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| {{DrugProjectFormSinglePage | | {{Details0|Irinotecan hydrochloride (Camptosar)}} |
| |authorTag={{AP}}
| | {{Details0|Irinotecan hydrochloride (Onivyde)}} |
| |genericName=Irinotecan hydrochloride | |
| |aOrAn=an
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| |drugClass=[[antineoplastic agent]] and [[topoisomerase I inhibitor]]
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| |indicationType=treatment
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| |indication=metastatic [[colon carcinoma]] and [[rectum carcinoma]]
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| |hasBlackBoxWarning=Yes
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| |blackBoxWarningTitle=<b><span style="color:#FF0000;">WARNING: DIARRHEA AND MYELOSUPPRESSION</span></b>
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| |blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i>
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| *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.
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| *Severe myelosuppression may occur.
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| |fdaLIADAdult====Colorectal Cancer Combination Regimens 1 and 2===
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| *Administer CAMPTOSAR as a 90-minute intravenous infusion followed by LV and [[5-FU]]. The currently recommended regimens are shown in Table 1.
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| *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.
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| [[file:Irinotecan Dosage1.png|none|300px]]
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| Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients.
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| ====Dose Modification====
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| *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.
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| [[file:Irinotecan DOsage2.png|none|300px]]
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| ===Colorectal Single Agent Regimens 1 and 2===
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| *Administer CAMPTOSAR as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 3.
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| *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.
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| [[file:Irinotecan Dosage3.png|none|300px]]
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| ====Dose Modifications====
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| *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.
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| [[file:Irinotecan Dosage4.png|none|300px]]
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| ===Dosage in Patients with Reduced UGT1A1 Activity===
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| *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 Tables 1–4).
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| ===Premedication===
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| *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.
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| *Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms.
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| ===Preparation of Infusion Solution===
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| *Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe.
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| *CAMPTOSAR Injection 20 mg/mL is intended for single use only and any unused portion should be discarded.
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| *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.
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| *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.
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| *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).
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| ===Safe Handling===
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| *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.
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| ===Extravasation===
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| *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.
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| |offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Irinotecan in adult patients.
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| |offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Irinotecan in adult patients.
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| |offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Irinotecan in pediatric patients.
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| |offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Irinotecan in pediatric patients.
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| |contraindications=*CAMPTOSAR Injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.
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| |alcohol=Alcohol-Irinotecan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
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| }} | |
| {{Drugbox| | |
| |IUPAC_name = (''S'')-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-<br>3,14-dioxo1''H''-pyrano[3’,4’:6,7]-indolizino[1,2-b]quinolin-<br>9-yl-[1,4’bipiperidine]-1’-carboxylate
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| | image = irinotecan.svg
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| | width = 240px
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| | CAS_number=100286-90-6
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| | ATC_prefix=L01
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| | ATC_suffix=XX19
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| | PubChem=3750
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| | DrugBank=APRD00579
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| | C = 33 |H = 38 |N = 4 |O = 6
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| | molecular_weight = 586.678 [[Gram|g]]/[[Mole (unit)|mol]]<br>677.185 g/mol ([[hydrochloride]])
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| | bioavailability= NA
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| | metabolism = [[Liver|Hepatic]] [[glucuronidation]]
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| | elimination_half-life= 6 to 12 [[hour]]s
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| | excretion = Biliary and [[Kidney|renal]]
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| | pregnancy_category = D <small>([[Australia|Au]], [[United States|U.S.]])</small>
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| | legal_status = [[Prescription drug|POM]] <small>([[United Kingdom|UK]])</small>, ℞-only <small>(U.S.)</small>
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| | routes_of_administration= [[Intravenous therapy|Intravenous]]
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| }}
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| {{SI}}
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| ==Overview==
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| '''Irinotecan''' is a chemotherapy agent that is a [[Type I topoisomerase|topoisomerase 1]] [[Enzyme inhibitor|inhibitor]]. Chemically, it is a semisynthetic analogue of the natural alkaloid [[camptothecin]].
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| 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.
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| Irinotecan was first introduced in Japan by the Pharmaceutical arm of [[Yakult|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.
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| ==Mechanism==
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| Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by [[glucuronidation]] by [[UGT1A1|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.
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| ==Side effects==
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| The most significant adverse effects of irinotecan are severe diarrhea and extreme suppression of the immune systems.
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| ===Diarrhea===
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| 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.
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| ===Immunosuppression===
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| The immune system is adversely impacted by irinotecan. This is reflected in dramatically lowered [[white blood cell]] counts in the blood, in particular the [[neutrophil|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.
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| ==Pharmacogenomics==
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| 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 TA<sub>7</sub>, 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 <ref> Journal of Clinical Oncology, Vol 22, No 8 April 15, 2004: pp. 1382-1388</ref>.
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| 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
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| <ref name="Innocenti2004">{{
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| cite journal
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| |url=http://www.jco.org/cgi/content/abstract/22/8/1382
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| |author=Innocenti F et al
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| |journal=[[Journal of Clinical Oncology]]
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| |title=Genetic Variants in the UDP-glucuronosyltransferase 1A1 Gene Predict the Risk of Severe Neutropenia of Irinotecan
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| |year = 2004
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| |month = Apr
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| |volume = 22
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| |issue = 8
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| |pages = 1382-88
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| |id = PMID 15007088
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| }}</ref>.
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| 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<ref name="ODwyer2006">{{
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| cite journal
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| |url=http://www.jco.org/cgi/content/full/24/28/4534
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| |author=O'Dwyer PJ, Catalano RP
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| |journal=[[Journal of Clinical Oncology]]
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| |title=Uridine Diphosphate Glucuronosyltransferase (UGT) 1A1 and Irinotecan: Practical Pharmacogenomics Arrives in Cancer Therapy
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| |year = 2006
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| |month = Oct
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| |volume = 24
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| |issue = 28
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| |pages = 4534-38
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| |id = PMID 17008691
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| }}</ref>.
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| ==See also==
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| *[[Camptothecin]]
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| *[[Topotecan]] (Hycamtin®)
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| *[[Pharmacogenomics]]
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| == References ==
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| <references/>
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| ==External links==
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| *[http://camptosar.com/products/camptosar.aspx Pfizer website]
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| *[http://www.pharmgkb.org/do/serve?objId=PA2001&objCls=Pathway Irinotecan Pathway on PharmGKB]
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| {{Chemotherapeutic agents}}
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| [[Category:Cancer treatments]]
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| [[Category:Chemotherapeutic agents]]
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| [[Category:Prodrugs]]
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| [[de:Irinotecan]]
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| [[ja:イリノテカン]]
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| [[zh:愛萊諾迪肯]]
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| [[ru:Иринотекан]]
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| [[fi:Irinotekaani]]
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| {{WH}}
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| {{WikiDoc Sources}}
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