versus 23% [40/171]; p=0.002). In another study of 183 patients treated on the weekly schedule, the frequency of grade 3 or 4 late diarrhea in patients ≥ 65 years of age was 28.6% [26/91] and in patients < 65 years of age was 23.9% [22/92].

Renal Impairment

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

Hepatic Impairment

Irinotecan clearance is diminished in patients with hepatic impairment while exposure to the active metabolite SN-38 is increased relative to that in patients with normal hepatic function. The magnitude of these effects is proportional to the degree of liver impairment as measured by elevations in total bilirubin and transaminase concentrations. Therefore, use caution in patients with hepatic impairment. The tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than 2 mg/dl) has not been assessed sufficiently, and no recommendations for dosing can be made [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

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