Irinotecan

Also from Answers.com... Men's Health Important facts for men to live a healthy life.

Key Terms: Alkaloid, Anorexia, Apoptosis, Diuretic, Inflammation.

Definition

Irinotecan is a drug used to treat certain types of cancer. Irinotecan, also known as CPT-11, is available under the trade name Camptosar, and may also be referred to as irinotecan hydrochloride or camptothecin-11.

Purpose

Irinotecan is an antineoplastic agent used to treat cancer. A primary use of the drug is treatment of colon or rectal cancers that have recurred or progressed while the patient was on 5-FU (fluorouracil) therapy. Irinotecan also can be given as first line therapy with 5-FU and leucovorin for patients with metastatic colon or rectal cancer. Other uses for irinotecan include treatment of small cell lung cancer, nonsmall cell lung cancer, ovarian cancer, stomach cancer, breast cancer, pancreatic cancer, leukemia, lymphoma, and cervical cancer.

Several 2003 studies showed some potential new uses for irinotecan. One reported that a combination of irinotecan and docetaxel can help patients with esophageal cancer who have been extensively pretreated with cisplatin. Weekly use of irinotecan has shown preliminary results in treating patients with nonsmall cell lung cancer with minimal side effects. Another 2003 study reported that when used in combination with cancer drugs cisplatin and epirubicin, irinotecan might have promising broad antitumor activity. In the future, irinotecan might be used in combination therapies to treat many types of tumors.

Description

Irinotecan is a synthetic derivative of the naturally occurring compound camptothecin. Camptothecin belongs to a group of chemicals called alkaloids and is extracted from plants such as camptotheca acuminata. Captothecin was initially investigated as a chemotherapeutic agent due to its anticancer activity in laboratory studies. The chemical structure and biological action of irinotecan is similar to that of camptothecin and topotecan.

Irinotecan inhibits the normal functioning of the enzyme topoisomerase I. The normal role of topoisomerase I is to aid in the replication, recombination, and repair of deoxyribonucleic acid (DNA). Higher levels of topoisomerase I have been found in certain cancer tumors compared to healthy tissue. Inhibiting topoisomerase I causes DNA damage. This damage leads to apoptosis, or programmed cell death.

Recommended Dosage

Patients should be carefully monitored during irinotecan treatment for toxicity. Irinotecan is given at a dose of 125 mg per square meter of body surface area per week for four weeks, followed by a two week rest period. Other dosing schedules include 100 mg per square meter of body surface area per day for three days every three weeks, or 100-115 mg per square meter of body surface area per week, or 200-350 mg per square meter of body surface area every 3 weeks. The drug is administered through the vein over a 90-minute period. The initial dose of irinotecan may be adjusted downward depending on patient tolerance to the toxic side effects of irinotecan.

Treatment may be continued as long as intolerable side effects do not develop and patients continue to benefit from the treatment.

Precautions

Irinotecan should only be used under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Special caution, especially in those 65 years and older, should be taken to monitor the toxic effects of irinotecan, particularly diarrhea, nausea, and vomiting. Because irinotecan is administered intravenously, the site of infusion should be monitored for signs of inflammation. Should inflammation occur, flushing the site with sterile water and applying ice are recommended. Irinotecan may cause nausea and vomiting, and premedication with antiemetic agents is recommended.

Neither the effects of irinotecan in patients with significant liver dysfunction nor the safety of irinotecan in children have been established. Irinotecan should not be administered to pregnant women. Women of child-bearing age are advised not to become pregnant during treatment with this drug.

Side Effects

Early- or late-onset diarrhea are common side effects of irinotecan. Late-onset diarrhea, occurring more than 24 hours after irinotecan administration, can be life-threatening and should be treated promptly. Patients should immediately report diarrhea to their physician. Patients can also take the antidiarrheal drug loperamide as prescribed by their physician at the first sign of diarrhea. Suppression of bone marrow function is another serious side effect commonly observed in this treatment. Additional side effects, including nausea, vomiting, anorexia (loss of appetite), pain, fatigue, and hair loss (alopecia) may occur.

Interactions

Irradiation treatment during the course of irinotecan treatment is not recommended. Patients who have received prior pelvic or abdominal irradiation treatment should notify their physician. Since irinotecan may cause diarrhea, the use of laxatives should be avoided. The use of diuretics should be closely monitored. The adverse side effects caused by irinotecan may be increased by other antineoplastic agents having similar adverse effects and should generally be avoided.

Resources

Periodicals

"Cisplatin, Irinotecan, and Epirubicin Have Promising Broad Antitumor Activity." Cancer Weekly October 14, 2003:12.

"Irinotecan and Docetaxel Shows Some Activity in Extensively Pretreated Patients." Clinical Trials Week October 13, 2003: 25.

"Weekly Irinotecan Showed Antitumoral Activity and Minimum Toxicity in NSCCLC." Clinical Trials Week October 13, 2003: 25.

—Marc Scanio; Teresa G. Odle

Brand names: Camptosar®

Chemical formula:

Español:
• Clorhidrato de irinotecan, Solución para inyección

Irinotecan Hydrochloride Solution for injection

What is this medicine?

IRINOTECAN is a chemotherapy drug. It is used to treat colon and rectal cancer.

This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
• blood disorders
• dehydration
• diarrhea
• infection (especially a virus infection such as chickenpox, cold sores, or herpes)
• liver disease
• low blood counts, like low white cell, platelet, or red cell counts
• recent or ongoing radiation therapy
• an unusual or allergic reaction to irinotecan, sorbitol, other chemotherapy, other medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should I use this medicine?

This drug is given as an infusion into a vein. It is administered in a hospital or clinic by a specially trained health care professional.

Talk to your pediatrician regarding the use of this medicine in children. Special care may be needed.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.

What may interact with this medicine?

Do not take this medicine with any of the following medications:
• ketoconazole
• St. John's Wort

This medicine may also interact with the following medications:
• dexamethasone
• diuretics
• laxatives
• medicines for seizures like carbamazepine, mephobarbital, phenobarbital, phenytoin, primidone
• medicines to increase blood counts like filgrastim, pegfilgrastim, sargramostim
• prochlorperazine
• vaccines

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medicine?

Your condition will be monitored carefully while you are receiving this medicine. You will need important blood work done while you are taking this medicine.

This drug may make you feel generally unwell. This is not uncommon, as chemotherapy can affect healthy cells as well as cancer cells. Report any side effects. Continue your course of treatment even though you feel ill unless your doctor tells you to stop.

In some cases, you may be given additional medicines to help with side effects. Follow all directions for their use.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how this medicine affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells.

Call your doctor or health care professional for advice if you get a fever, chills or sore throat, or other symptoms of a cold or flu. Do not treat yourself. This drug decreases your body's ability to fight infections. Try to avoid being around people who are sick.

This medicine may increase your risk to bruise or bleed. Call your doctor or health care professional if you notice any unusual bleeding.

Be careful brushing and flossing your teeth or using a toothpick because you may get an infection or bleed more easily. If you have any dental work done, tell your dentist you are receiving this medicine.

Avoid taking products that contain aspirin, acetaminophen, ibuprofen, naproxen, or ketoprofen unless instructed by your doctor. These medicines may hide a fever.

Do not become pregnant while taking this medicine. Women should inform their doctor if they wish to become pregnant or think they might be pregnant. There is a potential for serious side effects to an unborn child. Talk to your health care professional or pharmacist for more information. Do not breast-feed an infant while taking this medicine.

What side effects may I notice from receiving this medicine?

Side effects that you should report to your doctor or health care professional as soon as possible:
• allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
• low blood counts - this medicine may decrease the number of white blood cells, red blood cells and platelets. You may be at increased risk for infections and bleeding.
• signs of infection - fever or chills, cough, sore throat, pain or difficulty passing urine
• signs of decreased platelets or bleeding - bruising, pinpoint red spots on the skin, black, tarry stools, blood in the urine
• signs of decreased red blood cells - unusually weak or tired, fainting spells, lightheadedness
• breathing problems
• chest pain
• diarrhea
• feeling faint or lightheaded, falls
• flushing, runny nose, sweating during infusion
• mouth sores or pain
• pain, swelling, redness or irritation where injected
• pain, swelling, warmth in the leg
• pain, tingling, numbness in the hands or feet
• problems with balance, talking, walking
• stomach cramps, pain
• trouble passing urine or change in the amount of urine
• vomiting as to be unable to hold down drinks or food
• yellowing of the eyes or skin

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
• constipation
• hair loss
• headache
• loss of appetite
• nausea, vomiting
• stomach upset

This list may not describe all possible side effects.

Where should I keep my medicine?

This drug is given in a hospital or clinic and will not be stored at home.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

Irinotecan
Systematic (IUPAC) name
(S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy- 3,14-dioxo1H-pyrano[3’,4’:6,7]-indolizino[1,2-b]quinolin- 9-yl-[1,4’bipiperidine]-1’-carboxylate
Identifiers
CAS number	100286-90-6
ATC code	L01XX19
PubChem	3750
DrugBank	APRD00579
Chemical data
Formula	C33H38N4O6
Mol. mass	586.678 g/mol 677.185 g/mol (hydrochloride)
Pharmacokinetic data
Bioavailability	NA
Metabolism	Hepatic glucuronidation
Half life	6 to 12 hours
Excretion	Biliary and renal
Therapeutic considerations
Pregnancy cat.	D (Au, U.S.)
Legal status	POM (UK), ℞-only (U.S.)
Routes	Intravenous

Irinotecan is a chemotherapy agent that is a topoisomerase 1 inhibitor. Chemically, it is a semisynthetic analogue of the natural alkaloid camptothecin.

Its main use is in colon cancer, particularly in combination with other chemotherapy agents. This includes the regimen FOLFIRI which consists of infusional 5-fluorouracil, leucovorin, and irinotecan.

Irinotecan was first introduced in Japan by the Pharmaceutical arm of Yakult Honsha as Campto®. In 1994, it received accelerated FDA approval in the United States, where it is now marketed by Pfizer as Camptosar®. It is also known as CPT-11.

Mechanism

Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.

Side effects

The most significant adverse effects of irinotecan are severe diarrhea and extreme suppression of the immune systems.

Diarrhea

Irinotecan-associated diarrhea is severe and clinically significant, sometimes leading severe dehydration requiring hospitalization or intensive care unit admission. This side effect is managed with the aggressive use of antidiarrheals such as loperamide or Lomotil with the first loose bowel movement.

Immunosuppression

The immune system is adversely impacted by irinotecan. This is reflected in dramatically lowered white blood cell counts in the blood, in particular the neutrophils. While the bone marrow, where neutrophils are made, cranks up production to compensate, the patient may experience a period of neutropenia, that is, a clinical lack of neutrophils in the blood.

Pharmacogenomics

Irinotecan is converted by an enzyme into its active metabolite SN-38, which is in turn inactivated by the enzyme UGT1A1. People with variants of the UGT1A1 called TA₇, also known as the *28 variant, express fewer UGT1A1 enzymes in their liver. During chemotherapy, these patients effectively receive a larger than expected dose because their bodies are not able to clear irinotecan as fast as others. In studies this corresponds to higher incidences of severe diarrhea and neutropenia ^[1].

In 2004, a clinical study was performed that both validated prospectively the association of the *28 variant with greater toxicity and the ability of genetic testing in predicting that toxicity before chemotherapy administration ^[2].

In 2005, the FDA made changes to the labelling of irinotecan to add pharmacogenomics recommendations that patients with polymorphisms in UGT1A1 gene, specifically the *28 variant, should perhaps receive reduced drug doses. Irinotecan is one of the first widely-used chemotherapy agents that is dosed for each patient according to his genotype^[3].

See also

• Camptothecin
• Topotecan (Hycamtin®)
• Pharmacogenomics

References

1. ^ Journal of Clinical Oncology, Vol 22, No 8 April 15, 2004: pp. 1382-1388
2. ^ Innocenti F et al (Apr 2004). "Genetic Variants in the UDP-glucuronosyltransferase 1A1 Gene Predict the Risk of Severe Neutropenia of Irinotecan". Journal of Clinical Oncology 22 (8): 1382-88. PMID 15007088. 
3. ^ O'Dwyer PJ, Catalano RP (Oct 2006). "Uridine Diphosphate Glucuronosyltransferase (UGT) 1A1 and Irinotecan: Practical Pharmacogenomics Arrives in Cancer Therapy". Journal of Clinical Oncology 24 (28): 4534-38. PMID 17008691. 

External links

• Pfizer website
• Irinotecan Pathway on PharmGKB

Chemotherapeutic agents/Antineoplastic agents (L01)
Alkylating agents	Nitrogen mustards: (Chlorambucil, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan). Nitrosoureas:(Carmustine, Fotemustine, Lomustine, Streptozocin). Platinum: (Carboplatin, Cisplatin, Oxaliplatin, BBR3464). Busulfan, Dacarbazine, Procarbazine, Temozolomide, ThioTEPA, Uramustine
Antimetabolites	Folic acid: (Aminopterin, Methotrexate, Pemetrexed, Raltitrexed). Purine:(Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Pentostatin, Thioguanine). Pyrimidine:(Capecitabine, Cytarabine, Fluorouracil, Floxuridine, Gemcitabine)
Spindle poison/mitotic inhibitor	Taxane: (Docetaxel, Paclitaxel). Vinca: (Vinblastine, Vincristine, Vindesine, Vinorelbine).
Cytotoxic/antitumor antibiotics	Anthracycline family: (Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Valrubicin) - streptomyces (Actinomycin, Bleomycin, Mitomycin, Plicamycin) - Hydroxyurea
Topoisomerase inhibitors	Camptotheca: (Camptothecin, Topotecan, Irinotecan), Podophyllum:(Etoposide, Teniposide)
CI monoclonal antibodies	Alemtuzumab, Bevacizumab, Cetuximab, Gemtuzumab, Panitumumab, Rituximab, Tositumomab, Trastuzumab
Photosensitizers	Aminolevulinic acid, Methyl aminolevulinate, Porfimer sodium, Verteporfin
Tyrosine kinase inhibitors	Dasatinib, Erlotinib, Gefitinib, Imatinib, Lapatinib, Nilotinib, Sorafenib, Sunitinib
Other	retinoids (Alitretinoin, Tretinoin) - Altretamine, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase (Pegaspargase), Bexarotene, Bortezomib, Denileukin diftitox, Estramustine, Masoprocol, Mitotane

This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)