Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Irinotecan Hydrochloride Injection, USP is available in single-dose amber glass vials in the following package sizes: 100 mg/5 mL NDC 0143-9583-01 Store at 20° to 25° C (68° to 77° F). See USP Controlled Room Temperature (excursions permitted to 15° to 30° C (59°to 86° F)). Protect from light. Keep the vial in the carton until the time of use. Protect from freezing. Inspect the vial for damage and visible signs of leaks before removing from the carton. If damaged, incinerate the unopened package.; PRINCIPAL DISPLAY PANEL NDC 0143- 9583- 01 Rx ONLY Irinotecan HCl Injection, USP 100 mg per 5 mL (20 mg/mL) as the trihydrate For Intravenous use ONLY MUST BE DILUTED - CYOTOXIC AGENT 5 mL Single Dose Vial NDC 0143- 9583- 01 Rx ONLY Irinotecan Hydrochloride Injection, USP 100 mg per 5 mL (20 mg/mL)* as the trihydrate For Intravenous use ONLY MUST BE DILUTED CYOTOXIC AGENT 1 x 5 mL Single Dose Vial Vial carton; SERIALIZATION IMAGE Representative Carton Serialization Image Representative Carton Serialization Image
- 16 HOW SUPPLIED/STORAGE AND HANDLING Irinotecan Hydrochloride Injection, USP is available in single-dose amber glass vials in the following package sizes: 100 mg/5 mL NDC 0143-9583-01 Store at 20° to 25° C (68° to 77° F). See USP Controlled Room Temperature (excursions permitted to 15° to 30° C (59°to 86° F)). Protect from light. Keep the vial in the carton until the time of use. Protect from freezing. Inspect the vial for damage and visible signs of leaks before removing from the carton. If damaged, incinerate the unopened package.
- PRINCIPAL DISPLAY PANEL NDC 0143- 9583- 01 Rx ONLY Irinotecan HCl Injection, USP 100 mg per 5 mL (20 mg/mL) as the trihydrate For Intravenous use ONLY MUST BE DILUTED - CYOTOXIC AGENT 5 mL Single Dose Vial NDC 0143- 9583- 01 Rx ONLY Irinotecan Hydrochloride Injection, USP 100 mg per 5 mL (20 mg/mL)* as the trihydrate For Intravenous use ONLY MUST BE DILUTED CYOTOXIC AGENT 1 x 5 mL Single Dose Vial Vial carton
- SERIALIZATION IMAGE Representative Carton Serialization Image Representative Carton Serialization Image
Overview
Irinotecan Hydrochloride Injection, USP is an antineoplastic agent of the topoisomerase I inhibitor class. Irinotecan Hydrochloride Injection, USP is supplied as a sterile, pale yellow, clear, aqueous solution. Each milliliter of solution contains 20 mg of irinotecan hydrochloride (on the basis of the trihydrate salt), 45 mg of sorbitol, NF, and 0.9 mg of lactic acid, USP. The pH of the solution has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. Irinotecan Hydrochloride Injection, USP is intended for dilution with 5% Dextrose Injection, USP (D5W), or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion. The preferred diluent is 5% Dextrose Injection, USP. Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata or is chemically synthesized . The chemical name is ( S ) -4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1 H -pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4'bipiperidine]-1'-carboxylate, monohydrochloride, trihydrate. Its empirical formula is C 33 H 38 N 4 O 6 •HCl•3H 2 O and molecular weight is 677.19. It is slightly soluble in water and organic solvents. Its structural formula is as follows: Chemical structure
Indications & Usage
Irinotecan Hydrochloride Injection, USP is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. Irinotecan Hydrochloride Injection, USP is a topoisomerase inhibitor indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.
Dosage & Administration
Colorectal cancer single agent regimen 1: irinotecan hydrochloride injection 125 mg/m 2 intravenous infusion over 90 minutes on days 1, 8, 15, 22 then 2-week rest. ( 2.1 ) Colorectal cancer single agent regimen 2: irinotecan hydrochloride injection 350 mg/m 2 intravenous infusion over 90 minutes on day 1 every 3 weeks. ( 2.1 ) 2.1 Colorectal Single Agent Regimens 1 and 2 Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 1. A reduction in the starting dose by one dose level of irinotecan hydrochloride injection may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients. Table 1. Single-Agent Regimens of Irinotecan Hydrochloride Injection and Dose Modifications Regimen 1 (weekly) Subsequent doses may be adjusted as high as 150 mg/m 2 or to as low as 50 mg/m 2 in 25 to 50 mg/m 2 decrements depending upon individual patient tolerance. 125 mg/m 2 intravenous infusion over 90 minutes, days 1,8,15,22 then 2-week rest Starting Dose and Modified Dose Levels Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. (mg/m 2 ) Starting Dose Dose Level -1 Dose Level -2 125 100 75 Regimen 2 (every 3 weeks) Subsequent doses may be adjusted as low as 200 mg/m 2 in 50 mg/m 2 decrements depending upon individual patient tolerance. 350 mg/m 2 intravenous infusion over 90 minutes, once every 3 weeks Starting Dose and Modified Dose Levels (mg/m 2 ) Starting Dose Dose Level -1 Dose Level -2 350 300 250 Dose Modifications Based on recommended dose-levels described in Table 1, Single-Agent Regimens of Irinotecan Hydrochloride Injection and Dose Modifications, subsequent doses should be adjusted as suggested in Table 2, Recommended Dose Modifications for Single-Agent Schedules. All dose modifications should be based on the worst preceding toxicity. Table 2. Recommended Dose Modifications For Single-Agent Schedules All dose modifications should be based on the worst preceding toxicity A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm 3 , and the platelet count has recovered to ≥100,000/mm 3 , and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing irinotecan hydrochloride injection. Worst Toxicity NCI Grade National Cancer Institute Common Toxicity Criteria (version 1.0) (Value) During a Cycle of Therapy At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cycle Weekly Weekly Once Every 3 Weeks No toxicity Maintain dose level ↑ 25 mg/m 2 up to a maximum dose of 150 mg/m 2 Maintain dose level Neutropenia 1 (1500 to 1999/mm 3 ) Maintain dose level Maintain dose level Maintain dose level 2 (1000 to 1499/mm 3 ) ↓ 25 mg/m 2 Maintain dose level Maintain dose level 3 (500 to 999/mm 3 ) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 ↓ 25 mg/m 2 ↓ 50 mg/m 2 4 (<500/mm 3 ) Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m 2 ↓ 50 mg/m 2 ↓ 50 mg/m 2 Neutropenic fever Omit dose until resolved, then ↓ 50 mg/m 2 when resolved ↓ 50 mg/m 2 ↓ 50 mg/m 2 Other hematologic toxicities Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above. Diarrhea 1 (2–3 stools/day > pretx Pretreatment ) Maintain dose level Maintain dose level Maintain dose level 2 (4–6 stools/day > pretx) ↓ 25 mg/m 2 Maintain dose level Maintain dose level 3 (7–9 stools/day > pretx) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 ↓ 25 mg/m 2 ↓ 50 mg/m 2 4 (≥10 stools/day > pretx) Omit dose until resolved to ≤ grade 2 then ↓ 50 mg/m 2 ↓ 50 mg/m 2 ↓ 50 mg/m 2 Other nonhematologic Excludes alopecia, anorexia, asthenia toxicities 1 Maintain dose level Maintain dose level Maintain dose level 2 ↓ 25 mg/m 2 ↓ 25 mg/m 2 ↓ 50 mg/m 2 3 Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 ↓ 25 mg/m 2 ↓ 50 mg/m 2 4 Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m 2 ↓ 50 mg/m 2 ↓ 50 mg/m 2 2.2 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 irinotecan hydrochloride injection should be considered for patients known to be homozygous for the UGT1A1*28 allele [ see Dosage and Administration (2.1) and Warnings and Precautions (5.3) ]. 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 1–2). 2.3 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-HT 3 blocker (e.g., ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of irinotecan hydrochloride injection. Physicians should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms. 2.4 Preparation of Infusion Solution Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe. Irinotecan hydrochloride injection 20 mg/mL is intended for single use only and any unused portion should be discarded. Irinotecan hydrochloride injection must be diluted prior to infusion. Irinotecan hydrochloride injection 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 irinotecan hydrochloride injection and admixtures of irinotecan hydrochloride injection may result in precipitation of the drug and should be avoided. The irinotecan hydrochloride 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), irinotecan hydrochloride 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). 2.5 Safe Handling Care should be exercised in the handling and preparation of infusion solutions prepared from irinotecan hydrochloride injection. The use of gloves is recommended. If a solution of irinotecan hydrochloride injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If irinotecan hydrochloride injection contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available. 2.6 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.
Warnings & Precautions
Diarrhea and cholinergic reactions : Early diarrhea (occurring during or shortly after infusion of irinotecan hydrochloride injection) is usually transient and may be accompanied by cholinergic symptoms. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). Late diarrhea (generally occurring more than 24 hours after administration of irinotecan hydrochloride injection) can occur. Monitor and replace fluid and electrolytes. Treat with loperamide. Use antibiotic support for ileus and fever. Interrupt irinotecan hydrochloride injection and reduce subsequent doses if severe diarrhea occurs. ( 5.1 ) Myelosuppression : Manage promptly with antibiotic support. Interrupt irinotecan hydrochloride injection and reduce subsequent doses if necessary. ( 5.2 ) Patients with Reduced UGT1A1 Activity: Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of irinotecan hydrochloride injection treatment. ( 5.3 ) Hypersensitivity: Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue irinotecan hydrochloride injection if this occurs. ( 5.4 ) Renal Impairment/Renal Failure: Rare cases of renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhea. ( 5.5 ) Pulmonary Toxicity: Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred. Interrupt for new or progressive dysnpnea, cough, and fever pending evaluation. If IPD diagnosed, discontinue and institute appropriate treatment as needed. ( 5.6 ) Toxicity of the 5 Day Regimen: Irinotecan hydrochloride injection should not be used in combination with a regimen of 5-FU/LV administered for 4–5 consecutive days every 4 weeks outside of a clinical study. ( 5.7 ) Embryo-Fetal Toxicity: Irinotecan hydrochloride injection can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. Advise male patients with female partners of reproductive potential to use condoms. ( 5.9 , 8.1 , 8.3 ) Patients with Hepatic Impairment: In clinical trials, irinotecan hydrochloride injection has not been administered to patients with serum bilirubin > 2.0 mg/dL, or transaminases > 3 times ULN if no liver metastases, or transaminases > 5 times ULN if liver metastases. With the weekly dosage schedule, patients with total bilirubin levels 1.0–2.0 mg/dL had greater likelihood of grade 3–4 neutropenia. ( 5.10 ) 5.1 Diarrhea and Cholinergic Reactions Early diarrhea (occurring during or shortly after infusion of irinotecan hydrochloride injection) 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 irinotecan hydrochloride injection) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Grade 3–4 late diarrhea occurred in 23–31% of patients receiving weekly dosing. In the clinical studies, the median time to the onset of late diarrhea was 5 days with 3-week dosing and 11 days with weekly dosing. Late diarrhea can be complicated by colitis, ulceration, bleeding, ileus, obstruction, and infection. Cases of megacolon and intestinal perforation have been reported. Patients should have loperamide readily available to begin treatment for late diarrhea. Begin loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normal. One dosage regimen for loperamide is 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg of loperamide every 4 hours. Monitor and replace fluid and electrolytes. Use antibiotic support for ileus, fever, or severe neutropenia. Subsequent weekly chemotherapy treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without anti-diarrhea medication. Patients must not be treated with irinotecan until resolution of the bowel obstruction. If grade 2, 3, or 4 late diarrhea recurs, subsequent doses of irinotecan hydrochloride injection should be decreased [ see Dosage and Administration (2) ]. Avoid diuretics or laxatives in patients with diarrhea. 5.2 Myelosuppression Irinotecan Hydrochloride Injection can cause severe myelosuppression. Bacterial, viral, and fungal infections have occurred in patients treated with Irinotecan Hydrochloride Injection. Deaths due to sepsis following severe neutropenia have been reported in patients treated with irinotecan hydrochloride injection. 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 (5.1) ]. Hold irinotecan hydrochloride injection if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm 3 . After recovery to an absolute neutrophil count ≥1000/mm 3 , subsequent doses of irinotecan hydrochloride injection should be reduced [ see Dosage and Administration (2) ]. 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 irinotecan hydrochloride injection. Based on sparse available data, the concurrent administration of irinotecan hydrochloride injection 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 irinotecan hydrochloride injection. 5.3 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 irinotecan hydrochloride injection treatment. In a study of 66 patients who received single-agent irinotecan hydrochloride injection (350 mg/m 2 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). When administered in combination with other agents or as a single-agent, a reduction in the starting dose by at least one level of irinotecan hydrochloride injection 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) ]. 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. 5.4 Hypersensitivity Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue irinotecan hydrochloride injection if anaphylactic reaction occurs. 5.5 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. 5.6 Pulmonary Toxicity Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred in patients receiving irinotecan (in combination with 5-FU/LV 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 irinotecan hydrochloride injection therapy. In Japanese studies, a reticulonodular pattern on chest x-ray was observed in a small percentage of patients. New or progressive, dyspnea, cough, and fever should prompt interruption of chemotherapy, pending diagnostic evaluation. If IPD is diagnosed, irinotecan hydrochloride injection and other chemotherapy should be discontinued and appropriate treatment instituted as needed [ see Adverse Reactions (6.1) ]. 5.7 Toxicity of the 5 Day Regimen Outside of a well-designed clinical study, irinotecan hydrochloride 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. Irinotecan hydrochloride injection should be used as recommended in Table 2 [ see Dosage and Administration (2) ]. 5.8 Increased Toxicity in Patients with Performance Status 2 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. 5.9 Embryo-Fetal Toxicity Based on its mechanism of action and findings in animals, irinotecan hydrochloride injection can cause fetal harm when administered to a pregnant woman. In animal studies, intravenous administration of irinotecan during the period of organogenesis resulted in embryofetal mortality and teratogenicity in pregnant animals at exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 125 mg/m 2 . Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment with irinotecan hydrochloride injection and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use condoms during treatment and for 3 months after the final dose of irinotecan hydrochloride injection [see Use in Specific Populations ( 8.1 ), ( 8.3 ) and Nonclinical Toxicology ( 13.1 )] . 5.10 Patients with Hepatic Impairment The use of irinotecan hydrochloride injection in patients with significant hepatic impairment has not been established. In clinical trials of either dosing schedule, irinotecan was not administered to patients with serum bilirubin >2.0 mg/dL, or transaminase >3 times the upper limit of normal if no liver metastasis, or transaminase >5 times the upper limit of normal with liver metastasis. In clinical trials of the weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) had a significantly greater likelihood of experiencing first-cycle, grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/226]; p<0.001) [ see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ].
Boxed Warning
DIARRHEA AND MYELOSUPPRESSION Early and late forms of diarrhea can occur. Early diarrhea may be accompanied by cholinergic symptoms which may be prevented or ameliorated by atropine. Late diarrhea can be life threatening and should be treated promptly with loperamide. Monitor patients with diarrhea and give fluid and electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe neutropenia. Interrupt irinotecan hydrochloride injection and reduce subsequent doses if severe diarrhea occurs [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ] . Severe myelosuppression may occur [see Warnings and Precautions (5.2) ] . WARNING: DIARRHEA and MYELOSUPPRESSION See full prescribing information for complete boxed warning. 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 irinotecan hydrochloride injection and reduce subsequent doses if severe diarrhea occurs. ( 2.1 , 5.1 ) Severe myelosuppression may occur. ( 5.2 )
Contraindications
Irinotecan hydrochloride injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients. Hypersensitivity to irinotecan hydrochloride injection or its excipients ( 4 )
Adverse Reactions
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, alopecia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Common adverse reactions (≥30%) observed in 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. 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 irinotecan hydrochloride injection. Seventeen of the patients died within 30 days of the administration of irinotecan hydrochloride injection; 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 irinotecan hydrochloride injection. The primary reasons for drug-related hospitalization were diarrhea, with or without nausea and/or vomiting (18.4%); neutropenia/leukopenia, with or without diarrhea and/or fever (8.2%); and nausea and/or vomiting (4.9%). The first dose of at least one cycle of irinotecan hydrochloride injection was reduced for 67% of patients who began the studies at the 125-mg/m 2 starting dose. Within-cycle dose reductions were required for 32% of the cycles initiated at the 125-mg/m 2 dose level. The most common reasons for dose reduction were late diarrhea, neutropenia, and leukopenia. Thirteen (4.3%) patients discontinued treatment with irinotecan hydrochloride injection because of adverse events. The adverse events in Table 3 are based on the experience of the 304 patients enrolled in the three studies described in Clinical Studies ( 14.1 ). Table 3. Adverse Events Occurring in >10% of 304 Previously Treated Patients with Metastatic Carcinoma of the Colon or Rectum Severity of adverse events based on NCI CTC (version 1.0) % of Patients Reporting Body System & Event NCI Grades 1–4 NCI Grades 3 & 4 GASTROINTESTINAL Diarrhea (late) Occurring > 24 hours after administration of irinotecan hydrochloride injection 88 31 7–9 stools/day (grade 3) - (16) ≥10 stools/day (grade 4) - (14) Nausea 86 17 Vomiting 67 12 Anorexia 55 6 Diarrhea (early) Occurring ≤24 hours after administration of irinotecan hydrochloride injection 51 8 Constipation 30 2 Flatulence 12 0 Stomatitis 12 1 Dyspepsia 10 0 HEMATOLOGIC Leukopenia 63 28 Anemia 60 7 Neutropenia 54 26 500 to <1000/mm 3 (grade 3) - (15) <500/mm 3 (grade 4) - (12) BODY AS A WHOLE Asthenia 76 12 Abdominal cramping/pain 57 16 Fever 45 1 Pain 24 2 Headache 17 1 Back pain 14 2 Chills 14 0 Minor infection Primarily upper respiratory infections 14 0 Edema 10 1 Abdominal enlargement 10 0 METABOLIC AND NUTRITIONAL ↓ Body weight 30 1 Dehydration 15 4 ↑ Alkaline phosphatase 13 4 ↑ SGOT 10 1 DERMATOLOGIC Alopecia 60 NA Not applicable; complete hair loss = NCI grade 2 Sweating 16 0 Rash 13 1 RESPIRATORY Dyspnea 22 4 ↑ Coughing 17 0 Rhinitis 16 0 NEUROLOGIC Insomnia 19 0 Dizziness 15 0 CARDIOVASCULAR Vasodilation (flushing) 11 0 Once-Every-3-Week Dosage Schedule A total of 535 patients with metastatic colorectal cancer whose disease had recurred or progressed following prior 5-FU therapy participated in the two phase 3 studies: 316 received irinotecan, 129 received 5-FU, and 90 received best supportive care. Eleven (3.5%) patients treated with irinotecan died within 30 days of treatment. In three cases (1%, 3/316), the deaths were potentially related to irinotecan treatment and were attributed to neutropenic infection, grade 4 diarrhea, and asthenia, respectively. One (0.8%, 1/129) patient treated with 5-FU died within 30 days of treatment; this death was attributed to grade 4 diarrhea. Hospitalizations due to serious adverse events occurred at least once in 60% (188/316) of patients who received irinotecan, 63% (57/90) who received best supportive care, and 39% (50/129) who received 5-FU-based therapy. Eight percent of patients treated with irinotecan and 7% treated with 5-FU-based therapy discontinued treatment due to adverse events. Of the 316 patients treated with irinotecan, the most clinically significant adverse events (all grades, 1–4) were diarrhea (84%), alopecia (72%), nausea (70%), vomiting (62%), cholinergic symptoms (47%), and neutropenia (30%). Table 4 lists the grade 3 and 4 adverse events reported in the patients enrolled to all treatment arms of the two studies described in Clinical Studies ( 14.1 ). Table 4. Percent Of Patients Experiencing Grade 3 & 4 Adverse Events In Comparative Studies Of Once-Every-3-Week Irinotecan Therapy Severity of adverse events based on NCI CTC (version 1.0) Adverse Event Study 1 Study 2 Irinotecan N=189 BSC BSC = best supportive care N=90 Irinotecan N=127 5-FU N=129 TOTAL Grade 3/4 Adverse Events 79 67 69 54 GASTROINTESTINAL Diarrhea 22 6 22 11 Vomiting 14 8 14 5 Nausea 14 3 11 4 Abdominal pain 14 16 9 8 Constipation 10 8 8 6 Anorexia 5 7 6 4 Mucositis 2 1 2 5 HEMATOLOGIC Leukopenia/Neutropenia 22 0 14 2 Anemia 7 6 6 3 Hemorrhage 5 3 1 3 Thrombocytopenia 1 0 4 2 Infection without grade 3/4 neutropenia 8 3 1 4 with grade 3/4 neutropenia 1 0 2 0 Fever without grade 3/4 neutropenia 2 1 2 0 with grade 3/4 neutropenia 2 0 4 2 BODY AS A WHOLE Pain 19 22 17 13 Asthenia 15 19 13 12 METABOLIC AND NUTRITIONAL Hepatic Hepatic includes events such as ascites and jaundice 9 7 9 6 DERMATOLOGIC Hand and foot syndrome 0 0 0 5 Cutaneous signs Cutaneous signs include events such as rash 2 0 1 3 RESPIRATORY Respiratory includes events such as dyspnea and cough 10 8 5 7 NEUROLOGIC Neurologic includes events such as somnolence 12 13 9 4 CARDIOVASCULAR Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction 9 3 4 2 OTHER Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss 32 28 12 14 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 irinotecan hydrochloride injection 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of irinotecan hydrochloride injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Myocardial ischemic events have been observed following irinotecan hydrochloride injection therapy. Thromboembolic events have been observed in patients receiving irinotecan hydrochloride injection. 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 irinotecan hydrochloride injection; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan. Interaction between irinotecan hydrochloride injection 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. Infections: fungal and viral infections have been reported.
Drug Interactions
Strong CYP3A4 Inducers: Do not administer strong CYP3A4 inducers with Irinotecan Hydrochloride Injection. ( 7.2 ) Strong CYP3A4 Inhibitors: Do not administer strong CYP3A4 inhibitors with Irinotecan Hydrochloride Injection. (7.3) 7.1 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 irinotecan hydrochloride injection therapy. Do not administer strong CYP3A4 inducers with irinotecan hydrochloride injection unless there are no therapeutic alternatives. 7.2 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 , [see Clinical Pharmacology (12.3) ] . Patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Coadministration of irinotecan hydrochloride injection 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 irinotecan hydrochloride injection therapy. Do not administer strong CYP3A4 or UGT1A1 inhibitors with irinotecan hydrochloride injection unless there are no therapeutic alternatives.
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