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Living Proof Question & Answer Guide
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Camptosar

Efficacy

Q

What is CAMPTOSAR® (irinotecan HCl) injection?

A

CAMPTOSAR is indicated for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following 5-FU-based therapy. It is the first topoisomerase I inhibitor approved for this purpose. [1] Topoisomerases are nuclear enzymes that prepare DNA for replication. Topoisomerase inhibitors appear to act by binding to DNA-topoisomerase complexes, leading to DNA damage when replication enzymes collide with the drug-enzyme DNA complex. [2], [3]

Q

What survival benefit does CAMPTOSAR provide?

A

Two phase III multicenter, randomized trials evaluated CAMPTOSAR 350 mg/m2 once every 3 weeks in a total of 535 patients (intent-to-treat). The primary endpoint in both studies was survival. One trial compared CAMPTOSAR and Best Supportive Care (BSC) with BSC alone; the other compared CAMPTOSAR with Infusional 5-FU-based therapy. In the trial vs BSC, median survival was 9.2 months with CAMPTOSAR and 6.5 months with BSC (P=.0001). CAMPTOSAR increased median survival by 41%.

Survival With CAMPTOSAR 350 mg/m2 once very 3 weeks vs Best Supportive Care

survivalchart1

Please see full prescribing information
©1999 Pharmacia & Upjohn Company

In the comparative trial vs 5-FU, median survival was 10.8 months with CAMPTOSAR and 8.5 months with Infusional 5-FU (P=.035). CAMPTOSAR increased median survival by 27%.

Survival With CAMPTOSAR 350 mg/m2 once very 3 weeks vs Infusional 5-FU

survivalchart2

Q

Does CAMPTOSAR reduce disease-related symptoms?

A

The phase III studies measured clinical benefit as defined by certain disease-related symptoms periodically up to 1 year. The data were collected prospectively and the analyses defined retrospectively:


Months (median)


CAMPTOSAR

BSC

P

Time to Onset of Pain

6.9

2.0

.003

Time to 5% Weight Loss

6.4

4.2

.018

Time to Performance Status

5.7

3.3

.0001

Symptom-related measurements did not show significant differences between CAMPTOSAR and Infusional 5-FU.

Q

Are there any data on quality-of-life indices for CAMPTOSAR® (irinotecan HCl) injection?

A

During the phase III studies, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) instrument was utilized. The EORTC questionnaire assessed global health status, functional abilities, and symptoms in a series of 15 subscales. Compared with Best Supportive Care, CAMPTOSAR produced significantly better results in:

  • Global health status (P=.03)
  • Physical functioning (P=.0003)
  • Role functioning (P=.02)
  • Appetite loss (P=.0007)
  • Constipation (P=.03)
  • Fatigue (P=.03)
  • Pain (P=.009)

BSC produced a significantly better result than CAMPTOSAR only in regard to diarrhea (P=.01). There were no significant differences between CAMPTOSAR and BSC in regard to insomnia, dyspnea, nausea/vomiting, financial impact, and cognitive, emotional, and social functioning. Nor did the EORTC QLQ-C30 show any significant differences between CAMPTOSAR and Infusional 5-FU.

Q

How is CAMPTOSAR dosed?

A

During the phase III studies, patients received CAMPTOSAR in a 90-minute infusion once every 3 weeks. The starting dose for most patients was 350 mg/m2; the starting dose for patients 70 years of age or older, or having a performance status of 2, was 300 mg/m2. CAMPTOSAR can also be administered according to a weekly dosing schedule starting at 125 mg/m2. For more specific information on dosing of CAMPTOSAR, see the DOSAGE AND ADMINISTRATION section of this booklet.

Q

What is the tumor response to CAMPTOSAR?

A

CAMPTOSAR was also evaluated in 3 phase II studies designed to measure tumor response rate (n=304). These studies did not provide information on actual clinical benefit, such as effect on survival and disease-related symptoms. In these studies, the patients received CAMPTOSAR in a 90-minute infusion once weekly for 4 consecutive weeks, followed by a 2-week rest. The starting dose varied from 100 mg/m2 to 150 mg/m2; the usual starting dose was 125 mg/m2. Most patients received more than one course.

The objective tumor response rate across the 3 studies was 15% at a dose of 125 mg/m2 and 12.8% at all doses. The results included 2 complete responses and 27 partial responses. Patients responded at approximately the same rate regardless of gender, age, cancer site (colon or rectum), single or multiple metastatic sites, and prior pelvic radiotherapy.

For patients beginning therapy at 125 mg/m2, the median response duration was 5.8 months. Most responses were observed by the 2nd course; all but one were seen by the 4th course (response seen in one patient after 8th course). The data suggest that typically physicians can make decisions about the use of CAMPTOSAR relatively early in therapy.

 

Adverse Effects
Q

What are the clinically significant adverse effects of CAMPTOSAR® (irinotecan HCl) injection and how often do they occur?

A

To some extent, the incidence of clinically significant adverse effects varies with the dose of CAMPTOSAR:

 


PHASE III:
350 mg/m2 once
every 3 weeks

PHASE II:
125 mg/m2 once
weekly x 4


Grades
3-4

All
grades

Grades
3-4

All
grades


% of patients reporting)

(% of patients reporting)

Adverse Effect


Diarrhea (early) and Other Cholinergic Effects

2-12

47

8

51

Diarrhea (late)

22

84

31

88

Nausea

11-14

70

17

86

Vomiting

14

62

12

67

Abd. Cramping/pain

9-14

40

16

57

Leukopenia

-a

-

28

63

Neutropenia

14-22

30

26

54

Asthenia

13-15

50

12

76

Alopecia

-b

72

-b

60

a In the phase III studies, leukopenia was reported with neutropenia.
b The highest grade of alopecia is grade 2, signifying complete hair loss.

 

Q

How often do events associated with CAMPTOSAR cause discontinuations, hospitalizations, and fatalities?

A

During the phase II studies with CAMPTOSAR 125 mg/m2 weekly, adverse effects caused 4.3% (13/304) of patients to discontinue therapy. In the phase III studies with CAMPTOSAR 350 mg/m2 every 3 weeks, 8.0% (25/316) of patients discontinued therapy due to adverse events compared to 7.0% (9/129) of patients receiving 5-FU. During the phase II studies, the percentage of patients hospitalized for adverse events related to CAMPTOSAR was 26.6%. In the phase III studies, 60% of patients who received CAMPTOSAR were hospitalized at least once for serious adverse events whether or not related to study treatment. The corresponding percentages for patients who received 5-FU or BSC only were, respectively, 39% and 63%. In phase II and phase III studies, the incidence of potentially drug-related deaths associated with CAMPTOSAR was 1.6% (5/304) and 1% (3/316) respectively. The causes of death in the phase III study were grade 4 diarrhea, asthenia, and neutropenic infection.

Q

How can the events associated with the use of CAMPTOSAR be managed?

A

With appropriate patient education and monitoring, most clinically significant adverse effects of CAMPTOSAR can be managed with symptomatic measures, which are discussed in the next several sections. The management may also involve changes in the dose and continuity of treatment, particularly for more serious events. Recommended dose modifications are discussed in a later section.

Q

What is the symptomatic management for the cholinergic effects of CAMPTOSAR® (irinotecan HCl) injection?

A

Cholinergic effects that may be associated with CAMPTOSAR include rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, intestinal hyperperistalsis, and early-onset diarrhea.

These effects can be prevented or treated with atropine 0.25 to 1.0 mg subcutaneously or intravenously, unless clinically contraindicated. It is recommended that patients experiencing these effects receive atropine prophylactically with subsequent administration of CAMPTOSAR.

Q

What is the symptomatic management for diarrhea associated with the use of CAMPTOSAR?

A

With CAMPTOSAR, diarrhea can have an early or a late onset. Early-onset diarrhea and other cholinergic symptoms occur during or shortly after an infusion. While it can be severe, it is usually transient and relatively mild. As discussed above, early-onset diarrhea can be prevented or treated with atropine. Late-onset diarrhea generally occurs after the first 24 hours. Its median time to onset is 11 days after a CAMPTOSAR infusion at 125 mg/m2 and 5 days after an infusion at 350 mg/m2. The mechanism of late-onset diarrhea has not been determined. [4], [5] Late-onset diarrhea can be prolonged, may lead to dehydration and electrolyte imbalance, and can be life-threatening. At a weekly dose of 125 mg/m2, its median duration is 3 to 7 days, depending on grade.

Late-onset diarrhea should be treated promptly with loperamide. The use of loperamide to prevent late diarrhea is not recommended. Loperamide is usually self-administered by the patient, according to the following instructions:

  • Write and keep a description of your usual bowel habits, ie, the frequency of your bowel movements and the shape and firmness of your stools.
  • Keep loperamide available.
  • At the first episode of diarrhea, eg, loose or poorly formed stools or an increase in the frequency of bowel movements, start taking loperamide immediately. Do not delay.
  • Take 4 mg (2 caplets) of loperamide at the start, then 2 mg (1 caplet) every 2 hours during the day, and 4 mg (2 caplets) every 4 hours during the night.
  • Continue taking loperamide until you have had no diarrhea for 12 hours. If your diarrhea persists after taking loperamide for 24 hours, call your physician.

The patient should also avoid the use of laxatives. Patients with severe diarrhea should be monitored closely for dehydration and electrolyte imbalances and replacement therapy promptly implemented as needed. If grade 3 or 4 diarrhea occurs, CAMPTOSAR administration should be delayed until the patient recovers and subsequent doses should be decreased.

Q

What is the symptomatic management for nausea and vomiting associated with the use of CAMPTOSAR?

A

Nausea and vomiting may be prevented with antiemetic agents. Prophylaxis is recommended. In clinical studies of the weekly dosage schedule, the majority of patients received dexamethasone 10 mg given in conjunction with a 5-HT3 blocker such as ondansetron or granisetron. The antiemetic agents should be started on the same day, at least 30 minutes before the infusion of CAMPTOSAR. If nausea and vomiting is persistent after CAMPTOSAR infusion, the patient should be instructed to take prophylactic oral antiemetics after each subsequent infusion, for a period from 48 to 72 hours. One antiemetic agent commonly used with antineoplastic agents is prochlorperazine, which can cause akathisia.

The incidence of akathisia is higher when prochlorperazine and CAMPTOSAR are given on the same day than on different days. Even when they are given on the same day, however, the incidence of akathisia remains in the range reported with premedication of prochlorperazine with other chemotherapies.

Q

What is the recommended management for the hematologic effects of CAMPTOSAR® (irinotecan HCl) injection?

A

Myelosuppression caused by CAMPTOSAR can be severe. The principle effects are neutropenia, leukopenia (including lymphocytopenia), and anemia. Deaths due to sepsis following severe myelosuppression have been reported. Serious thrombocytopenia is uncommon. Careful monitoring of the white blood cell count with differential is recommended before each dose of CAMPTOSAR. Hematologic effects are usually managed with changes in CAMPTOSAR dosing (see below). In the event of significant neutropenia, a physician may wish to consider the use of colony-stimulating factor (CSF). The routine use of CSF is not necessary.

Grade 3 or 4 neutropenia concomitant with grade 3 or 4 late diarrhea should be treated aggressively with IV hydration, loperamide, and oral antibiotics.

Q

What drugs exacerbate adverse events associated with the use of CAMPTOSAR?

A

The likelihood of lymphocytopenia reported with the use of CAMPTOSAR may be enhanced by dexamethasone, but no serious opportunistic infections have been observed, and no complications have specifically been attributed to lymphocytopenia. Dexamethasone can also intensify hyperglycemia, which has been observed in some patients on CAMPTOSAR, especially those with a history of diabetes mellitus or glucose intolerance.

Side effects with CAMPTOSAR, such as myelosuppression and diarrhea, are also likely to be exacerbated by other antineoplastic agents having similar adverse effects. See the section above on the management of nausea and vomiting for discussion of akathisia associated with concomitant use of CAMPTOSAR and prochlorperazine.

Q

What patients are at special risk of adverse events associated with the use of CAMPTOSAR?

A

In studies using the weekly dosage schedule, grade 3 or 4 neutropenia was significantly more frequent in patients with a history of pelvic/abdominal radiotherapy than in those without, and in patients with a serum total bilirubin of 1.0 mg/dL or more than in patients whose serum total bilirubin was lower. (During clinical studies, CAMPTOSAR was not administered to patients whose baseline serum total bilirubin was >2 mg/dL.) The incidence of grade 3 or 4 neutropenia does not vary significantly with age or gender.

Grade 3 or 4 late diarrhea was significantly more frequent in patients with a history of pelvic/abdominal radiotherapy than in those without. Patients 65 years of age or older or those with a low WHO performance status were more likely to experience grade 3 or 4 late diarrhea. [6]

Patients 65 years of age or older or those with a history of pelvic/abdominal radiotherapy should be monitored with special care. Women of childbearing potential should be advised to avoid becoming pregnant and that nursing be discontinued when receiving therapy.

Q

What should patients be taught about the possible adverse events associated with the use of CAMPTOSAR?

A

Patients should be informed of the expected toxic effects of CAMPTOSAR, particularly nausea, vomiting, diarrhea, and alopecia. Patients should be instructed to notify their physician in the event of vomiting, fever or other evidence of infection, or symptoms of dehydration such as fainting, light-headedness, and dizziness. These and other instructions are explained fully in the following patient education materials:

  • What You Need to Know Before Your First Treatment
  • A Treatment Guide for You

 

Dosage & Administration

Q

How is CAMPTOSAR® (irinotecan HCl) injection administered?

A

CAMPTOSAR is administered intravenously. The infusion site should be observed for signs of inflammation. If extravasation occurs, the site should be flushed with sterile water and ice applied.

Q

What are the dosing schedule options?

A

CAMPTOSAR can be administered according to a once-every-3-week dosage schedule or a weekly dosage schedule. In the q3 week schedule, the recommended starting dose is 350 mg/m2 administered over 90 minutes. If a patient is 70 years of age or older, has a performance status of 2, or has a history of prior pelvic/abdominal radiotherapy, the recommended starting dose is 300 mg/m2.

CAMPTOSAR can also be administered on a weekly basis, at a starting dose of 125 mg/m2 over 90 minutes. The recommended treatment regimen is one weekly treatment for 4 weeks, followed by a 2-week rest period. If a patient has a history of pelvic/abdominal radiotherapy combined with elevated serum total bilirubin levels (1.0 to 2.0 mg/dL), the physician should consider a starting dose of 100 mg/m2.

After the start of therapy, the dose should be modified on the basis of toxicity, as shown in the table below.

Q

How may the dose be modified in case of myelosuppression or diarrhea?

A

If the patient's granulocyte count falls below 1,500/mm3 or platelet count falls below 100,000/mm3 or grade 3-4 diarrhea is experienced, treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicity. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing CAMPTOSAR.

Q

How can an overdose be managed?

A

Adverse events in patients administered single doses of CAMPTOSAR up to 750 mg/m2 were similar to those reported with the recommended dosage and regimen. The management of overdosage consists of supportive care for dehydration due to diarrhea and treatment of infectious complications. There is no known antidote for overdosage of CAMPTOSAR.

 

Dosage Table

 

Metabolism & Pharmacokinetics
Q

How is CAMPTOSAR® (irinotecan HCl) injection metabolized and excreted?

A

CAMPTOSAR is metabolized primarily in the liver. Its chief metabolite is SN-38, which is about 1,000 times more active than the parent compound. [2] CAMPTOSAR and SN-38 each exist in active lactone and inactive hydroxy acid anion forms. SN-38 undergoes conjugation to SN-38 glucuronide, which has been shown to be 50 to 100 times less active than SN-38 in vitro.

CAMPTOSAR and its metabolites are excreted by the kidneys and in the bile. In two patients, the cumulative urinary and biliary excretion of CAMPTOSAR and its known metabolites over a period of 48 hours after intravenous infusion ranges from 25% to 50%. These data suggest that some metabolites of CAMPTOSAR have yet to be identified.

Q

What are the pharmacokinetics of CAMPTOSAR?

A

The pharmacokinetics of CAMPTOSAR have not been fully elucidated. Selected mean pharmacokinetic parameters for CAMPTOSAR and SN-38 following a 90-minute infusion of CAMPTOSAR are shown below:


CAMPTOSAR

SN-38

Dose (mg/m2)

125
(n=64)

340
(n=6)

125
(n=64)

340
(n=6)

AUC0-24 (ngh/mL)

10,200
3,270

20,604
6,027

229
108

474
245

t1/2 (hrs)

5.8
0.7

11.7
1.0

10.4
3.1

21.0
4.3

Over the recommended dose range, the AUC of CAMPTOSAR increases linearly with dose, while that of SN-38 increases less than proportionally with dose.

The effects of hepatic and renal insufficiency on the pharmacokinetics of CAMPTOSAR have not been formally studied. The pharmacokinetics of CAMPTOSAR do not appear to be influenced by gender. The effect of age on the pharmacokinetics of CAMPTOSAR has been evaluated in studies involving the weekly schedule, but not the q3 week schedule. In the former, the dose-normalized AUC0-24 for SN-38 is 11% higher in patients 65 years of age or older than in younger patients. The terminal half-life of CAMPTOSAR was 6.0 hours in patients 65 years of age or older and 5.5 hours in patients younger than 65 years. The pharmacokinetics of the q3 week schedule has not been studied in older patients. The lower starting dose is recommended for patients 70 years of age or older based on the clinical experience of toxicity, not on pharmacokinetic studies.

 

References

  1. U.S. Food and Drug Administration. Drug for colon and rectal cancer [Updates]. FDA Consumer. 1996;30(7).
  2. Slichenmyer WJ, Rowinsky EK, Donehower RC, Kaufmann SH. The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst. 1993;85:271-291.
  3. Creemerst GJ, Lund B, Verweij J. Topoisomerase I inhibitors: topotecan and irenotecan. Cancer Treat Rev. 1994;20:73-96.
  4. Potmesil M. Camptothecins: From bench research to hospital wards. Cancer Res. 1994;54:1431-1439.
  5. Rothenberg ML. CPT-11: An original spectrum of clinical activity. Semin Oncol. 1996;23(1, suppl 3):21-26.
  6. Rougier P, Bugat R. CPT-11 in the treatment of colorectal cancer: Clinical efficacy and safety profile. Semin Oncol. 1996;23 (1, suppl 3):34-41.

 

Camptosar


Pharmacia & Upjohn Yakult Daiichi

© 1999 Pharmacia & Upjohn Company


USX 2962.00 May 1999

 

Full Prescribing Information

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