|
|
| (One intermediate revision by one other user not shown) |
| Line 1: |
Line 1: |
| {{DrugProjectFormSinglePage | | {{Details0|Irinotecan hydrochloride (Camptosar)}} |
| |authorTag={{AP}}
| | {{Details0|Irinotecan hydrochloride (Onivyde)}} |
| |genericName=Irinotecan hydrochloride | |
| |aOrAn=an
| |
| |drugClass=[[antineoplastic agent]] and [[topoisomerase I inhibitor]]
| |
| |indicationType=treatment
| |
| |indication=metastatic [[colon carcinoma]] and [[rectum carcinoma]]
| |
| |hasBlackBoxWarning=Yes
| |
| |adverseReactions=[[nausea]], [[vomiting]], [[abdominal pain]], [[diarrhea]], [[constipation]], [[anorexia]], [[mucositis]], [[neutropenia]], [[leukopenia]] (including [[lymphocytopenia]]), [[anemia]], [[thrombocytopenia]], [[asthenia]], [[pain]], [[fever]], [[infection]], [[abnormal bilirubin]], [[alopecia]]
| |
| |blackBoxWarningTitle=<b><span style="color:#FF0000;">WARNING: DIARRHEA AND MYELOSUPPRESSION</span></b>
| |
| |blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i>
| |
| *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.
| |
| |fdaLIADAdult====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.
| |
| | |
| [[file:Irinotecan Dosage1.png|none|300px]]
| |
| | |
| Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients.
| |
| | |
| ====Dose Modification====
| |
| *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.
| |
| | |
| [[file:Irinotecan DOsage2.png|none|300px]]
| |
| | |
| ===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.
| |
| | |
| [[file:Irinotecan Dosage3.png|none|300px]]
| |
| | |
| ====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.
| |
| | |
| [[file:Irinotecan Dosage4.png|none|300px]]
| |
| | |
| ===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. 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.
| |
| |offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Irinotecan in adult patients.
| |
| |offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Irinotecan in adult patients.
| |
| |offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Irinotecan in pediatric patients.
| |
| |offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Irinotecan in pediatric patients.
| |
| |contraindications=*CAMPTOSAR Injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.
| |
| |warnings=====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 CAMPTOSAR until resolution of the bowel obstruction. If grade 2, 3, or 4 late [[diarrhea]] recurs, subsequent doses of CAMPTOSAR should be decreased.
| |
| *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.
| |
| *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-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).
| |
| *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.
| |
| **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 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.
| |
| | |
| ====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.
| |
| | |
| ====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.
| |
| | |
| ====Embryofetal Toxicity====
| |
| *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%
| |
| |clinicalTrials=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.
| |
| *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 [[5-FU]]/LV, 14 (6.4%) patients who received [[5-FU]]/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 [[5-FU]]/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.
| |
| <br>
| |
| [[file:Irinotecan AR1.png|none|400px]]
| |
| <br>
| |
| =====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]].
| |
| *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.
| |
| <br>
| |
| [[file:Irinotecan AR2.png|none|400px]]
| |
| <br>
| |
| =====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%).
| |
| <br>
| |
| [[file:Irinotecan AR4.png|none|400px]]
| |
| <br>
| |
| 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=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 CAMPTOSAR 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 CAMPTOSAR 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.
| |
| |drugInteractions=====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 [[5-FU]] and LV administration compared with when irinotecan was given alone, this sequence of administration was used in the combination trials and is recommended. 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 CYP3A4 Inducers====
| |
| *Exposure to irinotecan or its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants [[phenytoin]], [[phenobarbital]], [[carbamazepine]], or [[St. John's wort]]. The appropriate starting dose for patients taking these or other strong inducers such as [[rifampin]] and [[rifabutin]] has not been defined. Consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of CAMPTOSAR therapy. Do not administer strong [[CYP3A4]] inducers with CAMPTOSAR unless there are no therapeutic alternatives.
| |
| | |
| ====Strong CYP3A4 or UGT1A1 Inhibitors====
| |
| *Irinotecan and its active metabolite, SN-38, are metabolized via the human cytochrome P450 3A4 isoenzyme ([[CYP3A4]]) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), respectively.
| |
| *Patients receiving concomitant [[ketoconazole]], a [[CYP3A4]] and [[UGT1A1]] [[inhibitor]], have increased exposure to irinotecan and its active metabolite SN-38. Coadministration of CAMPTOSAR with other inhibitors of [[CYP3A4]] (e.g., [[clarithromycin]], [[indinavir]], [[itraconazole]], [[lopinavir]], [[nefazodone]], [[nelfinavir]], [[ritonavir]], [[saquinavir]], [[telaprevir]], [[voriconazole]]) or [[UGT1A1]] (e.g., [[atazanavir]], [[gemfibrozil]], [[indinavir]]) may increase systemic exposure to irinotecan or SN-38. Discontinue strong [[CYP3A4]] inhibitors at least 1 week prior to starting CAMPTOSAR therapy. Do not administer strong [[CYP3A4]] or UGT1A1 inhibitors with CAMPTOSAR unless there are no therapeutic alternatives.
| |
| |FDAPregCat=D
| |
| |useInPregnancyFDA=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.
| |
| |useInNursing=*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.
| |
| |useInPed=*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 × 5 every 3 weeks or (daily × 5) × 2 weeks every 3 weeks].
| |
| |useInGeri=*Patients greater than 65 years of age should be closely monitored because of a greater risk of early and late diarrhea in this population. The starting dose of CAMPTOSAR in patients 70 years and older for the once-every-3-week-dosage schedule should be 300 mg/m2.
| |
| *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].
| |
| |useInRenalImpair=The influence of renal impairment on the pharmacokinetics of irinotecan has not been evaluated. Therefore, use caution in patients with impaired renal function. CAMPTOSAR is not recommended for use in patients on dialysis.
| |
| |useInHepaticImpair=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 when administering CAMPTOSAR to 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.
| |
| |overdose=I*n 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.
| |
| |drugBox={{Drugbox
| |
| | verifiedrevid = 477494806
| |
| | 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
| |
| | image = Irinotecan Structure.png
| |
| | |
| <!--Clinical data-->
| |
| | tradename = Camptosar
| |
| | Drugs.com = {{drugs.com|monograph|irinotecan-hydrochloride}}
| |
| | MedlinePlus = a608043
| |
| | pregnancy_category = D <small>(Australia, United States)</small>
| |
| | legal_status = [[Prescription drug|POM]] <small>(UK)</small>, ℞-only <small>(U.S.)</small>
| |
| | routes_of_administration = [[Intravenous therapy|Intravenous]]
| |
| | |
| <!--Pharmacokinetic data-->
| |
| | bioavailability = NA
| |
| | metabolism = [[Liver|Hepatic]] [[glucuronidation]]
| |
| | elimination_half-life = 6 to 12 hours
| |
| | excretion = Biliary and [[Kidney|renal]]
| |
| | |
| <!--Identifiers-->
| |
| | CASNo_Ref = {{cascite|correct|CAS}}
| |
| | CAS_number_Ref = {{cascite|correct|??}}
| |
| | CAS_number = 100286-90-6
| |
| | ATC_prefix = L01
| |
| | ATC_suffix = XX19
| |
| | PubChem = 60838
| |
| | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| |
| | DrugBank = DB00762
| |
| | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| |
| | ChemSpiderID = 54825
| |
| | UNII_Ref = {{fdacite|correct|FDA}}
| |
| | UNII = 7673326042
| |
| | KEGG_Ref = {{keggcite|correct|kegg}}
| |
| | KEGG = D08086
| |
| | ChEMBL_Ref = {{ebicite|correct|EBI}}
| |
| | ChEMBL = 481
| |
| | |
| <!--Chemical data-->
| |
| | C=33 | H=38 | N=4 | O=6 e
| |
| | molecular_weight = 586.678 [[Gram|g]]/[[Mole (unit)|mol]] (Irinotecan)<br>623.139 g/mol (Irinotecan [[hydrochloride]])<br>677.185 g/mol (Irinotecan hydrochloride trihydrate))
| |
| | smiles = O=C7OCC=6C(=O)N2C(\c1nc5c(c(c1C2)CC)cc(OC(=O)N4CCC(N3CCCCC3)CC4)cc5)=C/C=6[C@@]7(O)CC
| |
| | InChI = 1/C33H38N4O6/c1-3-22-23-16-21(43-32(40)36-14-10-20(11-15-36)35-12-6-5-7-13-35)8-9-27(23)34-29-24(22)18-37-28(29)17-26-25(30(37)38)19-42-31(39)33(26,41)4-2/h8-9,16-17,20,41H,3-7,10-15,18-19H2,1-2H3/t33-/m0/s1
| |
| | InChIKey = UWKQSNNFCGGAFS-XIFFEERXBR
| |
| | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| |
| | StdInChI = 1S/C33H38N4O6/c1-3-22-23-16-21(43-32(40)36-14-10-20(11-15-36)35-12-6-5-7-13-35)8-9-27(23)34-29-24(22)18-37-28(29)17-26-25(30(37)38)19-42-31(39)33(26,41)4-2/h8-9,16-17,20,41H,3-7,10-15,18-19H2,1-2H3/t33-/m0/s1
| |
| | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| |
| | StdInChIKey = UWKQSNNFCGGAFS-XIFFEERXSA-N
| |
| }}
| |
| |mechAction=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 I]]-[[DNA]] 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.
| |
| |structure=[[file:Irinotecan Structure.png|none|250px]]
| |
| |PD=*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 SN-38 is 95% bound to plasma proteins compared to approximately 50% bound to plasma proteins for irinotecan. The precise contribution of SN-38 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.
| |
| |PK=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:
| |
| | |
| [[file:Irinotecan PK1.png|none|300px]]
| |
| | |
| =====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=====
| |
| | |
| Irinotecan is subject to extensive metabolic conversion by various enzyme systems, including esterases to form the active metabolite SN-38, and UGT1A1 mediating glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several inactive oxidation products, one of which can be hydrolyzed by carboxylesterase to release SN-38. In vitro studies indicate that irinotecan, SN-38 and another metabolite aminopentane carboxylic acid (APC), do not inhibit cytochrome P-450 isozymes. 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 (5.3) and DOSAGE AND ADMINISTRATION (2.3)]. 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 (2)].
| |
| | |
| =====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.
| |
| | |
| =====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. CAMPTOSAR is not recommended for use in patients on dialysis.
| |
| | |
| =====Drug Interactions=====
| |
| *[[Dexamethasone]], a moderate [[CYP3A4]] inducer, does not appear to alter the pharmacokinetics of irinotecan.
| |
| |alcohol=Alcohol-Irinotecan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
| |
| }} | |