irinotecan

Action and Spectrum

Actions and Spectrum: 

irinotecan is an anticancer drug that is primarily used in the treatment of colorectal cancer. It belongs to class of drugs called as topoisomerase inhibitors. irinotecan acts by inhibiting the enzyme topoisomerase I, which is involved in cell DNA replication and repair processes. By inhibiting this enzyme, irinotecan disrupts the normal functioning of DNA and prevents cancer cells from dividing and growing. 

The spectrum of activity of irinotecan is mainly focused on colorectal cancer. It is used in the therapy of advanced or metastatic colorectal cancer. irinotecan may also be used with other chemotherapy drugs to treat other types of cancer, such as lung, pancreatic, and gastric cancers.Although, its effectiveness may vary depending on the specific cancer type and individual patient factors. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Neutropenia (>90%) 

Asthenia (70%) 

Elevated bilirubin (88%) 

Dyspnea (28%) 

Nausea (79%) 

Anorexia (34%) 

Abdominal pain (63%) 

Thrombocytopenia (>90%) 

Leukopenia (>90%) 

Mucositis (32%) 

Fever (42%) 

Rash (19%) 

Diarrhea (85%) 

Cough (27%) 

Dizziness (23%) 

Alopecia (43%) 

Constipation (41%) 

Pain (31%) 

Anemia (>90%) 

Infection (22%) 

1-10% 

Dyspepsia (10%) 

Vasodilation (9%) 

Abdominal fullness (10%) 

Ascites/jaundice (9%) 

Hypotension (6%) 

AST increased (10%) 

Thromboembolism (9%) 

Neutropenic fever (2-6%) 

Edema (10%) 

Black Box Warning

Black Box Warning: 

irinotecan carries a black box warning, the most severe warning issued by the U.S. Food and Drug Administration (FDA). The black box warning for irinotecan highlights essential safety information and potential risks associated with the medication. The specific black box warning for irinotecan includes: 

• Severe Diarrhea: irinotecan can cause severe diarrhea, which may lead to dehydration and electrolyte imbalance. Diarrhea can occur within 24 hours to several days after receiving the medication and can be life-threatening in some cases. Patients should be closely monitored for diarrhea and treated promptly to prevent complications. 
• Myelosuppression: irinotecan can cause severe myelosuppression, which diminishes the production of blood cells ( RBC, white blood cells, and platelets). This can increase the risk of infections, bleeding, and anemia. Blood cell counts should be regularly monitored during treatment with irinotecan. 
• Hypersensitivity Reactions: irinotecan may cause severe hypersensitivity reactions, including anaphylaxis. Signs of a hypersensitivity reaction may include difficulty breathing, chest tightness, swelling, hives, and rash. If a hypersensitivity reaction occurs, treatment should be stoped, and appropriate medical management should be initiated. 
• Interstitial Lung Disease: Rare cases of interstitial lung disease, including fatal cases, have been reported using irinotecan. Symptoms may include dyspnea (shortness of breath), cough, fever, and pulmonary infiltrates. If interstitial lung disease is suspected, treatment should be stoped, and appropriate measures should be taken. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

irinotecan has several contraindications, meaning situations or conditions in which its use is not recommended. These contraindications include: 

• Known hypersensitivity: irinotecan should not be administered to individuals with known hypersensitivity or severe allergic reactions to irinotecan or its components. Hypersensitivity reactions can be severe and potentially life-threatening. 
• Severe bone marrow suppression: irinotecan can cause myelosuppression, which diminishes the production of blood cells (white blood cells, red blood cells (RBC), and platelets). Suppose a patient has a pre-existing severe bone marrow suppression or is recovering from a recent bone marrow suppressive therapy. In that case, irinotecan may further exacerbate this condition and should be avoided. 
• Severe diarrhea: irinotecan is associated with the risk of severe diarrhea, as mentioned in the black box warning. If a patient has prior history of severe or uncontrolled diarrhea, it is generally contraindicated to use irinotecan due to the increased risk of dehydration and electrolyte imbalance. 
• Bowel obstruction: irinotecan is not recommended in patients with a known or suspected bowel obstruction. The drug can further worsen the obstruction or lead to complications. 
• Pregnancy and breastfeeding: irinotecan may cause harm to the developing fetus, and its use is contraindicated during pregnancy.  

Caution 

several cautions that should be considered when using irinotecan. These cautions indicate situations where the drug should be used cautiously and closely monitored. Some of the cautions associated with irinotecan include: 

• Hepatic impairment: irinotecan is primarily metabolized in the liver, so caution is advised when administering it to patients with pre-existing liver impairment. Reduced liver function can affect the metabolism and elimination of the drug, potentially leading to increased toxicity. Dose adjustments may be necessary for these patients. 
• Renal impairment: While renal excretion of irinotecan and its metabolites is relatively low, caution is still recommended in patients with severe renal impairment. Monitoring renal function and dose adjustment may be necessary in such cases. 
• Severe infections: In patients with severe infections, caution should be exercised when using irinotecan due to the risk of myelosuppression and increased susceptibility to infections. Close monitoring of blood cell counts and appropriate management of infections is essential in these situations. 
• Gastrointestinal disorders: Patients with a history of gastrointestinal disorders, such as inflammatory bowel disease or intestinal obstruction, should be closely monitored when receiving irinotecan. The drug can exacerbate these conditions or cause severe diarrhea, which may require prompt intervention. 
• Respiratory disorders: Patients with pre-existing respiratory disorders, like the chronic obstructive pulmonary disease (COPD) or interstitial lung disease, should be monitored closely during treatment with irinotecan. The drug can potentially worsen these conditions or cause interstitial lung disease, as mentioned in the black box warning. 
• Genetic variations: irinotecan is metabolized by various enzymes, including UDP-glucuronosyltransferase 1A1 (UGT1A1). Some individuals may have genetic variations that affect the activity of the UGT1A1 enzyme, resulting in altered drug metabolism and increased risk of toxicity. Genetic testing may be considered to identify patients at increased risk. 

Pregnancy / Lactation

Pregnancy consideration:  

AU TGA pregnancy category: D
US FDA pregnancy category: D 

Lactation:   

Excreted into human milk is Not known. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

irinotecan is a cytotoxic anticancer drug in the class of medications known as topoisomerase inhibitors.  

irinotecan exerts its anticancer effects by inhibiting the enzyme topoisomerase I. Topoisomerase I is involved in DNA replication and repair processes in cells. irinotecan binds to the DNA-topoisomerase I complex, preventing the resealing of DNA strands that the enzyme has cut. This leads to DNA damage accumulation and stable cleavable complexes, ultimately causing DNA breaks and interfering with DNA replication and transcription. The inhibition of topoisomerase I results in cell cycle arrest and apoptosis (programmed cell death) of cancer cells. 

Pharmacodynamics: 

Mechanism of action: irinotecan exerts its anticancer effects through its mechanism of action as a topoisomerase I inhibitor. Here is a detailed explanation of the mechanism of action of irinotecan: 

• Topoisomerase I inhibition: irinotecan specifically targets and inhibits the enzyme topoisomerase I. Topoisomerases are enzymes involved in the regulation of DNA topology and structure. They help relieve torsional stress and facilitate DNA replication, transcription, and repair. 
• Formation of the cleavable complex: irinotecan forms a complex with topoisomerase I and DNA. It binds to the DNA-topoisomerase I complex and stabilizes it, preventing the resealing of DNA strands that the enzyme has cut during its normal catalytic cycle. 
• Inhibition of DNA repair: By stabilizing the cleavable complex, irinotecan hinders the normal DNA repair processes. This leads to the accumulation of DNA damage, specifically single-strand breaks in DNA. 
• DNA strand breaks: The accumulation of single-strand breaks prevents the replication and transcription of DNA. It also interferes with the normal progression of the DNA replication fork. Consequently, the DNA strand breaks can progress into double-strand breaks. 
• Cell cycle arrest and apoptosis: The accumulation of DNA damage, particularly double-strand breaks, triggers cell cycle arrest and activates signaling pathways that induce apoptosis or programmed cell death. Apoptosis eliminates cells with extensive DNA damage, preventing their proliferation and promoting tumor cell death. 

Overall, irinotecan’s inhibition of topoisomerase I and the subsequent accumulation of DNA damage disrupt normal cellular processes and lead to cell cycle arrest and apoptosis in cancer cells. 

Pharmacokinetics: 

Absorption 

After intravenous administration, irinotecan is rapidly and completely absorbed into the systemic circulation. The absolute bioavailability of irinotecan following oral administration is low (approximately 33%) due to extensive first-pass metabolism in the liver. The oral prodrug form of irinotecan, known as irinotecan hydrochloride trihydrate, is converted to the active metabolite, SN-38, by carboxylesterases in the liver and intestinal mucosa. 

Distribution 

irinotecan and its active metabolite, SN-38, are extensively bound to plasma proteins, primarily albumin. The volume of distribution of irinotecan is relatively large, indicating that it distributes widely throughout the body. The concentration of SN-38 in tissues is generally higher than that of irinotecan, as SN-38 is the more potent and active form. 

Metabolism 

The metabolism of irinotecan involves enzymatic transformations, primarily in the liver. irinotecan is metabolized to its active metabolite, SN-38, by carboxylesterases. SN-38 is metabolized by the hepatic enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) to form SN-38G, which is an inactive glucuronide conjugate. UGT1A1 genetic polymorphisms can influence the metabolism and clearance of irinotecan, leading to interpatient variability in drug response and potential toxicity. 

Elimination and Excretion 

The primary route of excretion for irinotecan and its metabolites is through the bile into the feces. The inactive glucuronide conjugate SN-38G is the major metabolite excreted in the bile. A small portion of irinotecan and its metabolites may undergo enterohepatic circulation, reabsorbing from the intestines and returning to the liver via the portal circulation. Renal excretion of irinotecan and its metabolites is relatively low, with less than 10% of the dose excreted in the urine. 

Adminstartion

Administration: 

Intravenous administration 

irinotecan is typically administered intravenously (IV) under the supervision of a healthcare professional. The specific administration schedule and dosage may vary based on type of cancer being treated and the treatment schedule prescribed by the healthcare provider. Here are some general guidelines for the administration of irinotecan: 

• Pre-medication: Patients may be given medications to help prevent or minimize potential side effects such as nausea and vomiting before receiving irinotecan. These pre-medications may include antiemetics (anti-nausea drugs) and corticosteroids. 
• Intravenous infusion: irinotecan is given as an intravenous infusion over a specific period. The infusion can take anywhere from 30 to 90 minutes, depending on the prescribed dose and the treatment regimen. The infusion is typically administered through a vein in the arm/central venous catheter. 
• Treatment frequency: The frequency of irinotecan administration can vary. It may be given as single-agent therapy or combined with other chemotherapy drugs. The treatment cycle is often repeated every 2 to 3 weeks, allowing time for the body to recover between doses. 
• Dose adjustments: The irinotecan dosage may be adjusted based on several factors, including the patient’s body surface area, overall health status, blood cell counts, and tolerance to previous treatments. Dose adjustments are made to optimize treatment effectiveness and minimize potential side effects. 
• Monitoring and follow-up: During and after the infusion, patients are monitored for any signs of adverse reactions, such as hypersensitivity reactions, severe diarrhea, or myelosuppression. Regular blood tests are performed to monitor blood cell counts and assess the patient’s response to treatment. 

It’s important to note that the administration of irinotecan should be performed by trained healthcare professionals experienced in handling chemotherapy medications. They will follow specific protocols and guidelines to ensure the safe and proper administration of the drug. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: irinotecan 

Pronounced: [ EYE-ri-noe-TEE-kan ]  

Why do we use irinotecan? 

irinotecan is primarily used to treat colorectal cancer, particularly in advanced or metastatic stages. However, it may also be employed with other chemotherapy drugs to treat other types of cancer. Some of the common uses of irinotecan include: 

• Colorectal cancer: irinotecan is a critical component of chemotherapy regimens used for colorectal cancer. It might be used as a single agent or with drugs like 5-fluorouracil (5-FU) and leucovorin. It is often prescribed for advanced or metastatic colorectal cancer that has generally not responded to other treatments. 
• Small cell lung cancer: irinotecan can be used with other chemotherapy agents to treat small cell lung cancer (SCLC). It is often combined with cisplatin or carboplatin to form a standard treatment regimen for extensive-stage SCLC. 
• Pancreatic cancer: irinotecan, in combination with other drugs such as 5-FU and leucovorin, may be used as part of chemotherapy regimens for advanced pancreatic cancer. 
• Gastric (stomach) cancer: irinotecan, along with other chemotherapy agents like cisplatin, fluorouracil, and leucovorin, may be used to treat advanced or metastatic gastric cancer. 

It’s important to note that using irinotecan and its specific indications may depend on various factors, including the stage and type of cancer, individual patient characteristics, and the healthcare provider’s judgment.