Irinotecan HCL: Paving the Way to Victory Against Colorectal Cancer

Overview

Topoisomerase I inhibitors are a class of chemotherapeutic drugs that includes Irinotecan hydrochloride. It destroys cell DNA in irreversible ways. Cancer cells and other fast-dividing cells are stopped from growing as a result, and they eventually die. The United States Food and Drug Administration (USFDA) approved Irinotecan HCL on October 22nd, 1998.

Drug Group:

Irinotecan is a member of the class of medications known as topoisomerase I inhibitors.

Indications:

• Patients with cancer that has progressed to their colon or rectum are treated with Irinotecan HCL injection in addition to other medications. It is administered in combination with two additional medications, Leucovorin (LV) and 5-Fluorouracil (5-FU), as part of the initial course of treatment.

• Patients whose cancer has returned or worsened after receiving Fluorouracil treatment may also be treated with Irinotecan HCL alone.

Contraindications:

Patients who are known to be extremely sensitive to Irinotecan or any of its constituents should not utilize Irinotecan HCL injection.

Dosage Forms and Available Strengths:

The three sizes of Irinotecan HCL Injection each contain a single dose:

• A small vial with two milliliters (mL) of liquid and 40 milligrams (mg) of Irinotecan hydrochloride.

• A medium-sized vial holding five mL of liquid and 100 mg of Irinotecan hydrochloride.

• A bigger vial holding 15 mL of liquid and 300 milligrams of Irinotecan hydrochloride.

For Patients:

What Is Colorectal Cancer?

The term "colorectal cancer" refers to the overgrowth of potentially dangerous cells in the colon (large intestine) or rectum. Because it frequently originates in the colon, it is also known as colon cancer. The rectum is the portion that connects to the anus at the end of the colon, which is the large tube that removes waste from the stomach.

In the colon or rectum, little abnormal growths known as polyps can occasionally be seen. Over time, these polyps may develop into cancer. Screening tests are used to identify these polyps early on, allowing for their removal before they develop into cancer. Additionally, screening makes colorectal cancer easier to cure by detecting it early.

What Are the Clinical Uses of Irinotecan HCL?

Irinotecan is a medication used either alone or in combination with other medications to treat colorectal or colon cancer, which originates in the large intestine. It is a member of the class of medications known as topoisomerase I inhibitors, which are used to treat cancer. Irinotecan functions by inhibiting the proliferation of cancer cells.

How Should Irinotecan HCL Be Used?

Irinotecan is given intravenously or into a vein by a physician or nurse for 90 minutes. It is usually administered on a weekly maximum basis, alternating weeks when Irinotecan is treated and weeks when it is not. The doctor will select the schedule that best suits the patient.

If side effects occur, treatment may need to be postponed and the dosage changed. Patients should be open and honest about their concerns during their Irinotecan treatment. Before each Irinotecan dose, medication may be given to prevent nausea and vomiting. In addition, other medications might be used to address or avoid further adverse effects.

What Are the Side Effects of Irinotecan HCL?

Irinotecan-treated patients occasionally experienced blood clots in their hearts, brains, lungs, or legs. It is not possible to determine if Irinotecan caused the blood clots due to insufficient information. Side effects are possible with Irinotecan. If any of these symptoms are severe or persist, inform the doctor:

• Appetite loss.

• Weakness.

• Loss of weight.

• Constipation.

• Loss of hair.

• Sores and swelling in the mouth.

• Vomiting.

• Nausea.

• Heartburn.

• Tiredness.

• Aches, particularly in the back.

Certain adverse effects may be dangerous. Inform the doctor as soon as possible if any of the following symptoms occur:

• Yellowing of the skin or eyes.

• Swelling of the arms, hands, feet, ankles, or lower legs.

• Rash.

• Unusual or unexpected weight gain.

• Swollen stomach.

• Difficulty swallowing or breathing.

• Chest pain.

• Hives.

What Are the Things to Inform the Doctor About Before Taking Irinotecan HCL?

• Allergies: If one has an allergy to sorbitol, Irinotecan, or any other drug.

• Drug Interactions: Let the doctor know if one is taking Ketoconazole. It is recommended that Ketoconazole be stopped for a week either before or during Irinotecan treatment. Notify the physician if one takes St. John's wort. For two weeks before beginning Irinotecan medication and for the duration of the treatment, one should avoid ingesting St. John's wort. Notify the physician and pharmacist of any other prescription and over-the-counter drugs, vitamins, supplements, and herbal remedies that one is taking or intends to take. Inform about drugs like Rifampin, Gemfibrozil, and Atazanavir, as the doctor could need to change the dosage or keep an eye out for any negative effects.

• Medical Conditions: Let the doctor know if one has any kidney, liver, or lung conditions, diabetes, or fructose intolerance.

• Pregnancy and Breastfeeding: Let the doctor know whether the patient is expecting a child, is currently pregnant, or intends to become pregnant in the future. It is critical to utilize reliable birth control and prevent pregnancy while receiving Irinotecan medication. Contact the doctor if the patient becomes pregnant while receiving therapy since Irinotecan may harm the developing fetus. Tell the doctor if one is nursing a child. Do not breastfeed for seven days following the last dose of Irinotecan injection and while getting it.

• Fertility Concerns: Men and women may have a reduction in fertility after using Irinotecan. Talk to the doctor about the hazards.

• Surgical Considerations: Let the physician or dentist know if one will be obtaining Irinotecan and if one is scheduled for surgery, including dental surgery.

• Side Effects: Take caution since Irinotecan can impair eyesight or cause vertigo (a sudden spinning feeling that might be internal or external, usually brought on by moving the head too quickly), particularly in the 24 hours following a dose. Wait to operate machinery or drive a car until one knows how it will affect things.

• Vaccinations: Before getting any shots while undergoing Irinotecan medication, talk to the doctor.

Dietary Consideration: During therapy, the physician will give patients advice on a special diet to follow to help control diarrhea. Pay close attention to these instructions. Talk to the doctor about consuming grapefruits and grapefruit juice while taking this medication.

Overdose: If an unintentional overdose of the medication occurs, contact the poison control helpline. Make an immediate call to emergency services if the person has passed out, is having breathing difficulties, has a seizure, or cannot be roused.

Symptoms of an overdose can include

• Fever.

• Chills.

• Sore throat.

• Cough.

• Other infection-related symptoms.

• Excessive diarrhea

For Doctors

Pharmacodynamics: Irinotecan dissolves in the water. Once it is within the body, it transforms into SN-38, an extremely potent chemical that stops tumor growth. Irinotecan is converted into SN-38 through an enzyme-dependent mechanism. It is far more effective than Irinotecan at inhibiting topoisomerase I, a particular protein that is crucial for tumor cells. The amount of SN-38 in the blood is far lower than that of Irinotecan, even though SN-38 is substantially more effective than Irinotecan at killing tumor cells in laboratory experiments. The majority of SN-38's attachments are to blood proteins. It is unclear exactly how SN-38 contributes to the medication's efficacy at this point. In the body, SN-38 and Irinotecan can both exist in two separate forms: an inactive form and an active one. Their choice of shape is determined by how basic or acidic their environment is.

Mechanism of Action: Irinotecan is derived from a substance known as camptothecin. The mechanism of action of camptothecins involves targeting an enzyme called topoisomerase I, which temporarily splits strands of DNA to reduce stress. Irinotecan attaches itself to the complex produced by topoisomerase I and DNA, coupled with its active form known as SN-38, to stop DNA from being correctly repaired. It is difficult for cells to heal themselves as a result of this disruption, which damages both strands of DNA, especially during DNA replication.

Pharmacokinetics:

• Blood Concentration Decline: Irinotecan levels in the blood gradually drop after an IV (intravenous) injection. Irinotecan has a half-life of roughly six to 12 hours, whereas the half-life of SN-38, the active metabolite, is roughly 10 to 20 hours.

• Dependency on Dose: Irinotecan is given at larger doses, which raises its blood levels; however, the rise in SN-38 is not dose-related.

• Peak Concentration: SN-38 reaches its peak levels approximately one hour after the Irinotecan infusion is stopped.

• Protein Binding: SN-38 binds highly (about 95 percent) to human plasma proteins, primarily albumin, while Irinotecan binds modestly (30 percent to 68 percent) to plasma proteins.

• Metabolism: Enzymes change Irinotecan into its active metabolite, SN-38. SN-38 is further converted by glucuronidation into the inactive form SN-38G.

• Metabolism Variability: Genetic variations, such as the UGT1A1*28 polymorphism, can impact Irinotecan metabolism, resulting in different drug exposures.

• Excretion in the Urine and Bile: During 48 hours following treatment, a tiny portion of Irinotecan and its metabolites are eliminated through the urine and bile.

• Impacts of Gender, Age, and Race: The pharmacokinetics of Irinotecan did not appear to be influenced by gender, and there were no appreciable variations in the pharmacokinetics between patients 65 years of age and older. The effect of race on its pharmacokinetics, however, is still unknown.

• Hepatic Impairment: Hepatic impairment greatly affects SN-38 exposure and Irinotecan clearance; hence, dosage modifications are necessary, especially in situations of severe hepatic failure.

• Renal Impairment: The impact of renal function on the pharmacokinetics of Irinotecan has not been well investigated. Patients with reduced renal function should exercise caution.

What Is the Prescribed Dosage and Method of Administration For Irinotecan HCL?

• Combination Regimen 1:

  • Give LV (Leucovorin) and 5-FU (Fluorouracil) intravenously for 90 minutes, coupled with Irinotecan HCL.

  • The following dosages are advised: 5-FU 500 mg/m2, LV 20 mg/m2, and Irinotecan HCL 125 mg/m2 (milligrams per square meter).

  • Patients with specific problems, such as elevated bilirubin levels, performance status of 2, or history of pelvic or abdominal radiation, may benefit from a dose reduction.

  • The patient's level of toxicity should be taken into consideration when adjusting the dosage.

• Combination Regimen 2:

  • Similar to Regimen 1, but with infusional 5-FU or LV.

  • The following dosages are advised: LV 200 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 600 mg/m2, and Irinotecan HCL 180 mg/m2.

  • If the patient experiences toxicity, dose reductions can be required.

• Dose Modifications: Modify the following doses following the worst toxicity that occurred earlier, especially with regard to neutropenia, diarrhea, and other hematologic or nonhematologic toxicities.

• Single-Agent Regimens:

  • Give a 90-minute intravenous infusion of Irinotecan HCL alone.

  • Administration patterns that occur every three weeks or every week determine the recommended dosages.

• UGT1A1 Activity: If a patient's UGT1A1 activity is known to be lower, consider reducing their Irinotecan HCL dosage.

• Premedication: To manage any adverse effects, patients should take antiemetic medications before therapy.

• Infusion Solution Preparation: Use Irinotecan HCL right away after reconstitution and dilute it before infusion. To guarantee stability and prevent contamination, adhere to specified preparation and storage instructions.

• Safe Management and Displacement: Handle Irinotecan HCL with caution to prevent exposure and extravasation. Observe safety precautions when handling and discarding anticancer medications. Keep an eye out for any indications of irritation at the infusion sites and take necessary action if extravasation happens.

Drug Interactions:

• Interaction Between Leucovorin (LV) and 5-Fluorouracil (5-FU): It was discovered that the coadministration of Irinotecan, 5-Fluorouracil (5-FU), and Leucovorin (LV) did not significantly alter the patient's Irinotecan levels in a trial involving solid tumor patients. This sequence of administration is frequently employed in treatments, even though the active form of Irinotecan, known as SN-38, showed significantly lower levels when Irinotecan was administered after 5-FU and LV.

• Reaction With Strong Inducers of CYP3A4: Irinotecan's efficacy may be decreased if certain drugs are used with it, such as Carbamazepine, Phenytoin, Phenobarbital, or St. John's wort. Unless required, it is preferable to avoid taking these medications before beginning Irinotecan HCL treatment.

• Interaction With Potent Inhibitors of CYP3A4 or UGT1A1: There may be adverse effects if certain drugs, such as Ketoconazole, raise the body's Irinotecan levels. Unless there are no other options available, it is recommended to quit these medications for at least one week prior to beginning Irinotecan HCL treatment. Similarly, to prevent elevated levels of Irinotecan or its active metabolite, any medications that inhibit CYP3A4 or UGT1A1 should be avoided in conjunction with Irinotecan HCL.

Clinical Studies: Combining Irinotecan with Leucovorin (LV) and 5-Fluorouracil (5-FU) has been successful in treating advanced colorectal cancer. Two noteworthy trials have demonstrated its ability to reduce tumor size, halt the progression of cancer, and prolong patient life. Physicians have flexibility when it comes to administering Irinotecan because it can be done once a week or once every three weeks. Also, it helps in cases where cancer recurs after 5-FU first therapy. Even in those situations, it contributes to tumor shrinkage and life extension. Additionally, research revealed that Irinotecan users reported feeling better and experiencing fewer side effects than non-users. Furthermore, Irinotecan was proven to prolong patient life more effectively than certain other medicines in other studies.

Storage and Handling: Store the medication vial in a room or other location with a consistent temperature range of 59 degrees Fahrenheit to 86 degrees Fahrenheit (15 degrees Celsius to 30 degrees Celsius). Make sure there is no light exposure for it. Until one needs to use it, keep the vial in its original package. Make sure the vial is secure and leak-free before removing it. Avoid using it and properly dispose of it if it is damaged.

Warnings and Precautions:

• Cholinergic Reactions and Diarrhea: Early diarrhea is often transient and infrequently severe. It can occur during or immediately after Irinotecan infusion. Cholinergic symptoms such as watery eyes, narrow pupils, runny noses, flushing, and cramping in the stomach may accompany it. Heart rate can also slow down on occasion. Medications like Atropine can be used to treat or prevent these symptoms. Late diarrhea can be extremely dangerous and even fatal; it typically appears more than a day after Irinotecan. Dehydration, electrolyte imbalances, or infections may result from it. Severe cases might result in intestinal obstructions, bleeding, or colitis. Patients should start taking Loperamide as soon as they experience delayed diarrhea. Until the diarrhea ends, the dosage might be four mg first, then two mg every two hours after that. In addition to replacing lost fluids and electrolytes, patients who have a fever or a dangerously low white blood cell count may also require antibiotics.

• Myelosuppression: Due to extremely low white blood cell counts, several patients receiving Irinotecan treatment have experienced serious infections. Treatment with Irinotecan should be stopped if a fever is caused by a low white blood cell count or if the count falls below 1000/mm3 (per cubic millimeter). The dosage of Irinotecan can be decreased once the white blood cell count reaches a minimum of 1000/mm3.

• Individuals With Lower Activity of UGT1A1: Neutropenia after starting Irinotecan is more common in people with the gene UGT1A1*28. For some patients, the dosage of Irinotecan may need to be reduced.

• Hypersensitivity: With Irinotecan, some patients may experience severe allergic responses. Treatment with Irinotecan should be discontinued if this occurs.

• Renal Failure or Impairment: Kidney issues may arise in certain cases of Irinotecan, particularly in individuals who experience significant fluid loss due to vomiting or diarrhea.

• Pulmonary Toxicity: Rarely, pulmonary issues may arise in Irinotecan-treated individuals. Symptoms such as coughing or difficulty breathing should be reported immediately.

• The Five-Day Regimen's Toxicity: The risk of side effects may rise if Irinotecan is used for four to five days straight every four weeks, along with specific other medications. Avoid using this combo unless there are special circumstances.

• Patients With Performance Status 2 Experience Increased Toxicity: During Irinotecan treatment, patients with a low ability to do daily tasks (performance status 2) were more likely to experience side effects and require hospitalization.

• Embryo Fetal Toxicity: Irinotecan should not be used by pregnant women since it may harm the unborn baby. The patient should consult their doctor as soon as possible if they become pregnant while receiving Irinotecan therapy.

• Individuals With Impairment of Liver: Since Irinotecan has not been researched in people with significant liver issues, it is unknown if using it is safe for them.

Use in Specific Populations:

• Pregnancy: Unborn children may be harmed by Irinotecan. Research conducted on animals has indicated that it may result in pregnancy complications such as elevated fetal loss and congenital abnormalities. It is crucial to prevent getting pregnant while using this drug because there have not been enough studies done on pregnant women. During therapy, women who are potentially pregnant should utilize an effective birth control method.

• Nursing Mothers: While it is unclear if Irinotecan enters breast milk, nursing mothers should think about halting breastfeeding while taking this drug due to the possibility of major side effects on their unborn child.

• Pediatric Use: It is unclear how effectively Irinotecan works in younger patients. Research has yielded inconsistent outcomes, with certain children enduring severe adverse events such as diarrhea and neutropenia. To fully understand the effects of this medicine on youngsters, more research is required.

• Geriatric Use: Due to a potential increased risk of diarrhea, older persons, particularly those over 65, should be constantly monitored when taking Irinotecan. To reduce adverse effects, the initial dose may need to be changed for elderly people.

• Renal Impairment: Since Irinotecan has not been well investigated in patients with renal issues, people with reduced kidney function are advised to use this medicine with caution. In general, dialysis patients should avoid it.

• Hepatic Impairment: Individuals with liver issues may be more exposed to Irinotecan’s active metabolite and have different Irinotecan clearance. When giving this medication to individuals who have liver impairment, care should be taken; depending on the severity of liver dysfunction, dosage modifications might be required.