ایرینوتکان
Irinotecan Hydrochloride (Camptosar Injection)
ایرینوتکان

نام ژنریک

Irinotecan Hydrochloride

شکل دارویی

اشكال دارويي:


Injection: 20 mg/ml, 5ml , 20 mg/ml, 2ml


Injection, Powder For Reconstitution: 100m, 5ml, 40mg, 2ml

موارد مصرف

موارد و مقدار مصرف


خط اول درمان سرطان متاستاتيك كولوركتال همراه با
5- فلورواوراسيل (5-FU) و لكوورين


رژيم 1:


بزرگسالان: مقدار mg/m2 125 از راه تزريق وريدي طي 90 دقيقه، در روزهاي 1، 8، 15 و 22 مصرف شده و سپس لكوورين به ميزان mg/m2 20 به شكل بولوس و از راه وريدي در روزهاي 1، 8، 15 و 22 و 5- فلورواوراسيل، mg/m2 500 به شكل بولوس و از راه وريدي در روزهاي 1، 8، 15 و 22 تجويز مي‌گردند.


تنظيم دوز: در طي يك دوره درماني، در بيماراني كه تعداد نوتروفيل‌هاي آنها بين mm3/1499-1000 بوده يا چهار تا شش بار افزايش در ميزان دفع مدفوع آنها نسبت به معمول ايجاد شده باشد، دوز ايرينوتكان به mg/m2 100 و 5- فلورواوراسيل، به mg/m2 400 كاهش يافته و لكوورين با دوز mg/m2 20 ادامه مي‌يابد.


در بيماراني كه تعداد نوتروفيل آنها به mm3/999-500 كاهش يافته يا دفعات دفع مدفوع آنها 9-7 بار در روز از ميزان معمول افزايش پيدا كند، مصرف يك دوز حذف شده و بعد از آن دوز ايرينوتكان به mg/m2 100 و 5- فلورواوراسيل به mg/m2 400 كاهش يافته و مصرف لكوورين با دوز mg/m2 20 ادامه مي‌بايد و تا زمان افزايش تعداد نوتروفيل‌ها به mm3 /1000 يا بيشتر و كاهش دفع مدفوع به كمتر از 7 بار در روز، اين دوزها ادامه مي‌يابند.


در بيماراني كه تعداد نوتروفيل در آنها به كمتر از mm3 /500 كاهش يافته يا دفع مدفوع در آنها 10 بار يا بيشتر در روز از ميزان معمول افزايش پيدا كند، يك دوز حذف شده و پس از آن دوز ايرينوتكان به mg/m2 75 و 5- فلورواوراسيل به mg/m2 300 كاهش يافته و لكوورين با دوز mg/m2 20 ادامه پيدا مي‌كند تا زماني كه تعداد نوتروفيل‌ها به mm3 /1000 يا بيشتر افزايش و دفع مدفوع به كمتر از 7 بار در روز كاهش يابد، ادامه مي‌يابد.


در صورت بروز تب نوتروپنيك، يك دوز حذف شده و سپس دوز ايرينوتكان به mg/m2 75 و 5- فلورواوراسيل به mg/m2 300 كاهش يافته و لكوورين با دوز mg/m2 20 ادامه پيدا مي‌كند تا زماني كه تب نوتروپنيك برطرف شود.


در شروع سيكل‌هاي بعدي درمان، براي بيماراني كه تعداد نوتروفيل آنها
mm3 /999-500 بوده يا 9-7 بار افزايش دفع مدفوع در روز داشته‌اند، دوز ايرينوتكان به mg/m2 100 و 5- فلورواوراسيل به mg/m2 400 كاهش يافته و مصرف ايرينوتكان با دوز mg/m2 20 تجويز مي‌شود.


در بيماراني كه تعداد نوتروفيل آنها كمتر از mg/m2 500 بوده، تب نوتروپنيك داشته يا 10 بار يا بيشتر افزايش در دفعات دفع روزانه داشته‌اند، دوز ايرينوتكان به mg/m2 100 و 5- فلورواوراسيل به mg/m2 300 كاهش يافته و لكوورين با دوز mg/m2 20 ادامه مي‌يابد.


رژيم 2:


بزرگسالان: مقدار mg/m2 180 از راه تزريق وريدي طي 90 دقيقه، در روزهاي 1، 15 و 29 تجويز شده و سپس لكوورين با دوز mg/m2 200 از راه وريدي طي 2 ساعت در روزهاي 1، 2، 15، 16، 29 و 30 تزريق گرديده، و 5- فلورواوراسيل با دوز mg/m2 400 از راه تزريق وريدي به شكل بولوس در روزهاي 1، 2، 15، 16، 22 و سپس 30 و 5- فلورواوراسيل با دوز mg/m2 600 از طريق انفوزيون وريدي طي 22 ساعت در روزهاي 1، 2، 15، 16، 29 و 30 تزريق مي‌گردند.


تنظيم دوز: در طي سيكل درمان، در مورد بيماراني كه تعداد نوتروفيل‌ آنها mm3/1499-1000 بوده يا 6-4 بار افزايش در دفعات دفع روزانه داشته باشند، لازم است دوز ايرينوتكان به mg/m2 150، دوز بولوس 5- فلورواوراسيل به mg/m2 320 و دوز انفوزيون 5- فلورواوراسيل به mg/m2 480 كاهش يافته و لكوورين با دوز mg/m2 200 ادامه پيدا كند.


در بيماراني كه تعداد نوتروفيل آنها mm3 /999-500 بوده يا 9-7 بار يا بيشتر افزايش در دفعات دفع روزانه داشته باشند،‌ يك دوز حذف شده و سپس دوز ايرينوتكان به mg/m2 150، دوز بلوس 5- فلورواوراسيل به mg/m2 320، و دوز انفوزيون 5- فلورواوراسيل به mg/m2 480 كاهش يافته و لكوورين با دوز mg/m2 200 ادامه مي‌يابد و تا افزايش تعداد نوتروفيل‌ها به mm3/ 1000 يا بيشتر و كاهش دفعات دفع به كمتر از 7 بار در روز ادامه مي‌يابد.


در بيماراني كه تعداد نوتروفيل‌ها به كمتر از mm3/500 رسيده يا 10 بار بيشتر افزايش در تعداد دفعات دفع روزانه داشته باشند، بايد يك دوز حذف شده و سپس دوز ايرينوتكان به mg/m2 120، دوز بلوس 5- فلورواوراسيل به
mg/m2 240 و دوز انفوزيون 5- فلورواوراسيل به mg/m2 360 كاهش يافته و لكوورين با دوز mg/m2 200 ادامه پيدا كند و تا افزايش تعداد نوتروفيل‌ها به mm3 /1000 يا بيشتر و كاهش دفعات دفع روزانه به كمتر از 7 بار در روز ادامه مي‌يابد.


در بيماران دچار تب نوتروپنيك، يك دوز حذف شده و سپس دوز ايرينوتكان به mg/m2 120، دوز بلوس 5- فلورواوراسيل به mg/m2 240 و دوز انفوزيون
5- فلورواوراسيل به mg/m2 360 كاهش يافته و لكوورين با دوز mg/m2 200 تا زمان رفع تب نوتروپنيك ادامه پيدا مي‌كند.


در شروع سيكل‌هاي بعدي درمان، در مورد بيماراني كه تعداد نوتروفيل
mm3 /999-5000 داشته يا افزايش دفع روزانة آنها 9-7 بار يا بيشتر بوده، دوز ايرينوتكان به mg/m2 150، دوز بلوس 5- فلورواوراسيل به mg/m2 320 و دوز انفوزيون 5- فلورواوراسيل به mg/m2 480 كاهش يافته و لكوورين با دوز mg/m2 200 ادامه مي‌يابد.


در بيماران داراي تعداد نوتروفيل كمتر از mm3 /500، تب نوتروپينك يا افزايش دفع روزانه 10 بار يا بيشتر دوز ايرينوتكان به mg/m2 120، دوز بلوس
5- فلورواوراسيل به mg/m2 240 و دوز انفوزيون 5- فلورواوراسيل به
mg/m2 360 كاهش يافته و لكوورين با دوز mg/m2 200 ادامه پيدا مي‌كند.

موارد منع مصرف

موارد منع مصرف و احتياط


موارد منع مصرف: مصرف دارو در بيماران دچار حساسيت مفرط به دارو ممنوع مي‌باشد.


بايستي مصرف دارو در سالمندان و در كساني كه قبلاً تحت پرتوتاپي در ناحيه لگن يا شكم قرار گرفته‌اند، با احتياط صورت گيرد زيرا خطر سركوب شديد مغز استخوان وجود دارد. به دليل وجود خطرات احتمالي بر جنين، نبايد از اين دارو در دوره بارداري استفاده شود.

عوارض جانبی دارو

عوارض جانبي


اعصاب مرکزي: سرگيجه، تب، سردرد، بي‌خوابي، درد.


قلبي ـ عروقي: ادم، وازوديلاتاسيون.


دستگاه گوارش: كرامپ و درد شكم، اتساع شكم، بي‌اشتهايي، يبوست، اسهال، سوء‌هاضمه، نفخ، تهوع، استوماتيت، استفراغ.


خون: آنمي، لكوپني، نوتروپني.


متابوليك: دهيدراتاسيون، كاهش وزن.


عضلاني ـ اسكلتي: كمر درد.


تنفسي: تنگي نفس، افزايش سرفه.


پوست: آلوپسي، راش، تعريق.


ساير عوارض: لرز، عفونت، رينيت.


مسموميت و درمان


عوارض جانبي ايجاد شده در مصرف بيش از حد ايرينوتكان مشابه عوارض مشاهده شده در دوزاژ توصيه شده و رژيم درماني است.


هيچ آنتي‌دوت شناخته شده‌اي براي موارد مسموميت با اين دارو وجود ندارد. لازم است اقدامات درماني حمايتي در جهت جلوگيري از دهيدراتاسيون به دنبال اسهال و درمان هر نوع كامپليكاسيون عفوني صورت گيرد.

موارد قابل توجه

-

تداخل دارویی

تداخل دارويي


در مصرف همزمان ايرينوتكان با ساير داروهاي ضد نئوپلاسم، احتمال افزايش اثرات جانبي همچون سركوب مغز استخوان و اسهال وجود دارد و لازم است بيمار از نزديك پيگيري شود.

مکانیزم اثر

تداخل دارويي


در مصرف همزمان ايرينوتكان با ساير داروهاي ضد نئوپلاسم، احتمال افزايش اثرات جانبي همچون سركوب مغز استخوان و اسهال وجود دارد و لازم است بيمار از نزديك پيگيري شود.

فارماكوكینتیك

فارماكوكينتيك


جذب: از طريق وريدي تجويز مي‌شود.


پخش: حدود 68-30 درصد اتصال پروتئيني دارد؛ متابوليت فعال آن، SN-38، حدوداً 98 درصد به پروتئين پلاسما متصل مي‌شود.


متابوليسم: در كبد، تحت گنژوگاسيون گلوكورونيده شده و به متابوليت فعال SN-38 تبديل مي‌شود.


دفع: مقدار كمي از دارو و SN-38 از طريق ادرار دفع مي‌شود. نيمه‌ عمر نهايي ايرينوتكان در بيماران 65 سال به بالا، 6 ساعت و در افراد كمتر از 65 سال، 5/5 ساعت مي‌باشد. متوسط نيمه‌ عمر نهايي حذف SN-38 حدود 10 ساعت است.

سایر اطلاعات

طبقه‌بندي فارماكولوژيك: مهار كننده توپوايزومراز.


طبقه‌بندي درماني: ضد نئوپلاسم.


طبقه‌بندي مصرف در بارداري: رده D


نام‌هاي تجاري: Campto, Irinotecan


ملاحظات اختصاصي


1- دارو را با محلول دكستروز 5% (مايع انتخابي) يا نرمال‌سالين رقيق نموده و به غلظت نهايي mg/ml 8/2-12/0 رسانده شود. انفوزيون محلول آماده شده حداقل طي 90 دقيقه انجام مي‌شود.


2- نبايد ساير داروها را به انفوزيون ايرينوتكان افزود.


3- بيمار بايد از نظر بروز اسهال شديد پيگيري شود.


4- در صورتي كه بعد از تجويز ايرينوتكان اسهال بروز كرده و بيش از 24 ساعت طول بكشد، بايستي با لوپراميد درمان شود. درمان‌هاي بعدي را نيز بايد تا زمان طبيعي شدن عملكرد گوارشي به مدت 24 ساعت بدون استفاده از تركيب ضد اسهال، به تأخير انداخت.


5- قبل از تجويز هر دوز ايرينوتكان لازم است تعداد WBC، هموگلوبين و پلاكت بيمار مانيتور شود.


6- در صورت بروز تب نوتروپنيك يا افت تعداد نوتروفيل‌ها به كمتر از
mm3/500 بايد مصرف دارو به طور موقت قطع شود.


7- در صورت كاهش تعداد WBCها به كمتر از mm3/2000 و افت نوتروفيل‌ها به كمتر از mm3/1000، افت هموگلوبين به كمتر از g/dl 8 يا افت پلاكت‌ها به كمتر از mm3/100000 لازم است دوز دارو كاهش پيدا كند. در صورت بروز چنين شرايطي بايد به دستورالعمل كارخانه سازنده رجوع شود.


8- در صورت بروز نوتروپني شديد مي‌توان از فاكتورهاي تحريك كننده كلوني (CSF) استفاده نمود.


نكات قابل توصيه به بيمار


1- بايستي به خانم‌هاي داراي پتانسيل بارداري توصيه نمود كه از باردار شدن پرهيز كنند.


چرا كه اين دارو مي‌تواند منجر به آسيب به جنين شود.


2- لازم است به بيمار در مورد خطر بروز اسهال و زمان و چگونگي درمان آن در صورت بروز، توضيحات لازم داده شود.


3- در صورت بروز استفراغ،‌ تب، شواهد عفونت يا علائم دهيدراتاسيون (غش، سردرد يا گيجي) لازم است بيمار بلافاصله به پزشك اطلاع دهد.


4- به بيمار اطلاع داده شود كه ممكن است آلوپسي بروز كند.


مصرف در سالمندان: بايستي مصرف دارو در سالمندان به ويژه در كساني كه سابقه نارسايي قلبي و هايپوتانسيون دارند با احتياط صورت گيرد.


مصرف در كودكان: اثربخشي و بي‌ضرري دارو در كودكان به اثبات نرسيده است.


مصرف در شيردهي: در طي دوره درمان با ايرينوتكان شيردهي توصيه نمي‌شود.


مصرف در بارداري: اين دارو مي‌تواند براي جنين خطرناك باشد.


اثر بر آزمايشهاي تشخيصي


مصرف ايرينوتكان مي‌تواند منجر به افزايش سطح آلكالن فسفاتاز و AST گردد، ممكن است سطح هموگلوبين و هماتوكريت، WBC و نوتروفيل‌ها را كاهش دهد.

Irinotecan Hydrochloride (Camptosar Injection)

CAMPTOSAR
(irinotecan) Injection

WARNING

DIARRHEA AND MYELOSUPPRESSION

Early and late forms of diarrhea can occur. Early diarrhea may be accompanied by cholinergic symptoms which may be prevented or ameliorated by atropine. Late diarrhea can be life threatening and should be treated promptly with loperamide. Monitor patients with diarrhea and give fluid and electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe neutropenia. Interrupt CAMPTOSAR and reduce subsequent doses if severe diarrhea occurs.

Severe myelosuppression may occur.

DRUG DESCRIPTION

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:

CAMPTOSAR (Irinotecan) Structural Formula Illustration

What are the possible side effects of irinotecan (Camptosar)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • wheezing, feeling short of breath;
  • chest pain, dry cough;
  • pale skin, feeling light-headed, rapid heart rate, trouble concentrating;
  • fever, chills, body aches, flu symptoms, sores in your mouth and throat;
  • runny nose, watery eyes, increased sweating, stomach cramps, and flushing (warmth, redness, or tingly...

Read All Potential Side Effects and See Pictures of Camptosar Injection »

What are the precautions when taking irinotecan hydrochloride (Camptosar Injection)?

Before using irinotecan, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: bowel blockage (e.g., paralytic ileus), certain genetic metabolism disorder (fructose intolerance).

Before using this drug, tell your doctor your medical history, including: radiation treatments, blood/bone marrow disorders (e.g., low platelet/neutrophil/red blood cell levels), diabetes, liver disease, kidney disease, lung disease.

Before having surgery, tell...

Read All Potential Precautions of Camptosar Injection »

Last reviewed on RxList: 8/9/2012
This monograph has been modified to include the generic and brand name in many instances.

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.

Distributed by : Pharmacia & Upjohn Co., Division of Pfizer Inc, NY, NY 10017 . Licensed from Yakult Honsha Co., LTD, Japan, and Daiichi Pharmaceutical Co., LTD, Japan. Revised: July 2012

Last reviewed on RxList: 8/9/2012
This monograph has been modified to include the generic and brand name in many instances.

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.

Read the Camptosar Injection (irinotecan hydrochloride) Side Effects Center for a complete guide to possible side effects »

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.

Last reviewed on RxList: 8/9/2012
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

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].

Last reviewed on RxList: 8/9/2012
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

In U.S. phase 1 trials, single doses of up to 345 mg/m² of irinotecan were administered to patients with various cancers. Single doses of up to 750 mg/m² 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.

CONTRAINDICATIONS

CAMPTOSAR Injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.

Last reviewed on RxList: 8/9/2012
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase IDNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks.

Pharmacodynamics

Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold; however, the plasma area under the concentration versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN38 is 95% bound to plasma proteins compared to approximately 50% bound to plasma proteins for irinotecan. The precise contribution of SN38 to the activity of CAMPTOSAR is thus unknown. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the two forms such that an acid pH promotes the formation of the lactone, while a more basic pH favors the hydroxy acid anion form.

Administration of irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types.

Pharmacokinetics

After intravenous infusion of irinotecan in humans, irinotecan plasma concentrations decline in a multiexponential manner, with a mean terminal elimination half-life of about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. The half-lives of the lactone (active) forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid forms are in equilibrium.

Over the recommended dose range of 50 to 350 mg/m², the AUC of irinotecan increases linearly with dose; the AUC of SN-38 increases less than proportionally with dose. Maximum concentrations of the active metabolite SN-38 are generally seen within 1 hour following the end of a 90-minute infusion of irinotecan. Pharmacokinetic parameters for irinotecan and SN-38 following a 90-minute infusion of irinotecan at dose levels of 125 and 340 mg/m² determined in two clinical studies in patients with solid tumors are summarized in Table 9:

Table 9: Summary of Mean (±Standard Deviation) Irinotecan and SN-38 Pharmacokinetic Parameters in Patients with Solid Tumors

Dose (mg/m²) Irinotecan SN-38
Cmax (ng/mL) AUC0-24 (ng•h/mL) t½ (h) Vz (L/m²) CL (L/h/m²) Cmax (ng/mL) AUC0-24 (ng•h/mL) t½ (h)
125 (N=64) 1,660 ±797 10,200 ±3,270 5.8a ±0.7 110 ±48.5 13.3 ±6.01 26.3 ±11.9 229 ±108 10.4a ±3.1
340 (N=6) 3,392 ±874 20,604 ±6,027 11.7b ±1.0 234 ±69.6 13.9 ±4.0 56.0 ±28.2 474 ±245 21.0b ±4.3
Cmax -Maximum plasma concentration
AUC0-24 -Area under the plasma concentration-time curve from time 0 to 24 hours after the end of the 90-minute infusion
t½ - Terminal elimination half-life Vz - Volume of distribution of terminal elimination phase CL - Total systemic clearance
aPlasma specimens collected for 24 hours following the end of the 90-minute infusion.
bPlasma specimens collected for 48 hours following the end of the 90-minute infusion. Because of the longer collection period, these values provide a more accurate reflection of the terminal elimination half-lives of irinotecan and SN-38.

Distribution

Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound to human plasma proteins (approximately 95% bound). The plasma protein to which irinotecan and SN-38 predominantly binds is albumin.

Metabolism

The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and primarily occurs in the liver. In vitro studies indicate that irinotecan, SN-38 and another metabolite aminopentane carboxylic acid (APC), do not inhibit cytochrome P-450 isozymes. SN-38 is subsequently conjugated predominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele (also referred to as UGT1A1 7/7 genotype). In a prospective study, in which irinotecan was administered as a single-agent (350 mg/m²) on a once-every-3-week schedule, patients with the UGT1A1 7/7 genotype had a higher exposure to SN-38 than patients with the wild-type UGT1A1 allele (UGT1A1 6/6 genotype) [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION]. SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38 in cytotoxicity assays using two cell lines in vitro.

Excretion

The disposition of irinotecan has not been fully elucidated in humans. The urinary excretion of irinotecan is 11% to 20%; SN-38, < 1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of irinotecan in two patients ranged from approximately 25% (100 mg/m²) to 50% (300 mg/m²).

Effect of Age

The pharmacokinetics of irinotecan administered using the weekly schedule was evaluated in a study of 183 patients that was prospectively designed to investigate the effect of age on irinotecan toxicity. Results from this trial indicate that there are no differences in the pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide in patients < 65 years of age compared with patients ≥ 65 years of age. In a study of 162 patients that was not prospectively designed to investigate the effect of age, small (less than 18%) but statistically significant differences in dose-normalized irinotecan pharmacokinetic parameters in patients < 65 years of age compared to patients ≥ 65 years of age were observed. Although dose-normalized AUC0-24 for SN-38 in patients ≥ 65 years of age was 11% higher than in patients < 65 years of age, this difference was not statistically significant. No change in the starting dose is recommended for geriatric patients receiving the weekly dosage schedule of irinotecan [see DOSAGE AND ADMINISTRATION].

Effect of Gender

The pharmacokinetics of irinotecan do not appear to be influenced by gender.

Effect of Race

The influence of race on the pharmacokinetics of irinotecan has not been evaluated.

Effect of 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. However, 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 Use in Specific Populations].

Effect of Renal Impairment

The influence of renal impairment on the pharmacokinetics of irinotecan has not been evaluated. Therefore, caution should be undertaken in patients with impaired renal function. Irinotecan is not recommended for use in patients on dialysis [see Use In Specific Populations].

Clinical Studies

Irinotecan has been studied in clinical trials in combination with 5-fluorouracil (5-FU) and leucovorin (LV) and as a single agent [see DOSAGE AND ADMINISTRATION]. When given as a component of combination-agent treatment, irinotecan was either given with a weekly schedule of bolus 5-FU/LV or with an every-2-week schedule of infusional 5-FU/LV. Weekly and once-every-3-week dosage schedules were used for the single-agent irinotecan studies. Clinical studies of combination and single-agent use are described below.

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 5FU 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/mm³, 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: Study Results

  Study 1 Study 2
Irinotecan + Bolus 5-FU/LV weekly x 4 every 6 weeks Bolus 5-FU/LV daily x 5 every 4 weeks Irinotecan weekly x 4 every 6 weeks rinotecan + 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 (%) 89 92 90 74 76
No 11 8 10 26 24
Yes
Median duration of study treatmenta (months) 5.5 4.1 3.9 5.6 4.5
Median Relative Dose Intensity (%)a 72 75 87
Irinotecan 5-FU 71 86 86 93
Efficacy Results
Confirmed objective tumor 39 21 18 35 22
response rateb (%) (p < 0.0001)c (p < 0.005)c
Median time to tumor progressiond (months) 7.0 4.3 4.2 6.7 4.4
(p=0.004)d (p < 0.001)d
Median survival (months) 14.8 12.6 12.0 17.4 14.1
(p < 0.05)d (p < 0.05)d
aStudy 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)
bConfirmed ≥ 4 to 6 weeks after first evidence of objective response
cChi-square test
dLog-rank test

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

Figure 1: Survival
First-Line Irinotecan/5-FU/LV vs 5-FU/LV
Study 1

First-Line Irinotecan/5-FU/LV vs 5-FU/LV - Illustration

Figure 2: Survival
First-Line Irinotecan/5-FU/LV vs 5-FU/LV
Study 2

First-Line Irinotecan/5-FU/LV vs 5-FU/LV - Illustration

Second-Line Therapy After 5-FU-Based Treatment

4 Weekly Doses on a 6-Week Cycle: Studies 3, 4, and 5

Data from three open-label, single-agent, clinical studies, involving a total of 304 patients in 59 centers, support the use of CAMPTOSAR in the treatment of patients with metastatic cancer of the colon or rectum that has recurred or progressed following treatment with 5-FU-based therapy. 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 100, 125, or 150 mg/m², but the 150-mg/m² 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. All 90 patients enrolled in Study 4 received a starting dose of 125 mg/m². Study 5 was a multicenter study that enrolled 166 patients from 30 institutions. The initial dose in Study 5 was 125 mg/m² but was reduced to 100 mg/m² because the toxicity seen at the 125-mg/m² 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 11.

Table 11: Weekly Dosage Schedule: Study Results

  Study
  3 4 5
Number of Patients 48 90 64 102
Starting Dose (mg/m²/week x 4) 125a 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 Intensityb (median %) 74 67 73 81
Efficacy
Confirmed Objective Response Rate (%)c (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
a Nine patients received 150 mg/m² as a starting dose; two (22.2%) responded to CAMPTOSAR.
bRelative dose intensity for CAMPTOSAR based on planned dose intensity of 100, 83.3, and 66.7 mg/m²/wk corresponding with 150, 125, and 100 mg/m² starting doses, respectively.
cConfirmed ≥ 4 to 6 weeks after first evidence of objective response.

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/m². Among these 193 patients, 2 complete and 27 partial responses were observed, for an overall response rate of 15.0% (95% Confidence Interval [CI], 10.0% to 20.1%) at this starting dose. A considerably lower response rate was seen with a starting dose of 100 mg/m². 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). The median response duration for patients beginning therapy at 125 mg/m² was 5.8 months (range, 2.6 to 15.1 months). 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. The response rate was 18.5% in patients with a performance status of 0 and 8.2% in patients with a performance status of 1 or 2. 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/m² 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 12.1% (95% CI, 7.0% to 18.1%).

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. In both studies, irinotecan was administered intravenously at a starting dose of 350 mg/m² over 90 minutes once every 3 weeks. The starting dose was 300 mg/m² for patients who were 70 years and older or who had a performance status of 2. The highest total dose permitted was 700 mg. Dose reductions and/or administration delays were permitted in the event of severe hematologic and/or nonhematologic toxicities while on treatment. 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. In both studies, concomitant medications such as antiemetics, atropine, and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. If late diarrhea persisted for greater than 24 hours despite loperamide, a 7-day course of fluoroquinolone antibiotic prophylaxis was given. Patients in the control arm of the Study 8 received one of the following 5-FU regimens: (1) LV, 200 mg/m² IV over 2 hours; followed by 5-FU, 400 mg/m² IV bolus; followed by 5-FU, 600 mg/m² continuous IV infusion over 22 hours on days 1 and 2 every 2 weeks; (2) 5-FU, 250 to 300 mg/m²/day protracted continuous IV infusion until toxicity; (3) 5FU, 2.6 to 3 g/m² IV over 24 hours every week for 6 weeks with or without LV, 20 to 500 mg/m²/day every week IV for 6 weeks with 2-week rest between cycles. 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. When comparing irinotecan with best supportive care in Study 7, this analysis showed a statistically significant advantage for irinotecan, with longer time to development of pain (6.9 months versus 2.0 months), time to performance status deterioration (5.7 months versus 3.3 months), and time to > 5% weight loss (6.4 months versus 4.2 months). Additionally, 33.3% (33/99) of patients with a baseline performance status of 1 or 2 showed an improvement in performance status when treated with irinotecan versus 11.3% (7/62) of patients receiving best supportive care (p=0.002). Because of the inclusion of patients with non-measurable disease, intent-to-treat response rates could not be assessed.

Figure 3: Survival
Second-Line Irinotecan vs Best Supportive Care (BSC)
Study 7

CAMPTOSAR (Irinotecan) Figure 3 Illustration

Figure 4: Survival
Second-Line Irinotecan vs Infusional 5-FU
Study 8

CAMPTOSAR (Irinotecan) Figure 4 Illustration

Table 12: Once-Every-3-Week Dosage Schedule: Study Results

  Study 7 Study 8
Irinotecan BSCa 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 (2575)
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 %)b 94 -- 95 81-99
rvival
  Survival (median, months) (Log-rank test) 9.2(p=0.0001) 6.5 10.8 (p=0.035) 8.5
aBSC = best supportive care
bRelative dose intensity for irinotecan based on planned dose intensity of 116.7 and 100 mg/m²/wk corresponding with 350 and 300 mg/m² starting doses, respectively.

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 Scorea

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
aFor 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.

REFERENCES

NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.

OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.

Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

Last reviewed on RxList: 8/9/2012
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

  • Patients and caregivers should be informed of gastrointestinal complications, such as nausea, vomiting, abdominal cramping, and diarrhea. Patients should have loperamide readily available to begin treatment for late diarrhea (generally occurring more than 24 hours after administration of CAMPTOSAR). 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. Patients should contact their physician if any of the following occur: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; or inability to get diarrhea under control within 24 hours.
  • Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of CAMPTOSAR.
  • Explain the significance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever or infection.
  • CAMPTOSAR may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug.
  • Patients should be alerted to the possibility of alopecia.
  • Contains sorbitol.

Last reviewed on RxList: 8/9/2012
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

  • Patients and caregivers should be informed of gastrointestinal complications, such as nausea, vomiting, abdominal cramping, and diarrhea. Patients should have loperamide readily available to begin treatment for late diarrhea (generally occurring more than 24 hours after administration of CAMPTOSAR). 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. Patients should contact their physician if any of the following occur: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; or inability to get diarrhea under control within 24 hours.
  • Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of CAMPTOSAR.
  • Explain the significance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever or infection.
  • CAMPTOSAR may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug.
  • Patients should be alerted to the possibility of alopecia.
  • Contains sorbitol.

Last reviewed on RxList: 8/9/2012
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Camptosar Injection Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

IRINOTECAN - INJECTION

(eye-ree-no-TEE-kan)

COMMON BRAND NAME(S): Camptosar

WARNING: You will be closely monitored (e.g., blood tests) by your doctor while using this medication. Keep all medical and laboratory appointments.

Irinotecan may cause severe diarrhea, which can occur during or right after you receive this medication and/or more than 24 hours afterward. If the diarrhea starts immediately, you may also have other side effects such as runny nose, increased saliva, watery eyes, sweating, stomach cramps, or flushing. If the diarrhea starts later, it could be a different type that may be persistent and can cause serious (possibly fatal) loss of too much body water (dehydration), mineral imbalance, or serious infection (sepsis). Tell your doctor immediately if you have diarrhea and/or any of the symptoms that occur with the early form of diarrhea. Also tell your doctor if you have stomach/abdominal pain, extreme thirst, very dry mouth, muscle cramps/weakness, fast/slow/irregular heartbeat, fainting, dizziness, lightheadedness, or signs of infection (e.g., fever, persistent sore throat). Your doctor should prescribe other medications to treat the diarrhea and other symptoms.

This medication may cause very serious (possibly fatal) blood disorders (decreased bone marrow function leading to low number of blood cells such as white cells, red cells, and platelets). This effect can decrease your body's ability to fight an infection, cause your body to bruise or bleed easier, or cause anemia. Tell your doctor immediately if you develop any of the following: signs of infection (fever, persistent sore throat), easy bruising/bleeding, unusual tiredness, fast/pounding heartbeat.

USES: This medication is used to treat cancer of the colon and rectum.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used to treat other types of cancer (such as lung, bone cancer).

HOW TO USE: This medication is given by injection into a vein as directed by your doctor. The dosage is based on your medical condition, body size, and response to treatment.

If you are giving this medication to yourself at home, learn all usage instructions from your health care professional. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Learn how to store and discard medical supplies safely.

If this medication comes into contact with your skin, wash the skin immediately and completely with soap and water. If this medication gets into your eyes, mouth, or nose, flush completely with plenty of water. Consult your doctor for more details.

Disclaimer

Camptosar Injection Consumer (continued)

SIDE EFFECTS: See also Warning section.

Nausea, vomiting, loss of appetite, constipation, cough, drowsiness, mouth sores, weakness, or trouble sleeping may occur. Nausea and vomiting can be severe. In some cases, your doctor may prescribe medication to prevent or relieve nausea and vomiting. Eating several small meals, not eating before treatment, or limiting activity may help lessen some of these effects. If these effects persist or worsen, or if you are unable to drink/eat because of nausea/vomiting, tell your doctor or pharmacist promptly.

Temporary hair loss may occur. Normal hair growth should return after treatment has ended.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: pain/redness/swelling at the injection site or arms/legs, numbness/tingling/burning of arms/legs, black/bloody stools, change in the amount of urine, lung problems (such as shortness of breath, cough).

Get medical help right away if any of these unlikely but serious side effects occur: chest pain, weakness on one side of the body, slurred speech, confusion, trouble breathing.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

Irinotecan can commonly cause a mild rash that is usually not serious. However, you may not be able to tell it apart from a rare rash that could be a sign of a severe allergic reaction. Therefore, seek immediate medical attention if you develop any rash.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Camptosar Injection (irinotecan hydrochloride) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before using irinotecan, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: bowel blockage (e.g., paralytic ileus), certain genetic metabolism disorder (fructose intolerance).

Before using this drug, tell your doctor your medical history, including: radiation treatments, blood/bone marrow disorders (e.g., low platelet/neutrophil/red blood cell levels), diabetes, liver disease, kidney disease, lung disease.

Before having surgery, tell your doctor or dentist that you are using this medication.

This drug may make you dizzy or drowsy or cause blurred vision. Do not drive, use machinery, or do any activity that requires alertness or clear vision until you are sure you can perform such activities safely. Limit alcoholic beverages.

To avoid dizziness and lightheadedness when rising from a sitting or lying position, get up slowly.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose.

To lower your risk of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

Wash your hands well to prevent the spread of infections.

Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug, especially diarrhea.

This medication is not recommended for use during pregnancy. It may harm an unborn baby. Therefore, it is important to prevent pregnancy while using this medication. Consult your doctor for more details and to discuss using at least 2 reliable forms of birth control (e.g., condoms, birth control pills) while using this medication. If you become pregnant or think you may be pregnant, tell your doctor immediately.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

Disclaimer

Camptosar Injection Consumer (continued)

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: atazanavir, drugs affecting liver enzymes that remove irinotecan from your body (such as rifamycins including rifabutin, certain anti-seizure medicines including carbamazepine/phenytoin/phenobarbital), laxatives, "water pills"/diuretics (e.g., furosemide).

Avoid taking St. John's wort within 2 weeks before or during treatment with this medication, and avoid taking ketoconazole within 1 week before or during treatment with this medication.

Avoid eating foods or taking products containing tumeric (curcumin) while being treated with irinotecan. It may decrease this medication's effects. Consult your doctor or pharmacist for more details.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: signs of infection (e.g., persistent sore throat, fever), severe diarrhea.

NOTES: Laboratory and/or medical tests (e.g., complete blood count, hemoglobin, platelets) should be performed regularly to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Consult the product instructions and your pharmacist for storage details. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised May 2012. Copyright(c) 2012 First Databank, Inc.

Camptosar Injection Patient Information Including Side Effects

Brand Names: Camptosar

Generic Name: irinotecan (Pronunciation: EYE ri noe TEE kan)

What is irinotecan (Camptosar Injection)?

Irinotecan is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Irinotecan is used to treat cancers of the colon and rectum. It is usually given with other cancer medicines in a combination chemotherapy.

Irinotecan may also be used for purposes not listed in this medication guide.

What are the possible side effects of irinotecan (Camptosar Injection)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • wheezing, feeling short of breath;
  • chest pain, dry cough;
  • pale skin, feeling light-headed, rapid heart rate, trouble concentrating;
  • fever, chills, body aches, flu symptoms, sores in your mouth and throat;
  • runny nose, watery eyes, increased sweating, stomach cramps, and flushing (warmth, redness, or tingly feeling);
  • black, bloody, or tarry stools;
  • nausea or vomiting that keeps you from drinking enough fluids;
  • burning, pain, or swelling around the IV needle;
  • sudden numbness or weakness, problems with vision, speech, or balance;
  • swelling, rapid weight gain; or
  • feeling very thirsty or hot, being unable to urinate, heavy sweating, feeling light-headed, or hot and dry skin.

Less serious side effects may include:

  • dizziness;
  • temporary hair loss.
  • loss of appetite, constipation;
  • mild skin rash; or
  • redness or peeling of the skin on your hands and feet.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Camptosar Injection (irinotecan hydrochloride) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about irinotecan (Camptosar Injection)?

Irinotecan can cause severe diarrhea, which can be life-threatening if it leads to dehydration. Diarrhea can occur soon after your injection or more than 24 hours later.

Your doctor may recommend you have an anti-diarrhea medicine such as loperamide (Imodium) available at all times while you are receiving irinotecan. Take the anti-diarrhea medication at the first sign of loose or frequent bowel movements.

Call your doctor if you still have diarrhea after 24 hours of taking anti-diarrhea medicine.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while using irinotecan, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you.

Side Effects Centers

Camptosar Injection Patient Information including How Should I Take

What should I discuss with my healthcare provider before receiving irinotecan (Camptosar Injection)?

You should not use irinotecan if you are allergic to it.

To make sure you can safely receive irinotecan, tell your doctor if you have any of these other conditions:

  • liver or kidney disease;
  • diabetes;
  • asthma, chronic obstructive pulmonary disease (COPD), sleep apnea, or other breathing disorder;
  • an intestinal disorder or obstruction;
  • Gilbert's syndrome;
  • fructose intolerance (irinotecan contains sorbitol); or
  • if you are receiving radiation treatment to your abdomen or pelvic area.

FDA pregnancy category D. Do not use irinotecan if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether irinotecan passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using irinotecan.

How is irinotecan given (Camptosar Injection)?

Your doctor may recommend a DNA test before your first dose of irinotecan. Some people are genetically more likely to have certain side effects from irinotecan.

Irinotecan is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. Irinotecan must be given slowly, and the IV infusion can take up to 90 minutes to complete.

You may be given other medications to prevent nausea, vomiting, diarrhea, and other side effects while you are receiving irinotecan. You may need to keep using these medications for at least a day after your irinotecan injection.

Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when irinotecan is injected.

If any of the medicine gets on your skin, wash right away with soap and water.

Irinotecan can cause severe diarrhea, which can occur soon after your injection or more than 24 hours later. You can easily become dehydrated if you have ongoing diarrhea. You may also develop a severe infection or a serious electrolyte imbalance.

Your doctor may recommend you have an anti-diarrhea medicine such as loperamide (Imodium) available at all times while you are receiving irinotecan. Take the anti-diarrhea medication at the first sign of loose or frequent bowel movements.

Call your doctor if you still have diarrhea after 24 hours of taking anti-diarrhea medicine. Do not take loperamide for longer than 2 full days without your doctor's advice.

To be sure this medication is not causing harmful effects, your blood may need to be tested often. Your kidney or liver function may also need to be tested. Visit your doctor regularly.

If you need surgery, tell the surgeon ahead of time that you are using irinotecan.

Side Effects Centers

Camptosar Injection Patient Information including If I Miss a Dose

What happens if I miss a dose (Camptosar Injection)?

Call your doctor for instructions if you miss an appointment for your irinotecan injection.

What happens if I overdose (Camptosar Injection)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include some of the serious side effects listed in this medication guide.

What should I avoid while using irinotecan (Camptosar Injection)?

Avoid using a laxative or stool softener during treatment with irinotecan.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while using irinotecan, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you. Live vaccines include measles, mumps, rubella (MMR), oral polio, typhoid, chickenpox (varicella), BCG (Bacillus Calmette and Guérin), and nasal flu vaccine.

Irinotecan may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

What other drugs will affect irinotecan (Camptosar Injection)?

Before you are treated with irinotecan, tell your doctor about all other cancer medicines you have recently used.

Tell your doctor about all other medicines you use, especially:

  • atazanavir (Reyataz);
  • a diuretic (water pill);
  • ketoconazole (Extina, Ketozole, Nizoral, Xolegal);
  • rifabutin (Mycobutin);
  • rifampin (Rifadin, Rifater, Rifamate, Rimactane);
  • St. John's wort; or
  • seizure medicine such as carbamazepine (Carbatrol, Tegretol), phenobarbital (Solfoton), or phenytoin (Dilantin).

This list is not complete and other drugs may interact with irinotecan. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your doctor or pharmacist can provide more information about irinotecan.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 3.02. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

Healthwise

Side Effects Centers

توزیع کنندگان این دارو
شرکت های تولید کننده یا وارد کننده دارو

دارونـــما
نوآوری برای سلامت

طراحی و اجرا M.Ramezani
ارتباط با ما Info@darunama.com