Irinotecan

Usage

• Irinotecan is prescribed for metastatic colorectal cancer, often in combination with other chemotherapy agents like 5-fluorouracil (5-FU) and leucovorin. It is also used in combination regimens for various other cancers like small cell lung cancer, gastric cancer, and pancreatic cancer.
• Pharmacological classification: Irinotecan is a topoisomerase I inhibitor. It belongs to the antineoplastic agent class, specifically categorized under the miscellaneous antineoplastics.
• Mechanism of Action: Irinotecan and its active metabolite, SN-38, bind to the topoisomerase I-DNA complex, stabilizing it and thus inhibiting the religation of single-strand DNA breaks created by topoisomerase I during DNA replication. This leads to DNA damage and ultimately apoptosis (cell death) of cancer cells.

Alternate Names

• International Nonproprietary Name (INN): Irinotecan hydrochloride trihydrate
• Brand Names: Camptosar®, Campto®

How It Works

• Pharmacodynamics: Irinotecan exerts its cytotoxic effect by inhibiting topoisomerase I, leading to DNA damage and apoptosis in rapidly dividing cells, primarily targeting cancerous cells.

• Pharmacokinetics:

  • Absorption: Administered intravenously.
  • Metabolism: Irinotecan is a prodrug converted in the liver by carboxylesterase enzymes to its active metabolite, SN-38, which is substantially more potent than irinotecan itself. SN-38 is further metabolized by UGT1A1 enzyme primarily to the inactive metabolite, SN-38 glucuronide (SN-38G). Polymorphisms in UGT1A1 (specifically *28 allele) affect glucuronidation and increase the risk of severe side effects, such as neutropenia and diarrhea.
  • Elimination: Irinotecan and its metabolites are eliminated through biliary excretion into the feces, with approximately 25% excreted in urine.

• Mode of Action: Irinotecan and SN-38 create a ternary complex with topoisomerase I and DNA, preventing the enzyme from religating single-strand DNA breaks. This leads to double-strand DNA breaks during DNA replication, initiating cell cycle arrest and apoptosis.

• Receptor binding, enzyme inhibition, or neurotransmitter modulation: Irinotecan acts through inhibition of the enzyme topoisomerase I. SN-38 is also associated with anticholinesterase activity.

• Elimination pathways: Primarily through the hepatobiliary route, mainly fecal excretion, with a small amount excreted in the urine.

Dosage

Standard Dosage

Adults:

• Weekly Schedule:
  • 125 mg/m² IV infusion over 90 minutes once weekly for 4 weeks followed by a 2-week rest period.
  • Dose may be adjusted based on individual tolerance.
  • Maximum: 150 mg/m²
• Every-3-Weeks Schedule: 350 mg/m² IV infusion over 30-90 minutes every 3 weeks.
• Every-2-weeks Dosage Schedule: 250 mg/m2 by intravenous infusion.
• Several combination regimens for irinotecan exist, each requiring specific dosing and administration strategies. These should be referenced based on the exact clinical need.

Children: Safety and efficacy not fully established. Limited data available regarding usage and dosage in children.

Special Cases:

• Elderly Patients: Close monitoring is recommended due to potential increased sensitivity to toxicities, especially diarrhea. For patients ≥ 70 years, weekly dosing at 100mg/m² or q3w dosing at 300mg/m² should be considered as starting doses.
• Patients with Renal Impairment: No formal studies, but renal dose adjustment is not typically required as the kidney is not a major route of excretion.
• Patients with Hepatic Dysfunction: Reduce the starting dose based on bilirubin levels:
  • Bilirubin 1 to 1.5 x ULN: 350 mg/m² (monotherapy) or specific regimen guidelines.
  • Bilirubin 1.5 to 3 x ULN: 200 mg/m² (monotherapy) or specific regimen guidelines.
  • Bilirubin > 3 x ULN: Contraindicated.
• Patients with Comorbid Conditions: Exercise caution and consider dose adjustments, especially in individuals with prior pelvic or abdominal radiation therapy, Gilbert’s syndrome, UGT1A1 polymorphisms, or other conditions affecting drug metabolism and clearance.

Clinical Use Cases

Irinotecan is not typically indicated for use in situations like intubation, surgical procedures, mechanical ventilation, ICU use, or acute emergency situations. Its primary role is in chemotherapy regimens for specific cancer types, particularly metastatic colorectal cancer.

Dosage Adjustments

Dose adjustments are generally based on the individual patient’s tolerance and adverse reactions. Dose reductions are usually made in increments of 25 mg/m² for weekly regimens or 50 to 100 mg/m² for other administration schedules. Closely monitor complete blood counts, liver function tests, and other relevant clinical parameters.

Side Effects

Common Side Effects

• Diarrhea (can be severe and life-threatening), nausea, vomiting, neutropenia, leukopenia, anemia, thrombocytopenia, fatigue, alopecia, abdominal pain, anorexia. Early-onset diarrhea may manifest as a cholinergic syndrome and should be treated with atropine.

Rare but Serious Side Effects

• Severe neutropenia (increased risk of infections), febrile neutropenia, severe diarrhea with dehydration and electrolyte disturbances, interstitial lung disease, anaphylaxis.

Long-Term Effects

• Secondary malignancies, chronic gastrointestinal problems, persistent fatigue, cardiac toxicity.

Adverse Drug Reactions (ADR)

• Severe myelosuppression (neutropenia, thrombocytopenia, anemia), acute cholinergic syndrome (early-onset diarrhea, sweating, abdominal cramps, rhinorrhea, lacrimation), severe delayed-onset diarrhea, interstitial pneumonitis, hypersensitivity reactions, anaphylaxis.

Contraindications

• Hypersensitivity to irinotecan or any component of the formulation.
• Severe hepatic impairment (bilirubin >3 x ULN).
• History of severe allergic reactions to topoisomerase I inhibitors.
• Chronic inflammatory bowel disease (Crohn’s disease, ulcerative colitis).
• Pregnancy and breastfeeding (unless benefits outweigh risks), bowel obstruction. Concurrent use with St. John’s Wort is contraindicated.

Drug Interactions

• CYP450 interactions: Irinotecan is primarily metabolized by carboxylesterases, but its active metabolite SN-38 is subject to glucuronidation via UGT1A1. Concurrent use of inhibitors of UGT1A1 can lead to increased toxicity.
• Other clinically significant interactions:
  • Ketoconazole, itraconazole and other azole antifungals may enhance toxicity by increasing exposure to SN-38.
  • St. John’s Wort decreases efficacy through induction of CYP3A4.
  • Anticholinergic drugs may exacerbate constipation.
  • Drugs causing QT prolongation increase the risk of cardiac arrhythmias.
  • Immunosuppressants enhance myelosuppression.
  • Live attenuated vaccines (e.g. yellow fever) increased risk of severe infection.
  • Dexamethasone increase risk of hyperglycemia and lymphocytopenia.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D (Camptosar®)
• Irinotecan can cause fetal harm. Adequate contraception should be used during and for at least 6 months after treatment in women and 3 months after treatment in men.
• Breastfeeding is contraindicated. Irinotecan and SN-38 are excreted in breast milk and pose a risk to the infant.

Drug Profile Summary

• Mechanism of Action: Topoisomerase I inhibitor; causes DNA damage leading to apoptosis.
• Side Effects: Diarrhea (can be severe), neutropenia, nausea, vomiting, fatigue, alopecia.
• Contraindications: Hypersensitivity, severe hepatic dysfunction, pregnancy, breastfeeding.
• Drug Interactions: Ketoconazole, St. John’s Wort, immunosuppressants, live vaccines.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: Variable depending on regimen; see dosage section.
• Monitoring Parameters: Complete blood count (CBC), liver function tests (LFTs), bilirubin levels, signs and symptoms of diarrhea.

Popular Combinations

• 5-fluorouracil (5-FU) and leucovorin (FOLFIRI regimen) for colorectal cancer.
• Cetuximab or panitumumab may be added to FOLFIRI for certain types of colorectal cancer.
• Leucovorin and fluorouracil for metastatic adenocarcinoma of the pancreas.
• Cisplatin for cervical cancer.

Precautions

• General Precautions: Pre-hydration and pre-medication with antiemetics and corticosteroids is recommended. Patients should be monitored for myelosuppression, diarrhea, and other side effects. Advise patients about potential side effects and provide instructions on managing diarrhea, including prophylactic loperamide and maintaining adequate hydration.
• Specific Populations: Contraindicated in pregnancy and lactation. Carefully monitor elderly individuals and individuals with hepatic dysfunction. UGT1A1 testing should be performed where appropriate and results used to guide dosing.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Irinotecan?

A: The dosage varies greatly based on indication, patient factors (renal/hepatic function, comorbidities), and concomitant medications. For metastatic colorectal cancer, dosages of 125 mg/m² weekly for 4 weeks, followed by a 2 week rest, or 350 mg/m² every 3 weeks are common. Combination regimen dosing should be referenced based on the specific drugs used.

Q2: What are the most serious side effects to watch for in patients receiving Irinotecan?

A: Severe diarrhea (early-onset cholinergic and late-onset), myelosuppression (neutropenia, anemia, thrombocytopenia), and hypersensitivity reactions are the most serious side effects requiring immediate management.

Q3: How should Irinotecan-induced diarrhea be managed?

A: Early-onset diarrhea (within 24 hours of infusion) is often due to a cholinergic syndrome and is treated with atropine. Late-onset diarrhea may require aggressive fluid and electrolyte management and loperamide as described in relevant guidelines.

Q4: Can Irinotecan be given to pregnant or breastfeeding women?

A: No, Irinotecan is contraindicated during pregnancy and breastfeeding because it can cause fetal harm and is excreted in breast milk. Effective contraception is mandatory.

Q5: Are there any specific genetic considerations for Irinotecan dosing?

A: Yes. Patients with the UGT1A1*28 polymorphism have impaired SN-38 glucuronidation, increasing the risk of severe toxicities. A lower starting dose may be needed for homozygous individuals.

Q6: What are the key drug interactions with Irinotecan that clinicians should be aware of?

A: Ketoconazole, itraconazole and other azole antifungals and St John’s Wort have clinically significant interactions with Irinotecan. Concomitant use should be avoided where possible. Other interacting drugs including other chemotherapeutic agents should be evaluated on a case-by-case basis.

Q7: How should Irinotecan be administered?

A: It is administered intravenously after dilution, typically over 30-90 minutes. Premedication with antiemetics and corticosteroids is often required.

Q8: What are the major contraindications to Irinotecan therapy?

A: Hypersensitivity to Irinotecan or severe hepatic impairment are absolute contraindications. Pregnancy and lactation are also contraindications unless the benefits outweigh the risks (highly unlikely given the potential for harm). Bowel obstruction or severe chronic inflammatory bowel disease may also be contraindications.

Q9: What monitoring parameters are important during treatment?

A: Regularly monitor complete blood counts (CBC) to assess for neutropenia, anemia, and thrombocytopenia. Liver function tests (LFTs) and bilirubin levels should be monitored to evaluate hepatic function. Also, monitor for diarrhea, and any signs and symptoms of infection or hypersensitivity.