What Are the Most Common Side Effects of Irinotecan?

Irinotecan hydrochloride injection, the indication is suitable for the treatment of patients with advanced colorectal cancer: combined with 5-fluorouracil and folinic acid for patients with advanced colorectal cancer who have not previously received chemotherapy; as a single drug, -Patients who fail the fluorouracil chemotherapy regimen.

Drug Name: Irinotecan Hydrochloride Injection

Drug type: Prescription drugs, medicines for medical workers' injuries
Use classification: Cytotoxic drugs

Irinotecan hydrochloride injection ingredients

The main ingredients and chemical name of this product are: irinotecan hydrochloride, 4S-4,11-diethyl-4-hydroxy-9 [(4-piperidinylpiperidine) carbonyl] -1H pyran [3 ', Chemical structure of 4 ': 6,7] indolezine [1,2-b] quinoline-3,14 (4H, 12H) -dione hydrochloride:

Molecular formula: C ₃₃ H ₃₉ ClN ₄ O ₆
Molecular weight: 623.15
Name of excipients: sorbitol, lactic acid and water for injection. The pH of the solution was adjusted to 3.5 with sodium hydroxide.

Characters of Irinotecan Hydrochloride Injection

This product is a pale yellow clear liquid.

Indications of Irinotecan Hydrochloride Injection

This product is suitable for the treatment of patients with advanced colorectal cancer:
· Combined with 5-fluorouracil and folinic acid in patients with advanced colorectal cancer who have not previously received chemotherapy;
As a single drug, treat patients who have failed treatment with a 5-fluorouracil-containing chemotherapy regimen.

Irinotecan Hydrochloride Injection Specifications

2ml: 40mg of this product, containing 40mg of irinotecan hydrochloride intravenous drip concentrate, 5ml of this product: 0.1g, containing 0.1g of Irinotecan hydrochloride, intravenous drip concentrate, 15ml: 0.3g, containing 0.3g Irinotecan hydrochloride intravenous infusion concentrate

Irinotecan hydrochloride injection dosage

Prophylactic antiemetics are recommended. Consider prophylactic or therapeutic atropine therapy in patients with cholinergic syndrome (see Precautions).
Combined Dosage Scheme Irinotecan hydrochloride combined with 5-FU (5-fluorouracil) and LV (calcium folic acid) [u] Two-week dosing regimen [/ u]
Irinotecan hydrochloride 180mg / m ² intravenous infusion for 30 ~ 90 minutes, the first day; LV 400mg / m ² should be given immediately after infusion of irinotecan hydrochloride, the same infusion time, and then 5-FU immediately, Days 1 and 2; 5-FU 400 mg / m ² intravenous bolus, then 600 mg / m ² continuous intravenous infusion for 22 hours, on days 1 and 2. Repeat every 2 weeks.
Irinotecan hydrochloride 180mg / m ² intravenous infusion for 30 ~ 90 minutes, the first day; LV 400mg / m ² should be given immediately after the infusion of irinotecan hydrochloride, the same infusion time, the first day; 5-FU 400mg / m ² intravenous bolus, 1 day, then 1,200 mg / m ² / d × 2 continuous intravenous infusion (total 2,400 mg / m ² , infusion for 46 to 48 hours). Repeat every 2 weeks.
Dosage adjustments < br Carefully monitor and evaluate the patient's toxicity before each treatment, especially during the first cycle of treatment. The doses of irinotecan hydrochloride and 5-FU should be adjusted according to the patient's tolerance for the treatment. Table 1 shows the recommended dose adjustment protocol for the combination. All dose adjustments should be based on the most severe toxic response that has previously occurred. Patients can start the next course of treatment only if they do not have diarrhea (return to the state of bowel function before treatment) for at least 24 hours without using antidiarrheal drugs.
When the toxic effects return to NCI level 1 or lower, the granulocyte count returns to 1.5 x 10 ⁹ / L, the platelet count returns to 100 x 10 ⁹ / L, and the treatment-related diarrhea is completely resolved before the next new treatment cycle can be started . Treatment should be delayed for 1-2 weeks to help recover the associated toxic response. If the patient cannot recover after a 2-week delay, consideration should be given to stopping chemotherapy. If an intolerable toxicity does not occur, as long as the patient can continue to have clinical benefit, he / she should continue treatment with irinotecan hydrochloride / 5-FU / LV.
Table 1 Recommended dose adjustment methods of irinotecan hydrochloride / 5-FU / LV in the combined treatment cycle and at the beginning of the next treatment cycle NCI CTC classification [sup] a [/ sup] Next in the treatment cycle At the beginning of treatment [sup] b [/ sup]
No toxic response maintenance dose level maintenance dose level neutropenia reduction 1 maintenance dose level maintenance dose level 2 reduction 1 dose level maintenance dose level 3 discontinuation of drug until recovery to level 2 and then decrease 1 dose level and decrease 1 dose Level 4 Discontinue treatment until recovery to level 2, then reduce by 2 dose levels Decrease neutropenic fever by 2 dose levels Discontinue until recovery, then reduce 2 dose levels And at the beginning of the next course of treatment, the dose adjustment based on leukopenia and thrombocytopenia should also be based on the NCI toxicity assessment criteria and consistent with the above-mentioned dose adjustment protocol for neutropenia maintenance.
Diarrhea 1 Delayed medication until return to baseline level and then give the same dose to maintain the dose level 2 Delayed medication until return to baseline level and then reduce 1 dose level to maintain the dose level 3 Delayed medication until return to baseline level and then reduce 1 dose Decreased the level by 1 dose level 4 Delayed medication until return to baseline levels, then reduced by 2 dose levels Reduced by 2 dose levels Other non-hematological toxicity
1 Maintaining the dose level Maintaining the dose level 2 Discontinue the medicine until it returns to 1 level, and then reduce it by 1 dose level Maintain the dose level 3 Discontinue the medicine until it returns to 2 levels, then reduce 1 dose level and reduce 1 dose level 4 Discontinue the drug Until recovery to level 2, then decrease by 2 dose levels. Reduce by 2 dose levels.a. Severity of adverse events is assessed based on NCI CTC (version 2.0) criteria, see http://ctep.info.nih.gov/CTC3/default .htm
b Relative to the starting dose used in the previous chemotherapy cycle.
c For mucositis / stomatitis, as long as the 5-FU dose is reduced, the dose of irinotecan hydrochloride need not be reduced.
Monotherapy <br Dosage plan < br This product should be administered intravenously, the infusion time is greater than 90 minutes (see preparation of infusion solution), as shown in Table 2 weekly or every 3 weeks Schedule Table 2: This product's single-drug schedule and dose adjustment weekly schedulea
6 weeks a course of 125mg / m2 intravenous infusion for more than 90 minutes, on days 1, 8, 15, 22, and then rest for 2 weeks on day 43 and restart the starting dose and adjust c
Starting dose (mg / m ² ) Dose level -1 (mg / m ² ) Dose level-2 (mg / m ² )
125 100 75
Plan every 3 weeks b 350mg / m2 intravenous drip for more than 90 minutes, once every 3 weeks Start dose and adjustment c
Starting dose (mg / m ² ) Dose level -1 (mg / m ² ) Dose level-2 (mg / m ² )
350 300 250
a Subsequent dose can be increased to 150 mg / m ² or reduced to 50 mg / m ² , and decreased at a level of 50 mg / m ² in 25 patients according to individual patient tolerance.
b Subsequent doses can be adjusted to 200 mg / m ² , which decreases at a level of 50 mg / m ² according to the patient's tolerance.
c See Table 5.
Patients with any of the following conditions may consider reducing the starting dose of irinotecan hydrochloride by 1 dose level: older than 65 years of age, have received pelvic / abdominal radiation therapy, 2 points of physical status, or a moderate increase in bilirubin levels ( 17-34 mol / L).
Patients with liver impairment (monotherapy)
For patients with abnormal liver function, the following starting doses are recommended:
Table 3: Starting doses for patients with liver dysfunction-single drug regimen, serum total bilirubin concentration, serum ALT / AST concentration, starting dose, mg / m2
Single drug weekly plan 1.5-3.0 × IULN 5.0 × IULN 60
3.1-5.0 × IULN 5.0 × IULN 50
<1.5 × IULN 5.1-20.0 × IULN 60
1.5-5.0 × IULN 5.1-20.0 × IULN 40
Single medicine every 3 weeks 1.5-3.0 × IULN-200
Solution> 3.0 × IULN-not recommended
a In patients with bilirubin] 3.0 x IULN, the safety and pharmacokinetics of the irinotecan hydrochloride dosing regimen every 3 weeks is unknown. And this program is not recommended for such patients.
[u] Patients with impaired renal function (monotherapy) [/ u]
No clinical studies have been performed on patients with impaired renal function. Therefore, special attention should be paid to monitoring patients with impaired renal function. This drug is not recommended for dialysis patients.
Geriatric medications. In some studies, a weekly infusion of irinotecan hydrochloride has a terminal half-life of 6.0 hours in patients 65 years of age and 5.5 hours in patients 65 years of age. Dose of SN-38-standardized AUC0-24 was 11% higher in patients 65 years than in patients 65 years old. There are no pharmacokinetic data on dosing regimens every three weeks in elderly patients. Based on the clinical drug toxicity experience of this dosing regimen, it is recommended to use a lower initial dose in patients 65 years of age (reference dosage).
Medication for children <br The safety or effectiveness of this product for children is uncertain.
Dosage adjustment < br To closely monitor the patient's toxic response, the dose of irinotecan hydrochloride should be adjusted according to the patient's tolerance for the treatment. Based on the recommended dosages in Tables 2 and 3, the dosage of the subsequent course of this product can be adjusted according to the adjustment scheme suggested in Table 4. All dose adjustments should be based on the most severe toxic effects that have previously occurred.
Only after the toxic response returns to NCI level 1 or lower, the granulocyte count returns to 1.5 x 10 ⁹ / L, the platelet count returns to 100 x 10 ⁹ / L, and the treatment-related diarrhea is completely resolved can a new round of treatment be started . Treatment should be delayed for 1-2 weeks to help recover the associated toxic response. If the patient cannot recover after a 2-week delay, consideration should be given to stopping chemotherapy.
If an intolerable toxicity does not occur, as long as the patient can continue to have clinical benefit, he / she should continue treatment with irinotecan hydrochloride / 5-FU / LV.
Table 4: Dose-adjusted toxicity of the recommended single-drug regimen. NCIa classification at the beginning of the next course in a certain treatment cycle. Once a week. Once a week. There is no toxic reaction. Up to 150mg / m ²
Neutropenia 1 maintenance dose level maintenance dose level maintenance dose level 2 reduction 1 dose level maintenance dose level maintenance dose level 3 discontinuation of medication until recovery to level 2, decrease 1 dose level decrease 1 dose level then decrease 1 Each dose level 4 is discontinued until recovery to 2 levels, 2 dose levels are reduced by 1 dose level and then 2 dose levels are reduced. Neutropenia is stopped until recovery, 2 dose levels are reduced and 1 dose level is reduced Sexual fever then decreases by 2 dose levels. Toxicity dose adjustments based on leukopenia, thrombocytopenia, and anemia during other treatment cycles and at the beginning of the next course of treatment are also based on the NCI toxicity assessment criteria and are neutral with the above. The recommended dose adjustment protocol for granulocytopenia is consistent.
Diarrhea 1 Maintenance dose level Maintenance dose level Maintenance dose level 2 Reduce 1 dose level Maintenance dose level Maintenance dose level 3 Discontinue medication until recovery to 2 levels, reduce 1 dose level Reduce 1 dose level and then decrease 1 dose level 4 Stop the drug until it returns to 2, reduce 2 dose levels, reduce 1 dose level, and then reduce 2 dose levels. Other non-hematological toxicity 1 Maintenance dose level Maintenance dose level Maintenance dose level 2 Reduce 1 dose level to maintain dose level maintenance Dosage level 3 Stop until the drug returns to 2 levels, reduce 1 dose level by 1 dose level and then decrease 1 dose level 4 Stop drug until return to 2 levels, reduce 2 dose levels and decrease 1 dose level and then decrease 1 dose levela Based on NCI CTC (version 2.0) criteria to assess the severity of adverse events, see http://ctep.info.nih.gov/CTC3/default.htm
Precautions for preparation and administration As with other potentially toxic antineoplastic drugs, care must be taken when preparing this product infusion solution. Use of gloves is recommended. If the irinotecan hydrochloride solution comes in contact with the skin, immediately wash the skin thoroughly with soap and water. If the product comes into contact with mucous membranes, rinse thoroughly with water.
Preparation of infusion solution Like other injections, the solution of this product must be prepared strictly according to the principle of sterility.
Irinotecan hydrochloride injection can only be used once, and any unused portion must be discarded.
Irinotecan hydrochloride injection must be diluted with 5% glucose injection or 0.9% sodium chloride injection to a final concentration of 0.12 to 2.8 mg / ml before infusion. Other drugs cannot be added to the infusion. Check the infusion for visible particulate matter and discoloration before infusion.
At 5 ° C or 30 ° C / relative humidity and protected from light, irinotecan hydrochloride injection is diluted in an infusion solution (0.9% sodium chloride solution and 5% glucose solution) and stored in low density polyethylene or polymer The chemical and physical stability of vinyl chloride containers is maintained for 28 days. For example, its chemical and physical stability can be maintained for 3 days under light conditions.
However, in order to reduce the risk of microbial infection, it is recommended to prepare the infusion solution before use, and it should be used as soon as possible after the infusion solution is prepared. If not used immediately, the infusion solution should not be stored for more than 24 hours at 2-8 ° C, or less than 6 hours at room temperature (25 ° C).
Do not freeze irinotecan hydrochloride or its solution mixture as this may cause the drug to form.

Adverse reactions of irinotecan hydrochloride injection

Combination therapy In two phase III studies, a total of 995 patients with metastatic colorectal cancer received irinotecan / 5-FU / LV, 5-FU / LV alone, or irinotecan monotherapy (see table) 8. Clinical research). In these studies, 370 patients received irinotecan hydrochloride / 5-FU / LV combined therapy, 362 patients received 5-FU / LV monotherapy, and 223 patients received irinotecan hydrochloride monotherapy.
59 patients (6.1%) died within 30 days after the last treatment: 27 (7.3%) patients received irinotecan hydrochloride / 5-FU / LV combination and 19 (5.3%) received 5-FU alone / LV treatment, 13 patients (5.8%) received irinotecan hydrochloride monotherapy. Three patients (0.7%) died of irinotecan hydrochloride / 5-FU / LV combination (3 patients died of neutropenic fever / septicemia), and those receiving 5-FU / LV treatment Three (0.7%) of the patients died (1 died of neutropenic fever / septicemia, 1 died of central nervous system bleeding during thrombocytopenia, and 1 died of unknown cause), and received irinote hydrochloride Two patients (0.9%) died of Kang monotherapy (2 died of neutropenic fever) and there was a potential association with treatment. 18 patients (4.9%) received irinotecan hydrochloride / 5-FU / LV combination, 18 (5.0%) patients received 5-FU / LV treatment, and 15 (6.7%) patients received irinotecan hydrochloride Drug-treated patients died within 60 days of treatment. 26 patients (7.0%) received irinotecan / 5-FU / LV combined therapy, 15 (4.1%) patients received 5-FU / LV monotherapy and 26 (11.7%) patients received irinotecan hydrochloride Kang monotherapy patients discontinued due to adverse events.

The most clinically significant adverse events after the patient received irinotecan hydrochloride were diarrhea, nausea, vomiting, neutropenia, and hair loss (complete hair loss = grade 2). In patients receiving 5-FU / LV, the most clinically significant adverse events were diarrhea, neutropenia, neutropenic fever, and mucositis. In clinical study 1, the incidence of grade 4 neutropenia, neutropenic fever (defined as grade 2 fever and grade 4 neutropenia), and mucositis occurred in irinotecan / 5 The -FU / LV group is lower than the 5-FU / LV group.
Monotherapy The data of some adverse reactions of this product are derived from the following clinical studies. A total of 304 patients with metastatic colorectal cancer were enrolled in the phase II study of the weekly dosing regimen, with 316 patients. Participating studies A study of the dosing regimen every three weeks and a clinical study in Japan involving a total of 1,100 patients with different tumor types.
The types of toxic reactions observed in the three studies were similar. There were 4.3% of patients receiving a weekly dosing regimen and 8% of patients receiving a three-week dosing regimen discontinuing irinotecan hydrochloride because of adverse events. Of the 304 patients receiving the weekly dosing regimen, 17 died within 30 days of receiving this product, of which 5 (1.6%) may be drug-related. Eleven patients who received the irinotecan hydrochloride dosing regimen every three weeks died within 30 days after treatment, of which 3 (1%) may be related to irinotecan hydrochloride. The main causes of treatment-related deaths were neutropenic infection, grade 4 diarrhea, and fatigue.
The most common adverse events reported in single-agent second-line treatment studies are listed in Table 6. Following the form are additional information on adverse events, organized by physical system classification.

Gastrointestinal tract: Diarrhea, nausea, and vomiting are common adverse events after treatment with irinotecan hydrochloride and can be severe. In patients receiving a single-dose 125 mg / m ² weekly dosing regimen, any grade of delayed diarrhea occurred with a median duration of 3 days, of which the median duration of grade 3 or 4 delayed diarrhea was 7 day. Patients 65 years of age had a significantly higher frequency of grade 3 and 4 diarrhea (39.8% vs. 23.4%, p = 0.0025). For detailed handling principles, see [Notes]
Abdominal pain and cramps are associated with early-onset diarrhea (which occurs within 24 hours of administration). Atropine has been found in studies to help alleviate these symptoms. Colon ulcers were found, sometimes with gastrointestinal bleeding, obstruction, and infection, associated with the use of irinotecan hydrochloride.
Blood system: This product usually causes neutropenia, leukopenia (including lymphopenia) and anemia. Severe thrombocytopenia is rare. In a study evaluating a single-drug weekly dosing regimen, one death caused by neutropenic sepsis without fever was considered to be drug-related (0.3%, 1/304). 9.9% of patients received transfusion therapy. In studies evaluating single-agent weekly dosing regimens, the incidence of grade 3 or 4 neutropenia was significantly increased in patients who had previously received pelvic / abdominal radiotherapy (48.1% vs. 24.1%, p = 0.0356). In the same study, patients with a total serum bilirubin concentration of 17 mol / L or higher at baseline were significantly more likely to have grade 3 or 4 neutropenia in the first cycle of chemotherapy than serum bilirubin Patients with concentrations of less than 17 mol / L (50% vs. 17.7%, p [0.001).
Cholinergic Syndrome: Patients may develop cholinergic syndromes such as rhinitis, increased salivation, dilated pupils, tearing, sweating, flushing, and hyperintestinal peristalsis that can cause abdominal cramps or early-onset diarrhea. These symptoms occur at the same time as the IV drip or shortly after the end. They are thought to be related to the anticholinesterase activity of the parent compound of irinotecan hydrochloride, which is more likely to occur at high doses. These symptoms occurred at the same time as the peak plasma concentrations of parenteral irinotecan administration.
Metabolism and Nutrition: Dehydration due to diarrhea, nausea and vomiting occurred in 14.8% of patients in clinical studies.
Liver: NCI Grade 3 or 4 liver enzyme abnormalities have been found in less than 10% of patients in clinical studies evaluating single-agent weekly regimens. These events typically occur in patients who already have liver metastases. With a dosing regimen every three weeks, hepatic events such as ascites and NCI grade 3/4 jaundice occurred in 8.5% of patients in one study, and 8.7% of patients in another study.
Kidney: Increased serum creatinine or blood urea nitrogen is usually caused by concurrent infections or dehydration caused by nausea, vomiting, and diarrhea. Cases of acute renal failure have been reported. Very rare cases of renal impairment due to tumor lysis syndrome have also been reported.
Dermatology: Hair loss has been reported during irinotecan hydrochloride treatment. A rash has also been reported, but without interruption of treatment.
Respiratory system: Serious pulmonary adverse events are rare. In clinical studies evaluating single-agent weekly dosing regimens, more than half of patients with symptoms of dyspnea have lung metastases; malignant disease involving the lungs or other pre-existing lung diseases may be associated with dyspnea, but The extent of the impact is unknown. For the dosing regimen every three weeks, respiratory adverse events, such as dyspnea and NCI grade 3/4 cough, occurred in 10.1% of patients in one clinical study and 4.7% of patients in another study occur.
Earlier studies in Japan found a small number of patients with potentially fatal pulmonary syndromes, including dyspnea, fever, and chest X-rays showing reticular nodules. The effects of irinotecan hydrochloride on these events are difficult to assess because these patients themselves have lung tumors, and some patients have previously had non-malignant lung diseases. Because of these findings, clinical studies conducted in the United States rarely enroll patients with pulmonary dysfunction, significant ascites, or pleural effusion.
Nervous system: In clinical studies of single-agent weekly dosing regimens, the incidence of insomnia and dizziness was 19.4% and 14.8%, respectively, but they are not generally considered to be directly related to irinotecan hydrochloride. Dizziness is sometimes caused by orthostatic hypotension in dehydrated patients.
Cardiovascular system: Vasodilation (flushing) may occur during infusion of irinotecan hydrochloride. Irinotecan hydrochloride has anti-cholinesterase activity. Cardiovascular non-response related to medication may occur, including sudden death, transient darkening, and bradycardia. Monitor the patient for cholinergic effects during infusion of this product, and be prepared to give symptomatic treatment in a timely manner. Sudden death has not been reported in a phase II clinical study of a single-agent weekly regimen in 304 patients. In these studies, syncope occurred in 2 patients (0.7%) and bradycardia in one patient (0.3%).
Rare reports of thrombotic events in patients treated with this product include angina pectoris, arterial thrombosis, cerebral infarction, cerebrovascular accident, deep thrombophlebitis, lower extremity thrombosis, cardiac arrest, myocardial infarction, myocardial ischemia, peripheral vascular disorders , Pulmonary embolism, sudden death, thrombophlebitis, thrombosis and vascular disorders. The cause of these events is not clear.
Other: 1-10% of patients in clinical studies experienced other NCI grade 3/4 drug-related adverse events, including mucositis, bilirubinemia, and hypovolemia. Less than 1% of patients develop NCI grade 3 or 4 rectal disease, gastrointestinal candidiasis, hypokalemia, hypomagnesemia, increased GGTP, discomfort, sepsis, and gait abnormalities.
Postmarketing monitoring for gastrointestinal abnormalities: Few cases of intestinal obstruction, megacolon, or gastrointestinal bleeding, and rare cases of colitis including cecumitis (Ileocecal Syndrome), ischemia and ulcerative colitis . In some cases, colitis occurs with ulcers, bleeding, obstruction, or infection. Obstructions have also been reported in patients without previous colitis. Reports of bowel perforation are rare.
Hypovolemia: Reports of impaired renal function and acute renal failure are rare and generally occur in patients with infections and / or hypovolemia due to severe gastrointestinal toxic reactions. Patients who rarely experience diarrhea and / or vomiting or sepsis-induced dehydration develop renal insufficiency, hypotension, or circulatory failure.
Immune dysfunction: Allergic reactions including severe allergic or allergic reactions have also been reported.
Laboratory tests: Reports of hyponatremia, mainly related to diarrhea and vomiting, are rare. Increased serum transaminase (such as AST and ALT) levels in patients without liver metastases; transient increases in amylase and occasional transient increases in lipase are rarely reported.
Musculoskeletal and connective tissue abnormalities: Early reactions have been reported such as muscle contractures or painful cramps and paresthesias.
Respiratory, thoracic, and mediastinal abnormalities: Interstitial lung disease manifestations such as pulmonary infiltration are rare during irinotecan treatment. Early reactions such as dyspnea have been reported (see Precautions). Hiccup has also been reported.
Cardiac abnormalities: Myocardial ischemic events have been observed in patients receiving irinotecan hydrochloride, mainly in patients with underlying heart disease, other risk factors for heart disease, or patients who have received chemotherapy with cytotoxic drugs.
Nervous system disorders: Speech disorders have been reported in patients treated with irinotecan, usually transient. In some patients, the cause is cholinergic syndrome that occurs during or after irinotecan injection.

Contraindications to Irinotecan Hydrochloride Injection

Chronic enteritis and / or intestinal obstruction;
Have a history of severe allergic reactions to irinotecan hydrochloride trihydrate or excipients in this product;
Pregnancy and lactation;
Bilirubin exceeds 3 times the upper limit of normal value;
Severe bone marrow failure;
WHO General Status Score] 2.
This product is contraindicated in patients who are allergic to the drug or excipients. Irinotecan hydrochloride has not been found to be antigenic in clinical studies, but irinotecan hydrochloride is found to be antigenic in guinea pigs and rabbits 'passive intradermal allergic reactions and in guinea pigs' active systemic allergic reactions. In these experiments, all animals developed antibodies against irinotecan hydrochloride, and some guinea pigs died of allergies to irinotecan hydrochloride.
This product is contraindicated in pregnant women (refer to pharmacology and toxicology, carcinogenicity, mutagenicity and fertility impairment).
This product is contraindicated in pregnant and lactating women (refer to medication for pregnant and lactating women).

Precautions for Irinotecan Hydrochloride Injection

Application: This product should be used under the supervision and guidance of oncologists who have experience in using cytotoxic chemotherapy drugs. Complications can only be properly managed if adequate diagnostic and therapeutic equipment is readily available.
Drug extravasation: This product is administered by intravenous drip. Attention should be paid to prevent extravasation, and the site of intravenous drip should pay attention to observe whether inflammation occurs. In case of extravasation, rinse with sterile water and recommend ice.
Mayo Clinic regimen: Unless it is a well-designed clinical study, this product cannot be combined with the 5-FU / LV administration method in the Mayo Clinic regimen (continuous administration for 4-5 days, every 4 weeks, see Table 9) It is used because reports indicate increased toxicity, including toxic deaths. Irinotecan hydrochloride should be used as recommended in the "Dosage and Administration" section.
Immunosuppressive effects / increased susceptibility to infection: Vaccination with live or attenuated vaccines in patients with low immune function due to the use of chemotherapeutics including irinotecan hydrochloride may cause severe or fatal infections. Patients using irinotecan hydrochloride should avoid live vaccines. You can get a dead or inactivated vaccine, but it may reduce the effectiveness of the vaccine.
Cardiovascular system: Thrombus events rarely occur in patients using this product. The exact cause is still unknown (see Adverse Reactions in the Cardiovascular System).
Diarrhea and treatment methods < br This product can cause early-onset and late-onset diarrhea, which are caused by different mechanisms. Both types of diarrhea can be severe.
Early-onset diarrhea (which occurs during or shortly after the intravenous infusion of irinotecan hydrochloride) is due to cholinergic effects. It is usually temporary and rarely severe. It may be accompanied by rhinitis, increased salivation, dilated pupils, tearing, sweating, flushing, bradycardia, and hyperintestinal peristalsis that can cause abdominal cramps. Patients with cholinergic syndrome who develop cholinergic syndrome at or shortly after the use of irinotecan hydrochloride are given an atropine of 0.25 to 1 mg (total dose 1 mg / d) (unless contraindications are used). At the next use of this product, atropine sulfate should be used prophylactically. Patients 65 years of age are more likely to develop early-onset diarrhea and should be monitored more.
Delayed diarrhea (usually occurs 24 hours after using this product, and the median time for the first loose stool to occur on the 5th day after instillation) may be longer, which may lead to dehydration, electrolyte disturbance or infection, and even Fatal. In the event of delayed diarrhea, treatment with Yimeng should be given in time. Patients should be instructed to have susceptible to susceptibility to susceptibility to susceptibility to susceptibility to susceptibility to susceptibility to susceptibility to susceptibility to susceptibility to dysmenorrhea, as soon as stools are not formed or defecation or the frequency of defecation is greater than in the past. In the clinical study, the regimen of Yimeng stop was the first dose of 4mg, and then 2mg every 2 hours until 12 hours after the diarrhea stopped. In the evening, the patient can take 4 mg of irmenoxane every 4 hours. Continuous use of the above dose is not recommended for more than 48 hours, because it is at risk of paralytic intestinal obstruction, and it is not recommended to use it for less than 12 hours. Prophylactic dosing is not recommended.
Patients with diarrhea should be closely monitored. If dehydration occurs, water and electrolytes should be replenished. If intestinal obstruction, fever, or severe neutropenia occur, antibiotics should be given. After the first treatment, follow-up chemotherapy should be postponed until the patient no longer has diarrhea for at least 24 hours without the use of an antidiarrheal drug (returning to the state of bowel function before treatment). If NCI grade 2, 3, or 4 diarrhea occurs, the subsequent dose of irinotecan hydrochloride in this cycle will need to be reduced (see Dosage and Administration).
In addition to antibiotic treatment, hospitalization for diarrhea is recommended in the following cases: diarrhea with fever, severe diarrhea (requires intravenous fluid replacement), vomiting associated with late-onset diarrhea, and susceptibility to treatment at the first high dose Postdiarrhea lasts more than 48 hours; in some cases, patients may not follow the doctor's advice when treating adverse reactions (onset of delayed diarrhea requires immediate and long-term antidiarrheal treatment and a lot of fluid replacement).
Hematological diseases < br Irinotecan hydrochloride usually causes neutropenia, leukopenia, and anemia. These symptoms can be severe, so irinotecan hydrochloride cannot be used in patients with severe myelosuppression (see Adverse reactions in the blood system). Severe thrombocytopenia is uncommon.
Neutropenia It has been reported that patients who died of irinotecan hydrochloride died of sepsis caused by severe neutropenia. Antibiotics should be given promptly when complications of neutropenia occur. If neutropenic fever occurs or the absolute neutrophil count is less than 1.5 x 10 ⁹ / L, irinotecan hydrochloride chemotherapy should be suspended. The new course of chemotherapy should be started after the granulocyte count has returned to> 1.5 x 10 ⁹ / L. After the patient recovers, the subsequent dose of irinotecan hydrochloride should be reduced according to the patient's neutropenia (see Dosage and Administration). Colony-stimulating factor (CSF) treatment is not required routinely, but physicians may consider administering CSF to patients with neutropenia.
Colitis / Intestinal Obstruction < br There have been reports of colitis. In some cases, colitis is accompanied by ulcers, bleeding, intestinal obstruction, and infection. Cases of intestinal obstruction without previous colitis have also been reported. Patients with intestinal obstruction should receive antibiotic treatment in a timely manner.
Chronic inflammatory bowel disease and / or intestinal obstruction Patients cannot receive irinotecan hydrochloride until the symptoms of intestinal obstruction have resolved.
Patients with reduced UGT1A1 enzyme activity Uridine diphosphate glucuronyltransferase (UGT1A1) is encoded by the UGT1A1 gene and mediates the binding response of the active metabolite SN-38 (see Pharmacokinetics: Metabolism and Excretion ). The high polymorphism of the UGT1A1 gene causes differences in metabolic activity between different individuals. One of these polymorphisms occurs in the promoter region of UGT1A1, the UGT1A1 * 28 allele variant. This variant and congenital deficiency of UGT1A1 expression (such as Crigler-Najjar syndrome and Gilbert syndrome) are associated with decreased UGT1A1 enzyme activity and increased systemic exposure to SN-38. Patients with homozygous UGT1A1 * 28 alleles (also known as the UGT1A1 7/7 genotype) observed higher plasma SN-38 concentrations than patients with 1 or 2 wild-type alleles.
Patients with Crigler-Najjar syndrome (types I and II) or with UGT1A1 * 28 homozygotes (Gilbert syndrome) have grades 3 to 4 after using medium and high doses of irinotecan (> 150 mg / m ² ) The risk of hematological toxicity increases. However, the relationship between the UGT1A1 genotype and irinotecan-associated diarrhea is not fully understood.
For patients with UGT1A1 * 28 homozygotes, a regular dose of irinotecan should be given for initial administration and blood toxicity monitored. Patients who have experienced hematologic toxicity during previous treatment should consider reducing the initial dose of irinotecan. However, in such patients, it is not clear how much the initial dose is reduced, and the subsequent dose adjustment should be based on the patient's tolerance for the treatment.
Use with caution in the following cases : Patients with special risks: patients with poor physical status, elderly and patients who have received pelvic / abdominal radiation therapy should pay special attention to monitoring when receiving this product (see Adverse Reactions) ). Patients with poor physical status are at increased risk for irinotecan-related adverse events. Comparison of patients receiving irinotecan / 5-FU / LV or 5-FU / LV in clinical studies found hospitalization rate, neutropenic fever, thromboembolism, interruption rate of first course of chemotherapy, and incidence of early death Rates were higher in patients with a physical status score of 2 than in patients with 0 or 1. Patients with a physical status score of 3 or 4 cannot receive this product.
Renal impairment: No clinical studies have been conducted in patients with renal insufficiency (see Pharmacology, Pharmacokinetics and Pharmacokinetics in Specific Populations). Therefore, special attention should be paid to monitoring patients with renal insufficiency. This drug is not recommended for dialysis patients.
Radiotherapy: Patients who have received pelvic / abdominal radiotherapy have an increased risk of severe bone marrow suppression after receiving irinotecan hydrochloride. There is not enough research on the concurrent radiotherapy and this product, and this treatment is not recommended.
Hepatic insufficiency: In patients with hyperbilirubinemia, the clearance of irinotecan hydrochloride decreases, so there is an increased risk of hematological toxicity (see Pharmacology, Pharmacokinetics, and Pharmacokinetics in Specific Populations). In patients whose serum total bilirubin is more than three times the upper limit of normal, irinotecan hydrochloride as a single drug once every 3 weeks has not been determined. In clinical studies of single-agent weekly dosing regimens, patients with moderately elevated total bilirubin (17-34 mol / L) are likely to develop grade 3 or 4 neutropenia during the first cycle of treatment Higher than patients with serum total bilirubin less than 17 mol / L (50% to 18%; p <0.001) (see Pharmacology, Pharmacokinetics, and Pharmacokinetics and Dosage and Administration in Specific Populations). Patients with abnormal bilirubin glycolipidation, such as those with Gilbert syndrome, have a higher risk of myelosuppression after receiving this product. Cholinergic effects: Irinotecan hydrochloride has cholinergic effects, and patients with asthma or cardiovascular disease should be used with caution. Use with caution in patients with mechanical intestinal obstruction or urinary tract obstruction.
Respiratory system: Interstitial lung disease that manifests as infiltrates in the lungs is rare in the treatment of irinotecan hydrochloride. Interstitial lung disease can be fatal. Pre-existing lung disease, use of lung-toxic drugs, radiation therapy, and use of colony-stimulating factors may all be risk factors for the development of interstitial lung disease. Patients with these risk factors should closely observe respiratory symptoms before and during treatment with irinotecan hydrochloride.
Monitoring before administration: It is recommended to closely monitor the white blood cell count and classification, hemoglobin and platelet count before each use of this product. Monitor liver function before each dose, monthly or when clinically indicated.
Nausea and vomiting: Irinotecan hydrochloride can cause vomiting. Patients are advised to give antiemetics before administration. In a clinical study of a weekly dosing regimen, most patients received dexamethasone 10 mg in combination with another antiemetic such as a 5-HT ₃ blocker (such as ondansetron or granisetron).30

24
 
 
 
24

6 mg/kg/AUC 125 mg/m2 0.2 mg/m ²1/21.2 mg/kg/AUC125 mg/m2 1/406.0 mg/kg/

 5 4 65

65 6.0 65 5.5 65 SN-38 AUC0-2465 11%65

CYP3A SN38
SN38
St. John's WortSN-38
CYP3A4 UGT1A1 SN-38

8.5%, 4/47 )1.3%, 1/80 )8.5%

/

DNAISN-38ISN-38DNADNAS
SN-38P-^MDR
P03MA-16/CC38C51Co-4MX-1St-15SC-6P-^MDRP388

[u][/u]
9805-FU3II/III7655-FU1
1-5-FU

NA * II4553630%918
304II125 mg/90421710193125 mg/311
[u][/u]
38521III21180 mg/21200 mg/25-400 mg/600 mg/m ²2225-180 mg/500 mg/25-2300 mg/246
21982
2-

5FU 5-FA NS * 15FU/FA44.4%5FU/FA25.6%5FU/FA<500/mm ³ 5.8%5FU/FA2.4%
5FU/FAP=0.046
IIIEORTC QLQ-C30/

After using this drug, the intensity of major toxic and side effects (such as leukocytopenia and diarrhea) is related to the area under the curve of the parent drug and its metabolite SN-38. In monotherapy, the degree of hematological toxicity (leukocytes and neutrophils decreased to the lowest point) or diarrhea was significantly related to the area under the curve of irinotecan and its metabolite SN-38.
The pharmacokinetic properties of irinotecan and SN-38 (its active metabolites) were studied in a phase I clinical trial. 60 patients received the recommended dose regimen of pharmacotherapy, which is an intravenous infusion of this product in 30 minutes. 100 -750 mg / m ² . The kinetics of irinotecan are dose-independent. Patients enrolled in clinical studies received different irinotecan dosing regimens with similar pharmacokinetics.
The plasma decay mode is both two- and three-chamber. The average plasma half-life in the three-compartment model was 12 minutes in the first phase, 2.5 hours in the second phase, and 14.2 hours in the final phase. At the end of the intravenous infusion of the recommended dose of 350 mg / m ² , the peak plasma concentrations of irinotecan and SN-38 were 7.7 ug / mL and 56 ug / mL, respectively, and the areas under the curve were 34 ug / h / mL. , 451 ug / h / mL, its steady-state distribution volume is large, and remains relatively stable, as a function of dose, with an average of 157 L / m ² . The total body clearance was 15 L / h / m ² on average, and remained stable in different treatment cycles of the same patient. The drug metabolism parameters of SN-38 vary greatly in different individuals.
The 24-hour average urinary excretion rates of irinotecan and SN-38 were 19.9% and 0.25% of the dose used, respectively.
A phase II clinical trial of irinotecan pharmacokinetics was performed in 72 patients with tumors. The pharmacokinetic parameters calculated by the restricted sampling model are very close to those of the Phase I study.
In vitro experiments, the plasma protein binding rates of irinotecan and SN-38 were 65% and 95%, respectively.
When the patient's bilirubin was 1.5-3 times the upper limit of normal, irinotecan clearance was reduced by about 40%. The plasma drug concentration of irinotecan 200 mg / m ² in these patients was the same as that of 350 mg / m ^{2 of} irinotecan in cancer patients with normal liver function.
Combined with 5-fluorouracil / folic acid, does not change the pharmacokinetic properties of irinotecan.

Storage of Irinotecan Hydrochloride Injection

Special precautions for storage:
Concentrates for intravenous drip infusion in vials should be protected from light.
Instructions for use and storage:
Like other anti-tumor substances, this product needs to be carefully prepared and handled, and wearing glasses, masks, gloves, etc. are required.
If the solution or infusion solution comes into contact with the skin, immediately rinse thoroughly with soap and water.
If the product solution or infusion solution contacts the skin, rinse immediately with water.
Preparation before intravenous infusion:
As with other injections, the preparation of this product solution must follow the principle of sterility.
If a precipitate is found in the solution or in the prepared injection, it should be discarded according to the standard treatment procedure for cytotoxic drugs.
Use a calibrated syringe to aseptically extract the required dose of the product solution from the vial, pour it into a 250ml infusion bag or bottle containing 0.9% sodium chloride solution or 5% glucose solution, and shake it by hand to completely mix.
The infusion of this product should be infused into the peripheral or central vein. This product cannot be injected intravenously, and the infusion time should not be less than 30 minutes or more than 90 minutes.
Disposal < br All materials used for dilution or infusion need to be disposed of according to standard procedures for cytotoxic drugs.

Irinotecan Hydrochloride Injection Packaging

Brown, glass bottle.
Packaging specifications: 2ml per bottle: 40mg, 1 bottle per box; 5ml per bottle: 0.1g, 1 bottle per box

Validity of Irinotecan Hydrochloride Injection

Unopened medicines have a shelf life of 36 months.
This product solution does not contain antibacterial preservatives, so it should be used immediately after dissolution and dilution. If dissolved and diluted under strict aseptic conditions (such as on a laminar flow bench), the solution of this product can be stored at room temperature for 12 hours after being opened for the first time, and stored at 2-8 ° C for 24 hours.