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| {{DrugProjectFormSinglePage | | {{Details0|Irinotecan hydrochloride (Camptosar)}} |
| |authorTag={{AP}}
| | {{Details0|Irinotecan hydrochloride (Onivyde)}} |
| |genericName=Irinotecan hydrochloride
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| |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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| |warnings=====Diarrhea and Cholinergic Reactions====
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| *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.
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| *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 CAMPTOSAR until resolution of the bowel obstruction. If grade 2, 3, or 4 late [[diarrhea]] recurs, subsequent doses of CAMPTOSAR should be decreased.
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| *Avoid diuretics or laxatives in patients with diarrhea.
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| ====Myelosuppression====
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| *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 [see WARNINGS AND PRECAUTIONS (5.2)]. 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 (2)].
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| 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.
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| 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.
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| 5.3 Patients With Reduced UGT1A1 Activity
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| Individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of CAMPTOSAR treatment.
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| In a study of 66 patients who received single-agent CAMPTOSAR (350 mg/m2 once-every-3-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).
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| 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.
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| 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.
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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 DOSAGE AND ADMINISTRATION (2)].
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| UGT1A1 Testing
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| 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.
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| 5.4 Hypersensitivity
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| Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue CAMPTOSAR if anaphylactic reaction occurs.
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| 5.5 Renal Impairment/Renal Failure
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| Renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhea.
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| 5.6 Pulmonary Toxicity
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| Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred in patients receiving irinotecan (in combination and as monotherapy). Risk factors include pre-existing lung disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during CAMPTOSAR therapy. In Japanese studies, a reticulonodular pattern on chest x-ray was observed in a small percentage of patients. New or progressive, dyspnea, cough, and fever should prompt interruption of chemotherapy, pending diagnostic evaluation. If IPD is diagnosed, CAMPTOSAR and other chemotherapy should be discontinued and appropriate treatment instituted as needed [see ADVERSE REACTIONS (6.1)].
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| 5.7 Toxicity of the 5 Day Regimen
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| 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 (2)].
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| 5.8 Increased Toxicity in Patients with Performance Status 2
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| 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.
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| 5.9 Embryofetal Toxicity
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| 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.
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| 5.10 Patients with Hepatic Impairment
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| 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%
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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|
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| |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 | |
| |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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