Camptosar Drug Information
Generic name: IRINOTECAN HYDROCHLORIDE
Uses of Camptosar
- CAMPTOSAR is indicated as a component of first-line therapy in combination with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic carcinoma of the colon or rectum.
- CAMPTOSAR is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. CAMPTOSAR is a topoisomerase inhibitor indicated for:
- First-line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum.
- Patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.
Dosage & Administration of Camptosar
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 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.
Dosage in Patients With Reduced UGT1A1 Activity
When administered in combination with other agents, or as a single-agent, consider a reduction in the starting dose by at least one level of CAMPTOSAR for patients known to be homozygous for the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or compound heterozygous for the UGT1A1*28 and *6 alleles (*6/*28). Subsequent dosage modifications may be required based on individual patient tolerance to treatment.
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-HT 3 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 using aseptic technique.
Other drugs should not be added to the infusion solution. Prepare the infusion solution immediately prior to use and commence infusion as soon as possible after preparation. If visible particulates are present in the infusion solution discard.
If it is not possible to use the infusion solution immediately, the infusion solution may be stored for up to 24 hours at 2 °C to 8 °C or discarded.
Safe Handling CAMPTOSAR is a hazardous drug
Follow applicable special handling and disposal procedures. 1 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.
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.
| Regimen 1 6-wk cycle with bolus 5-FU/LV (next cycle begins on day 43) | CAMPTOSAR LV 5-FU | 125 mg/m 2 intravenous infusion over 90 minutes, days 1,8,15,22 20 mg/m 2 intravenous injection bolus, days 1,8,15,22 500 mg/m 2 intravenous injection bolus, days 1,8,15,22 | ||
| Starting Dose & Modified Dose Levels (mg/m 2 ) | ||||
| 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 | 180 mg/m 2 intravenous infusion over 90 minutes, days 1,15,29 | ||
| LV | 200 mg/m 2 intravenous infusion over 2 hours, days 1,2,15,16,29,30 | |||
| 5-FU Bolus | 400 mg/m 2 intravenous injection bolus, days 1,2,15,16,29,30 | |||
| 5-FU Infusion Infusion follows bolus administration. | 600 mg/m 2 intravenous infusion over 22 hours, days 1,2,15,16,29,30 | |||
| Starting Dose & Modified Dose Levels (mg/m 2 ) | ||||
| Starting Dose | Dose Level -1 | Dose Level -2 | ||
| CAMPTOSAR | 180 | 150 | 120 | |
| LV | 200 | 200 | 200 | |
| 5-FU Bolus | 400 | 320 | 240 | |
| 5-FU Infusion | 600 | 480 | 360 | |
| 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/mm 3, and the platelet count has recovered to ≥100,000/mm 3, 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 Grade National Cancer Institute Common Toxicity Criteria (version 1.0) (Value) | During a Cycle of Therapy | At the Start of Subsequent Cycles of Therapy Relative to the starting dose used in the previous cycle |
| No toxicity | Maintain dose level | Maintain dose level |
| Neutropenia | ||
| 1 (1500 to 1999/mm 3 ) | Maintain dose level | Maintain dose level |
| 2 (1000 to 1499/mm 3 ) | ↓ 1 dose level | Maintain dose level |
| 3 (500 to 999/mm 3 ) | Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level | ↓ 1 dose level |
| 4 (<500/mm 3 ) | 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 > pretx Pretreatment ) | 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 toxicities Excludes alopecia, anorexia, asthenia | ||
| 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. | |
| Regimen 1 (weekly) Subsequent doses may be adjusted as high as 150 mg/m 2 or to as low as 50 mg/m 2 in 25 to 50 mg/m 2 decrements depending upon individual patient tolerance. | 125 mg/m 2 intravenous infusion over 90 minutes, days 1,8,15,22 then 2-week rest | ||
| Starting Dose and Modified Dose Levels Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. (mg/m 2 ) | |||
| Starting Dose | Dose Level -1 | Dose Level -2 | |
| 125 | 100 | 75 | |
| Regimen 2 (every 3 weeks) Subsequent doses may be adjusted as low as 200 mg/m 2 in 50 mg/m 2 decrements depending upon individual patient tolerance. | 350 mg/m 2 intravenous infusion over 90 minutes, once every 3 weeks | ||
| Starting Dose and Modified Dose Levels (mg/m 2 ) | |||
| Starting Dose | Dose Level -1 | Dose Level -2 | |
| 350 | 300 | 250 | |
| A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm 3, and the platelet count has recovered to ≥100,000/mm 3, 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 Grade National Cancer Institute Common Toxicity Criteria (version 1.0) (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 Cycle | |
| Weekly | Weekly | Once Every 3 Weeks | |
| No toxicity | Maintain dose level | ↑ 25 mg/m 2 up to a maximum dose of 150 mg/m 2 | Maintain dose level |
| Neutropenia | |||
| 1 (1500 to 1999/mm 3 ) | Maintain dose level | Maintain dose level | Maintain dose level |
| 2 (1000 to 1499/mm 3 ) | ↓ 25 mg/m 2 | Maintain dose level | Maintain dose level |
| 3 (500 to 999/mm 3 ) | Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 | ↓ 25 mg/m 2 | ↓ 50 mg/m 2 |
| 4 (<500/mm 3 ) | Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m 2 | ↓ 50 mg/m 2 | ↓ 50 mg/m 2 |
| Neutropenic fever | Omit dose until resolved, then ↓ 50 mg/m 2 when resolved | ↓ 50 mg/m 2 | ↓ 50 mg/m 2 |
| 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 > pretx Pretreatment ) | Maintain dose level | Maintain dose level | Maintain dose level |
| 2 (4–6 stools/day > pretx) | ↓ 25 mg/m 2 | Maintain dose level | Maintain dose level |
| 3 (7–9 stools/day > pretx) | Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 | ↓ 25 mg/m 2 | ↓ 50 mg/m 2 |
| 4 (≥10 stools/day > pretx) | Omit dose until resolved to ≤ grade 2 then ↓ 50 mg/m 2 | ↓ 50 mg/m 2 | ↓ 50 mg/m 2 |
| Other nonhematologic Excludes alopecia, anorexia, asthenia toxicities | |||
| 1 | Maintain dose level | Maintain dose level | Maintain dose level |
| 2 | ↓ 25 mg/m 2 | ↓ 25 mg/m 2 | ↓ 50 mg/m 2 |
| 3 | Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 | ↓ 25 mg/m 2 | ↓ 50 mg/m 2 |
| 4 | Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m 2 | ↓ 50 mg/m 2 | ↓ 50 mg/m 2 |
Side Effects of Camptosar
Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Common adverse reactions (≥30%) observed in combination therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, and alopecia. Common adverse reactions (≥30%) observed in single agent therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and alopecia.
First-Line Combination Therapy A total of 955 patients with metastatic colorectal cancer received the recommended regimens of irinotecan in combination with 5-FU/LV, 5-FU/LV alone, or irinotecan alone. 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). 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. Table 5. Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies Severity of adverse events based on NCI CTC version: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies Severity of adverse events based on NCI CTC version 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.
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/m 2 starting dose. Within-cycle dose reductions were required for 32% of the cycles initiated at the 125-mg/m 2 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.
Table 7. Adverse Events Occurring in >10% of 304 Previously Treated Patients With Metastatic Carcinoma of the Colon or Rectum Severity of adverse events based on NCI CTC version 0 Once-Every-3-Week Dosage Schedule A total of 535 patients with metastatic colorectal cancer whose disease had recurred or progressed following prior 5-FU therapy participated in the two phase 3 studies: 316 received irinotecan, 129 received 5-FU, and 90 received best supportive care. Eleven (3.5%) patients treated with irinotecan died within 30 days of treatment.
In three cases (1%, 3/316), the deaths were potentially related to irinotecan treatment and were attributed to neutropenic infection, grade 4 diarrhea, and asthenia, respectively. Eight percent of patients treated with irinotecan and 7% treated with 5-FU-based therapy discontinued treatment due to adverse events. 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 Therapy Severity of adverse events based on NCI CTC version 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 CAMPTOSAR 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 CAMPTOSAR 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. Infections: fungal and viral infections have been reported.
| Adverse Event | Study 1 | |||||
|---|---|---|---|---|---|---|
| Irinotecan + Bolus 5-FU/LV weekly × 4 every 6 weeks N=225 | Bolus 5-FU/LV daily × 5 every 4 weeks N=219 | Irinotecan weekly × 4 every 6 weeks N=223 | ||||
| Grade 1–4 | Grade 3&4 | Grade 1–4 | Grade 3&4 | Grade 1–4 | Grade 3&4 | |
| TOTAL Adverse Events | 100 | 53.3 | 100 | 45.7 | 99.6 | 45.7 |
| GASTROINTESTINAL | ||||||
| Diarrhea | ||||||
| Late | 84.9 | 22.7 | 69.4 | 13.2 | 83.0 | 31.0 |
| grade 3 | -- | 15.1 | -- | 5.9 | -- | 18.4 |
| grade 4 | -- | 7.6 | -- | 7.3 | -- | 12.6 |
| Early | 45.8 | 4.9 | 31.5 | 1.4 | 43.0 | 6.7 |
| Nausea | 79.1 | 15.6 | 67.6 | 8.2 | 81.6 | 16.1 |
| Abdominal pain | 63.1 | 14.6 | 50.2 | 11.5 | 67.7 | 13.0 |
| Vomiting | 60.4 | 9.7 | 46.1 | 4.1 | 62.8 | 12.1 |
| Anorexia | 34.2 | 5.8 | 42.0 | 3.7 | 43.9 | 7.2 |
| Constipation | 41.3 | 3.1 | 31.5 | 1.8 | 32.3 | 0.4 |
| Mucositis | 32.4 | 2.2 | 76.3 | 16.9 | 29.6 | 2.2 |
| HEMATOLOGIC | ||||||
| Neutropenia | 96.9 | 53.8 | 98.6 | 66.7 | 96.4 | 31.4 |
| grade 3 | -- | 29.8 | -- | 23.7 | -- | 19.3 |
| grade 4 | -- | 24.0 | -- | 42.5 | -- | 12.1 |
| Leukopenia | 96.9 | 37.8 | 98.6 | 23.3 | 96.4 | 21.5 |
| Anemia | 96.9 | 8.4 | 98.6 | 5.5 | 96.9 | 4.5 |
| Neutropenic fever | -- | 7.1 | -- | 14.6 | -- | 5.8 |
| Thrombocytopenia | 96.0 | 2.6 | 98.6 | 2.7 | 96.0 | 1.7 |
| Neutropenic infection | -- | 1.8 | -- | 0 | -- | 2.2 |
| BODY AS A WHOLE | ||||||
| Asthenia | 70.2 | 19.5 | 64.4 | 11.9 | 69.1 | 13.9 |
| Pain | 30.7 | 3.1 | 26.9 | 3.6 | 22.9 | 2.2 |
| Fever | 42.2 | 1.7 | 32.4 | 3.6 | 43.5 | 0.4 |
| Infection | 22.2 | 0 | 16.0 | 1.4 | 13.9 | 0.4 |
| METABOLIC & NUTRITIONAL | ||||||
| Bilirubin | 87.6 | 7.1 | 92.2 | 8.2 | 83.9 | 7.2 |
| DERMATOLOGIC | ||||||
| Exfoliative dermatitis | 0.9 | 0 | 3.2 | 0.5 | 0 | 0 |
| Rash | 19.1 | 0 | 26.5 | 0.9 | 14.3 | 0.4 |
| Alopecia Complete hair loss = Grade 2 | 43.1 | -- | 26.5 | -- | 46.1 | -- |
| RESPIRATORY | ||||||
| Dyspnea | 27.6 | 6.3 | 16.0 | 0.5 | 22.0 | 2.2 |
| Cough | 26.7 | 1.3 | 18.3 | 0 | 20.2 | 0.4 |
| Pneumonia | 6.2 | 2.7 | 1.4 | 1.0 | 3.6 | 1.3 |
| NEUROLOGIC | ||||||
| Dizziness | 23.1 | 1.3 | 16.4 | 0 | 21.1 | 1.8 |
| Somnolence | 12.4 | 1.8 | 4.6 | 1.8 | 9.4 | 1.3 |
| Confusion | 7.1 | 1.8 | 4.1 | 0 | 2.7 | 0 |
| CARDIOVASCULAR | ||||||
| Vasodilatation | 9.3 | 0.9 | 5.0 | 0 | 9.0 | 0 |
| Hypotension | 5.8 | 1.3 | 2.3 | 0.5 | 5.8 | 1.7 |
| Thromboembolic events Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder. | 9.3 | -- | 11.4 | -- | 5.4 | -- |
| 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 | ||||
| late | 72.4 | 14.4 | 44.8 | 6.3 |
| grade 3 | -- | 10.3 | -- | 4.2 |
| grade 4 | -- | 4.1 | -- | 2.1 |
| Cholinergic syndrome Includes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping or diarrhea (occurring during or shortly after infusion of irinotecan) | 28.3 | 1.4 | 0.7 | 0 |
| 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 | 40.0 | 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 | 42.0 | 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 | 9.0 | 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 |
| Alopecia Complete hair loss = Grade 2 | 56.6 | -- | 16.8 | -- |
| RESPIRATORY | ||||
| Dyspnea | 9.7 | 1.4 | 4.9 | 0 |
| CARDIOVASCULAR | ||||
| Hypotension | 3.4 | 1.4 | 0.7 | 0 |
| Thromboembolic events Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder. | 11.7 | -- | 5.6 | -- |
| % of Patients Reporting | ||
|---|---|---|
| Body System & Event | NCI Grades 1–4 | NCI Grades 3 & 4 |
| GASTROINTESTINAL | ||
| Diarrhea (late) Occurring >24 hours after administration of CAMPTOSAR | 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) Occurring ≤24 hours after administration of CAMPTOSAR | 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/mm 3 (grade 3) | — | (15) |
| <500/mm 3 (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 infection Primarily upper respiratory infections | 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 | NA Not applicable; complete hair loss = NCI grade 2 |
| 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 |
| Study 1 | Study 2 | |||
|---|---|---|---|---|
| Adverse Event | Irinotecan N=189 | BSC BSC = best supportive care 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 neutropenia | 8 | 3 | 1 | 4 |
| with grade 3/4 neutropenia | 1 | 0 | 2 | 0 |
| Fever | ||||
| without grade 3/4 neutropenia | 2 | 1 | 2 | 0 |
| with grade 3/4 neutropenia | 2 | 0 | 4 | 2 |
| BODY AS A WHOLE | ||||
| Pain | 19 | 22 | 17 | 13 |
| Asthenia | 15 | 19 | 13 | 12 |
| METABOLIC AND NUTRITIONAL | ||||
| Hepatic Hepatic includes events such as ascites and jaundice | 9 | 7 | 9 | 6 |
| DERMATOLOGIC | ||||
| Hand and foot syndrome | 0 | 0 | 0 | 5 |
| Cutaneous signs Cutaneous signs include events such as rash | 2 | 0 | 1 | 3 |
| RESPIRATORY Respiratory includes events such as dyspnea and cough | 10 | 8 | 5 | 7 |
| NEUROLOGIC Neurologic includes events such as somnolence | 12 | 13 | 9 | 4 |
| CARDIOVASCULAR Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction | 9 | 3 | 4 | 2 |
| OTHER Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss | 32 | 28 | 12 | 14 |
Warnings & Cautions for Camptosar
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. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg of loperamide every 4 hours.
Monitor and replace fluid and electrolytes. Use antibiotic support for ileus, fever, or severe neutropenia. Subsequent weekly chemotherapy treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without anti-diarrhea medication.
Patients must not be treated with CAMPTOSAR until resolution of the bowel obstruction. If grade 2, 3, or 4 late diarrhea recurs, subsequent doses of CAMPTOSAR should be decreased. Avoid diuretics or laxatives in patients with diarrhea.
Myelosuppression CAMPTOSAR can cause severe myelosuppression
Bacterial, viral, and fungal infections have occurred in patients treated with CAMPTOSAR. Deaths due to sepsis following severe neutropenia have been reported in patients treated with CAMPTOSAR. In the clinical studies evaluating the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3% of the patients; 6% of patients received G-CSF for the treatment of neutropenia.
Manage febrile neutropenia promptly with antibiotic support. Hold CAMPTOSAR if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm 3. After recovery to an absolute neutrophil count ≥1000/mm 3, subsequent doses of CAMPTOSAR should be reduced.
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% versus 24%; 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 deficient glucuronidation of bilirubin, such as those with Gilbert's syndrome, may be at greater risk of myelosuppression when receiving therapy with CAMPTOSAR.
Increased Risk of Neutropenia in Patients With Reduced UGT1A1 Activity Published studies have shown that individuals who are homozygous for either the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or who are compound or double heterozygous for the UGT1A1*28 and *6 alleles (*6/*28) are at increased risk for severe or life-threatening neutropenia during treatment with CAMPTOSAR. These individuals are UGT1A1 poor metabolizers and experience increased systemic exposure to SN-38, an active metabolite of irinotecan. Individuals who are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*28, *1/*6) are intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia.
Consider UGT1A1 genotype testing for the *28 and *6 alleles to determine UGT1A1 metabolizer status. When administering CAMPTOSAR, consider a reduction in the CAMPTOSAR starting dose by at least one level for patients known to be homozygous or compound heterozygous for the UGT1A1*28 and/or *6 alleles (*28/*28, *6/*6, *6/*28). Closely monitor patients with UGT1A1 *28 or *6 alleles for neutropenia during and after treatment with CAMPTOSAR.
The precise dosage reduction in this patient population is not known. Subsequent dosage modifications may be required based on individual patient tolerance to treatment.
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 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 CAMPTOSAR 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, CAMPTOSAR and other chemotherapy should be discontinued and appropriate treatment instituted as needed.
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.
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.
Embryo-Fetal Toxicity Based on its mechanism of action and findings in animals, CAMPTOSAR can cause fetal harm when administered to a pregnant woman. In animal studies, intravenous administration of irinotecan during the period of organogenesis resulted in embryofetal mortality and teratogenicity in pregnant animals at exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 125 mg/m 2. Advise pregnant women of the potential risk to a fetus.
Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment with CAMPTOSAR and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use condoms during treatment and for 3 months after the final dose of 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.
Drug Interactions with Camptosar
Strong CYP3A4 Inducers Exposure to irinotecan or its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital, carbamazepine, or St. John's wort. The appropriate starting dose for patients taking these or other strong inducers such as rifampin and rifabutin has not been defined.
Consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of CAMPTOSAR therapy. Do not administer strong CYP3A4 inducers with CAMPTOSAR unless there are no therapeutic alternatives.
Strong CYP3A4 or UGT1A1 Inhibitors Irinotecan and its active metabolite, SN-38, are metabolized via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), respectively,. Patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Coadministration of CAMPTOSAR with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, indinavir) may increase systemic exposure to irinotecan or SN-38.
Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting CAMPTOSAR therapy.
Pregnancy Safety for Camptosar
Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, CAMPTOSAR can cause fetal harm when administered to a pregnant woman. Available postmarketing and published data reporting the use of CAMPTOSAR in pregnant women, are insufficient and confounded by the concomitant use of other cytotoxic drugs, to evaluate for any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, intravenous administration of irinotecan to rats and rabbits during the period of organogenesis resulted in embryofetal mortality and teratogenicity in pregnant animals at exposures lower than the human exposure based on AUC at the clinical dose of 125 mg/m 2 ( see Data ).
Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data Radioactivity related to 14 C-irinotecan crosses the placenta of rats following intravenous administration.
Intravenous administration of irinotecan to rats at a dose of 6 mg/kg/day (approximately 0.2 times the clinical exposure (AUC) at the 125 mg/m 2 dose based on exposure data from a separate rat study) during the period of organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses; at doses ≥ 1.2 mg/kg/day (approximately 0.03 times the clinical exposure (AUC) at the 125 mg/m 2 dose based on exposure data from a separate rat study) there were increases in a variety of external, visceral, and skeletal abnormalities. Administration of irinotecan to pregnant rabbits at a dose of 6 mg/kg (approximately half of the clinical dose of 125 mg/m 2 based on BSA) resulted in similar findings to those in rats, with increased post-implantation loss, decreased live fetuses, and increased external, visceral, and skeletal abnormalities. Irinotecan administered to rat dams for the period following organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring.
Pediatric Use of Camptosar
Pediatric Use The effectiveness of irinotecan in pediatric patients has not been established. Results from two open-label, single arm studies were evaluated. 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.
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%). 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.
Contraindications for Camptosar
- CAMPTOSAR Injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.
- Hypersensitivity to CAMPTOSAR or its excipients
Overdosage Information for Camptosar
In U.S. phase 1 trials, single doses of up to 345 mg/m 2 of irinotecan were administered to patients with various cancers. Single doses of up to 750 mg/m 2 of irinotecan have been given in non-U.S. trials. The adverse events in these patients were similar to those reported with the recommended dosage and regimen.
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 CAMPTOSAR.
Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.
Clinical Studies of Camptosar
- Metastatic Colorectal Cancer First-Line Therapy in Combination with 5-FU/LV: Studies 1 and 2 Two phase 3, randomized, controlled, multinational clinical trials support the use of CAMPTOSAR Injection as first-line treatment of patients with metastatic carcinoma of the colon or rectum. In each study, combinations of irinotecan with 5-FU and LV were compared with 5-FU and 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; an 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. In both studies, concomitant medications such as antiemetics, atropine, and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. In Study 2, 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/mm 3, even in the absence of fever or diarrhea. Patients in both studies also received treatment with intravenous antibiotics if they had persistent diarrhea or fever or if ileus developed. In both studies, the combination of irinotecan/5-FU/LV therapy resulted in significant improvements in objective tumor response rates, time to tumor progression, 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 arm. Patient characteristics and major efficacy results are shown in Table 10. Table 10.
- Combination Dosage Schedule: Improvement was noted with irinotecan-based combination therapy relative to 5-FU/LV when response rates and time to tumor 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). These studies were designed to evaluate tumor response rate and do not provide information on effects on survival and disease-related symptoms. In each study, CAMPTOSAR was administered in repeated 6-week cycles consisting of a 90-minute intravenous infusion once weekly for 4 weeks, followed by a 2-week rest period. Starting doses of CAMPTOSAR in these trials were, but the 150-mg/m 2 dose was poorly tolerated (due to high rates of grade 4 late diarrhea and febrile neutropenia). Study 3 enrolled 48 patients and was conducted by a single investigator at several regional hospitals. Study 4 was a multicenter study conducted by the North Central Cancer Treatment Group. Study 5 was a multicenter study that enrolled mg/m 2 because the toxicity seen at the 125-mg/m 2 dose was perceived to be greater than that seen in previous studies. All patients in these studies had metastatic colorectal cancer, and the majority had disease that recurred or progressed following a 5-FU-based regimen administered for metastatic disease. The results of the individual studies are shown in Table In the intent-to-treat analysis of the pooled data across all three studies, 193 of the 304 patients began therapy at the recommended starting dose of 125 mg/m 2. A considerably lower response rate was seen with a starting dose of 100 mg/m 2. The majority of responses were observed within the first two cycles of therapy, but responses did occur in later cycles of treatment (one response was observed after the eighth cycle). Of the 304 patients treated in the three studies, response rates to CAMPTOSAR were similar in males and females and among patients older and younger than 65 years. Rates were also similar in patients with cancer of the colon or cancer of the rectum and in patients with single and multiple metastatic sites. Patients with a performance status of 3 or 4 have not been studied. Over half of the patients responding to CAMPTOSAR had not responded to prior 5-FU. Patients who had received previous irradiation to the pelvis responded to CAMPTOSAR at approximately the same rate as those who had not previously received irradiation.
- Once-Every-3-Week Dosage Schedule Single Arm Study: Study 6 Data from an open-label, single-agent, single-arm, multicenter, clinical study involving a total of 132 patients support a once every-3-week dosage schedule of irinotecan in the treatment of patients with metastatic cancer of the colon or rectum that recurred or progressed following treatment with 5-FU. Patients received a starting dose of 350 mg/m 2 given by 30-minute intravenous infusion once every 3 weeks. Among the 132 previously treated patients in this trial, the intent-to-treat response rate was Randomized Studies: Studies 7 and 8 Two multicenter, randomized, clinical studies further support the use of irinotecan given by the once-every-3-week dosage schedule in patients with metastatic colorectal cancer whose disease has recurred or progressed following prior 5-FU therapy. In Study 7, second-line irinotecan therapy plus best supportive care was compared with best supportive care alone. In Study 8, second-line irinotecan therapy was compared with infusional 5-FU-based therapy. 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. Best supportive care was provided to patients in both arms of Study 7 and included antibiotics, analgesics, corticosteroids, transfusions, psychotherapy, or any other symptomatic therapy as clinically indicated. Patients were to be followed every 3 to 6 weeks for 1 year. A total of 535 patients were randomized in the two studies at 94 centers. The primary endpoint in both studies was survival. The studies demonstrated a significant overall survival advantage for irinotecan compared with best supportive care (p=0.0001) and infusional 5-FU-based therapy (p=0.035) as shown in Figures 3 and 4. In Study 7, median survival for patients treated with irinotecan was 9.2 months compared with 6.5 months for patients receiving best supportive care. In Study 8, median survival for patients treated with irinotecan was 10.8 months compared with 8.5 months for patients receiving infusional 5-FU-based therapy. Multiple regression analyses determined that patients' baseline characteristics also had a significant effect on survival. When adjusted for performance status and other baseline prognostic factors, survival among patients treated with irinotecan remained significantly longer than in the control populations (p=0.001 for Study 7 and p=0.017 for Study 8). Measurements of pain, performance status, and weight loss were collected prospectively in the two studies; however, the plan for the analysis of these data was defined retrospectively. Because of the inclusion of patients with non-measurable disease, intent-to-treat response rates could not be assessed. In the two randomized studies, the EORTC QLQ-C30 instrument was utilized. At the start of each cycle of therapy, 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 any trouble taking a long walk?" (Yes or No). The answers from the 30 questions were converted into 15 subscales, that were scored from 0 to 100, and the global health status subscale that was derived from two questions about the patient's sense of general well being in the past week. The results as summarized in Table 13 are based on patients' worst post-baseline scores. In Study 7, a multivariate analysis and univariate analyses of the individual subscales were performed and corrected for multivariate testing. Patients receiving irinotecan reported significantly better results for the global health status, on two of five functional subscales, and on four of nine symptom subscales. As expected, patients receiving irinotecan noted significantly more diarrhea than those receiving best supportive care. In Study 8, the multivariate analysis on all 15 subscales did not indicate a statistically significant difference between irinotecan and infusional 5-FU. Table 13.
- EORTC QLQ-C30: Mean Worst Post-Baseline Score 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. Figure 3 Figure 4
| Study 1 | Study 2 | ||||
|---|---|---|---|---|---|
| Irinotecan + Bolus 5-FU/LV weekly × 4 every 6 weeks | Bolus 5-FU/LV daily × 5 every 4 weeks | Irinotecan weekly × 4 every 6 weeks | Irinotecan + Infusional 5-FU/LV | Infusional 5-FU/LV | |
| Number of patients | 231 | 226 | 226 | 198 | 187 |
| Demographics and treatment administration | |||||
| Female/Male (%) | 34/65 | 45/54 | 35/64 | 33/67 | 47/53 |
| Median age in years (range) | 62 (25–85) | 61 (19–85) | 61 (30–87) | 62 (27–75) | 59 (24–75) |
| Performance status (%) | |||||
| 0 | 39 | 41 | 46 | 51 | 51 |
| 1 | 46 | 45 | 46 | 42 | 41 |
| 2 | 15 | 13 | 8 | 7 | 8 |
| Primary tumor (%) | |||||
| Colon | 81 | 85 | 84 | 55 | 65 |
| Rectum | 17 | 14 | 15 | 45 | 35 |
| Median time from diagnosis to randomization (months, range) | 1.9 (0–161) | 1.7 (0–203) | 1.8 (0.1–185) | 4.5 (0–88) | 2.7 (0–104) |
| Prior adjuvant 5-FU therapy (%) No Yes | 89 11 | 92 8 | 90 10 | 74 26 | 76 24 |
| Median duration of study treatment 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) (months) | 5.5 | 4.1 | 3.9 | 5.6 | 4.5 |
| Median Relative Dose Intensity (%) Irinotecan 5-FU | 72 71 | — 86 | 75 — | 87 86 | — 93 |
| Efficacy Results | |||||
| Confirmed objective tumor response rate Confirmed ≥ 4 to 6 weeks after first evidence of objective response (%) | 39 | 21 | 18 | 35 | 22 |
| (p<0.0001) Chi-square test | (p<0.005) | ||||
| Median time to tumor progression Log-rank test (months) | 7.0 | 4.3 | 4.2 | 6.7 | 4.4 |
| (p=0.004) | (p<0.001) | ||||
| Median survival (months) | 14.8 | 12.6 | 12.0 | 17.4 | 14.1 |
| (p<0.05) | (p<0.05) | ||||
| Study | ||||
|---|---|---|---|---|
| 3 | 4 | 5 | ||
| Number of Patients | 48 | 90 | 64 | 102 |
| Starting Dose (mg/m 2 /week × 4) | 125 Nine patients received 150 mg/m 2 as a starting dose; two (22.2%) responded to CAMPTOSAR. | 125 | 125 | 100 |
| Demographics and Treatment Administration | ||||
| Female/Male (%) | 46/54 | 36/64 | 50/50 | 51/49 |
| Median Age in years (range) | 63 (29–78) | 63 (32–81) | 61 (42–84) | 64 (25–84) |
| Ethnic Origin (%) | ||||
| White | 79 | 96 | 81 | 91 |
| African American | 12 | 4 | 11 | 5 |
| Hispanic | 8 | 0 | 8 | 2 |
| Oriental/Asian | 0 | 0 | 0 | 2 |
| Performance Status (%) | ||||
| 0 | 60 | 38 | 59 | 44 |
| 1 | 38 | 48 | 33 | 51 |
| 2 | 2 | 14 | 8 | 5 |
| Primary Tumor (%) | ||||
| Colon | 100 | 71 | 89 | 87 |
| Rectum | 0 | 29 | 11 | 8 |
| Unknown | 0 | 0 | 0 | 5 |
| Prior 5-FU Therapy (%) | ||||
| For Metastatic Disease | 81 | 66 | 73 | 68 |
| ≤ 6 months after Adjuvant | 15 | 7 | 27 | 28 |
| > 6 months after Adjuvant | 2 | 16 | 0 | 2 |
| Classification Unknown | 2 | 12 | 0 | 3 |
| Prior Pelvic/Abdominal Irradiation (%) | ||||
| Yes | 3 | 29 | 0 | 0 |
| Other | 0 | 9 | 2 | 4 |
| None | 97 | 62 | 98 | 96 |
| Duration of Treatment with CAMPTOSAR (median, months) | 5 | 4 | 4 | 3 |
| Relative Dose Intensity Relative dose intensity for CAMPTOSAR based on planned dose intensity of 100, 83.3, and 66.7 mg/m 2 /wk corresponding with 150, 125, and 100 mg/m 2 starting doses, respectively. (median %) | 74 | 67 | 73 | 81 |
| Efficacy | ||||
| Confirmed Objective Response Rate (%) Confirmed ≥ 4 to 6 weeks after first evidence of objective response. (95% CI) | 21 (9.3 – 32.3) | 13 (6.3 – 20.4) | 14 (5.5 – 22.6) | 9 (3.3 – 14.3) |
| Time to Response (median, months) | 2.6 | 1.5 | 2.8 | 2.8 |
| Response Duration (median, months) | 6.4 | 5.9 | 5.6 | 6.4 |
| Survival (median, months) | 10.4 | 8.1 | 10.7 | 9.3 |
| 1-Year Survival (%) | 46 | 31 | 45 | 43 |
| Study 7 | Study 8 | |||
| Irinotecan | BSC BSC = best supportive care | Irinotecan | 5-FU | |
| Number of patients | 189 | 90 | 127 | 129 |
| Demographics and treatment administration | ||||
| Female/Male (%) | 32/68 | 42/58 | 43/57 | 35/65 |
| Median age in years (range) | 59 (22–75) | 62 (34–75) | 58 (30–75) | 58 (25–75) |
| Performance status (%) | ||||
| 0 | 47 | 31 | 58 | 54 |
| 1 | 39 | 46 | 35 | 43 |
| 2 | 14 | 23 | 8 | 3 |
| Primary tumor (%) | ||||
| Colon | 55 | 52 | 57 | 62 |
| Rectum | 45 | 48 | 43 | 38 |
| Prior 5-FU therapy (%) | ||||
| For metastatic disease | 70 | 63 | 58 | 68 |
| As adjuvant treatment | 30 | 37 | 42 | 32 |
| Prior irradiation (%) | 26 | 27 | 18 | 20 |
| Duration of study treatment (median, months) (Log-rank test) | 4.1 | -- | 4.2 (p=0.02) | 2.8 |
| Relative dose intensity (median %) Relative dose intensity for irinotecan based on planned dose intensity of 116.7 and 100 mg/m 2 /wk corresponding with 350 and 300 mg/m 2 starting doses, respectively. | 94 | -- | 95 | 81–99 |
| Survival | ||||
| Survival (median, months) | 9.2 | 6.5 | 10.8 | 8.5 |
| (Log-rank test) | (p=0.0001) | (p=0.035) | ||
| QLQ-C30 Subscale | Study 7 | Study 8 | ||||
|---|---|---|---|---|---|---|
| Irinotecan | BSC | p-value | Irinotecan | 5-FU | p-value | |
| Global health status | 47 | 37 | 0.03 | 53 | 52 | 0.9 |
| Functional scales | ||||||
| Cognitive | 77 | 68 | 0.07 | 79 | 83 | 0.9 |
| Emotional | 68 | 64 | 0.4 | 64 | 68 | 0.9 |
| Social | 58 | 47 | 0.06 | 65 | 67 | 0.9 |
| Physical | 60 | 40 | 0.0003 | 66 | 66 | 0.9 |
| Role | 53 | 35 | 0.02 | 54 | 57 | 0.9 |
| Symptom Scales | ||||||
| Fatigue | 51 | 63 | 0.03 | 47 | 46 | 0.9 |
| Appetite loss | 37 | 57 | 0.0007 | 35 | 38 | 0.9 |
| Pain assessment | 41 | 56 | 0.009 | 38 | 34 | 0.9 |
| Insomnia | 39 | 47 | 0.3 | 39 | 33 | 0.9 |
| Constipation | 28 | 41 | 0.03 | 25 | 19 | 0.9 |
| Dyspnea | 31 | 40 | 0.2 | 25 | 24 | 0.9 |
| Nausea/Vomiting | 27 | 29 | 0.5 | 25 | 16 | 0.09 |
| Financial impact | 22 | 26 | 0.5 | 24 | 15 | 0.3 |
| Diarrhea | 32 | 19 | 0.01 | 32 | 22 | 0.2 |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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