Irinotecan (Conventional) is a chemotherapeutic drug. It is a semisynthetic plant alkaloid that is used to treat metastatic colorectal cancer and other cancers.

Irinotecan Uses:

• Metastatic Colorectal cancer:
  • Metastatic carcinoma of the colon or rectum, either in form of first-line therapy (in combination with fluorouracil and leucovorin), or for recurrent disease after initial fluorouracil-based treatment.
• Off Label Use of Irinotecan in Adults:
  • Cervical cancer (recurrent or metastatic)
  • CNS tumor, (recurrent glioblastoma)
  • Esophageal cancer (metastatic or locally advanced)
  • Ewing sarcoma (recurrent or progressive)
  • Gastric cancer (metastatic or locally advanced)
  • Non-small cell lung cancer (advanced)
  • Ovarian cancer (recurrent)
  • Pancreatic cancer (advanced or metastatic)
  • Pancreatic cancer, potentially curable, adjuvant therapy
  • Small cell lung cancer (extensive stage)
  • Small cell lung cancer (limited stage)
  • Unknown primary adenocarcinoma

Irinotecan dose in Adults

Note:

• Initial dose reduction by a minimum of one dose level should be thought of for initial pelvic and/or abdominal radiotherapy, performance status of 2, or known homozygosity for UGT1A1*28 allele (subsequent dosing/adjustments should be based on individual tolerance).
• Irinotecan (conventional) and irinotecan (liposomal) are NOT interchangeable.
• Dosing varies between formulations; verify the intended product and dose before preparation and administration.
• Pre-medications:
  • Premedication with atropine at dose 0.25 to 1 mg IV or SubQ should be considered in patients with cholinergic symptoms (such as increased salivation, rhinitis, miosis, diaphoresis, abdominal cramping) or early-onset diarrhea.
  • Irinotecan has the potential of causing moderate vomiting; antiemetics are recommended to prevent nausea and vomiting.

Irinotecan Dose as a single-agent therapy in the metastatic Colorectal cancer: IV:

• Weekly regimen:
  • 125 mg/m² over 90 minutes on days 1, 8, 15, and 22 of a 6-week treatment cycle (may adjust upward to 150 mg/m² if tolerated).
  • Adjusted dose level -1: 100 mg/m²
  • Adjusted dose level -2: 75 mg/m²
  • Further adjust to 50 mg/m² (in decrements of 25 to 50 mg/m²) if needed
• Once-every-3-week regimen:
  • 350 mg/m over 90 minutes, once every 3 weeks
  • Adjusted dose level -1: 300 mg/m²
  • Adjusted dose level -2: 250 mg/m²
  • Further adjust to 200 mg/m² (in decrements of 25 to 50 mg/m² ) if needed

Irinotecan dose in the treatment of metastatic colorectal cancer (in combination with fluorouracil and leucovorin): IV:

• Six-week (42-day) cycle:
  • Regimen 1:
    • 125 mg/m² over 1 and half hour on days 1, 8, 15, and 22; to be infused in combination with bolus/infusion leucovorin and fluorouracil (leucovorin administered immediately after irinotecan; fluorouracil immediately following leucovorin).
    • Adjusted dose level -1: 100 mg/m²
    • Adjusted dose level -2: 75 mg/m²
    • Further, adjust if needed in decrements of ~20%
  • Regimen 2:
    • Infuse over 1 and half-hour at 180 mg/m² on days 1, 15, and 29; to be infused in combination with infusional leucovorin and bolus/infusion fluorouracil (leucovorin administered immediately after irinotecan; fluorouracil immediately following leucovorin).
    • Adjusted dose level -1: 150 mg/m²
    • Adjusted dose level -2: 120 mg/m²
    • Further, adjust if needed in decrements of ~20%

Irinotecan dose in the treatment of metastatic colorectal cancer (off-label dosing): IV:

• FOLFOXIRI regimen:
  • 165 mg/m² over 1 hour once every 2 weeks (in combination with oxaliplatin, leucovorin, and fluorouracil)

Irinotecan dose in the treatment of recurrent or metastatic Cervical cancer (off-label):

• IV: 125 mg/m² over 90 minutes once weekly for 4 consecutive weeks followed by a 2-week rest during each 6-week treatment cycle.

Irinotecan dose in the treatment of recurrent glioblastoma CNS tumor (off-label):

• IV: 125 mg/m² over 90 minutes once every 2 weeks (in combination with bevacizumab).
• NOTE: In patients taking concurrent antiepileptic enzyme-inducing medications irinotecan dose was increased to 340 mg/m².

Irinotecan dose in the treatment of metastatic or locally advanced Esophageal cancer (off-label):

• IV: 65 mg/m² over 90 minutes days 1, 8, 15, and 22 of a 6-week treatment cycle (in combination with cisplatin) or
• 180 mg/m² over 90 minutes every 2 weeks (in combination with leucovorin and fluorouracil) or
• 250 mg/m² every 3 weeks (in combination with capecitabine).

Irinotecan dose in the treatment of recurrent or progressive Ewing sarcoma (off- use):

• IV: 20 mg/m² days 1 to 5 and days 8 to 12 every 3 weeks (in combination with temozolomide).

Irinotecan dose in the treatment of metastatic or locally advanced Gastric cancer (off-label):

• IV: 150 mg/m² (as a single agent) on days 1 and 15 of a 4-week treatment cycle or
• 65 mg/m² over 90 minutes days 1, 8, 15, and 22 of a 6-week treatment cycle (in combination with cisplatin) or
• 70 mg/m² over 90 minutes on days 1 and 15 of a 4-week treatment cycle (in combination with cisplatin) for up to 6 cycles or
• 180 mg/m² over 1 and half hour every 2 weeks (in combination with leucovorin and fluorouracil) or
• 250 mg/m² every 3 weeks (in combination with capecitabine).

Irinotecan dose in the treatment of advanced non-small cell lung cancer (off-label):

• IV: 60 mg/m² days 1, 8, and 15 every 4 weeks (in combination with cisplatin).

Irinotecan dose in the treatment of recurrent Ovarian cancer, platinum- and taxane-resistant (off-label):

• IV: 100 mg/m² days 1, 8, and 15 every 4 weeks (as a single-agent) for up to 6 cycles.

Irinotecan dose in the treatment of advanced or metastatic Pancreatic cancer (off-label use): IV:

• FOLFIRINOX regimen:
  • 180 mg/m² over 90 minutes every 2 weeks (in combination with oxaliplatin, leucovorin, and fluorouracil).

Irinotecan dose in the treatment of Pancreatic cancer, potentially curable, adjuvant therapy (off-label):

Note: American Society of Clinical Oncology (ASCO) guidelines suggests adjuvant therapy of 6 months in case of complete recovery; if preoperative chemotherapy therapy was received, a total of 6 months of adjuvant therapy (including the preoperative regimen) is suggested.

• mFOLFIRINOX regimen:
  • 150 mg/m² intravenously every 2 weeks (in combination with fluorouracil, leucovorin, and oxaliplatin; modified FOLFIRINOX regimen) for 6 months.
  • As per ASCO guidelines, mFOLFIRINOX is the best first-line adjuvant regimen for a potentially curable disease.

Irinotecan dose in the treatment of Small cell lung cancer, extensive-stage (off-label):

• IV: 60 mg/m² days 1, 8, and 15 every 4 weeks (in combination with cisplatin) or
• 65 mg/m² days 1 and 8 every 3 weeks (in combination with cisplatin) or
• 175 mg/m² day 1 every 3 weeks (in combination with carboplatin) or
• 50 mg/m² days 1, 8, and 15 every 4 weeks (in combination with carboplatin).
• According to ASCO guidelines, a combination of platinum-based therapy (cisplatin or carboplatin) with either irinotecan or etoposide for 4 to SIX cycles is suggested over other regimens for the disease of the extensive stage.

Irinotecan dose in the treatment of Small cell lung cancer, limited-stage (off-label):

• IV: Consolidation therapy (administer after induction cisplatin, etoposide, and radiation therapy):
  • 60 mg/m² days 1, 8, and 15 every 3 to 4 weeks (in combination with cisplatin) for 3 cycles.
  • Additional studies are important to further define the effects of irinotecan in the treatment of limited-stage disease.

Irinotecan dose in the treatment of Unknown primary adenocarcinoma (off-label):

• IV: 100 mg/m² days 1 and 8 every 3 weeks (in combination with gemcitabine) for 4 to 6 cycles.

Irinotecan dose in Childrens

Note:

• Initial dose reduction by a minimum of one dose level should be thought of for initial pelvic and/or abdominal radiotherapy, performance status of 2, or known homozygosity for UGT1A1*28 allele.
• Consider prophylaxis with third-generation oral cephalosporins, and/or IV atropine or SubQ for treatment in cholinergic symptoms (eg, increased salivation, diaphoresis, abdominal cramping) or diarrhea.
• Details concerning dosage in combination regimens should also be consulted. Irinotecan (conventional) and irinotecan (liposomal) are NOT interchangeable.
• Dosing varies between formulations; verify the intended product and dose before preparation and administration.

Irinotecan dose in the treatment of refractory (or palliative) Neuroblastoma: Limited data available:

• Children ≥2 years and Adolescents:
  • IV: 50 mg/m² over 1 hour once daily on days 1 to 5 (5 doses), in combination with temozolomide; repeat cycle every 21 days.

Irinotecan dose in the treatment of a refractory or relapsed solid tumor or CNS tumor (low-dose, protracted schedule):

• Children ≥2 years and Adolescents:
  • IV: 15 mg/m² over 1 hour once daily on days 1 to 5 (5 doses) and days 8 to 12 (5 doses) of a 28-day treatment cycle;
  • in the trial, a maximum dose of 30 mg/dose was observed;
  • The cycle may be repeated if tolerated in combination with temozolomide and vincristine

Irinotecan dose in the treatment of a refractory or relapsed solid tumor or CNS tumor: 

• Children and Adolescents:
  • Daily regimen:
    • IV: Children ≥2 years and Adolescents:
      • 50 mg/m² over 1 hour once daily on days 1 to 5 (5 doses) as a single agent;
      • repeat cycle every 21 days.
      • some protocols contain a combination with temozolomide
    • Oral: Children and Adolescents:
      • 90 mg/m² once daily on days 1 to 5 (5 doses) repeat every 3 weeks; in combination with vincristine and temozolomide.
  • Weekly regimen (Bomgaars 2006):
    • Heavily pretreated patients (eg, ≥2 prior chemotherapy regimens):
      • IV: 125 mg/m² /dose once weekly for 4 weeks over 90 minutes,
      • repeat cycle every 6 weeks
    • Less-heavily pretreated patients (≤2 prior chemotherapy regimens):
      • IV: 160 mg/m² /dose once weekly for 4 weeks over 90 minutes,
      • repeat cycle every 6 weeks

Irinotecan dose in the treatment of refractory or metastatic Rhabdomyosarcoma:

• Children and Adolescents:
  • IV: 50 mg/m² once daily for 5 days (maximum dose: 100 mg/dose) on protocol-specific weeks.
  • Dosing adjustment for toxicity:
    • The presented adjustments in doses are based on experience in adult patients; specific guidelines for pediatric patients are limited.
    • Refer to specific guidelines for management in pediatric patients if available. See tables for adult dosage recommendations.
    • It is suggested that new courses start only following the granulocyte count recovers to ≥1,500/mm³, the platelet counts get ≥100,000/mm³, and treatment-related diarrhea has fully resolved.
    • As per the patient's ability to tolerate therapy, adult doses should be adjusted in increments of 25 to 50 mg/m².
    • Treatment should be delayed 7 to 14 days to allow for recovery from treatment-related toxicities.
    • If the patient has not recovered after a 14 days delay, consider discontinuing irinotecan. See tables for adult dosage recommendations.

Colorectal Cancer: Single-Agent Schedule: Recommended Adult Dosage Modification

Toxicity NCI GradeB (Value)	During a Cycle of Therapy	At Start of Subsequent Cycles of Therapy (After Adequate Recovery), Compared to Starting Dose in the Previous Cycle
	Weekly	Weekly	Once Every 3 Weeks
No toxicity	Maintain dose level	↑ 25 mg/m2 up to a maximum dose of 150 mg/m2	Maintain dose level
Neutropenia
1 (1,500 to 1,999/mm3)	Maintain dose level	Maintain dose level	Maintain dose level
2 (1,000 to 1,499/mm3)	↓ 25 mg/m2	Maintain dose level	Maintain dose level
3 (500 to 999/mm3)	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2	↓ 25 mg/m2	↓ 50 mg/m2
4 (<500/mm3)	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2	↓ 50 mg/m2	↓ 50 mg/m2
Neutropenic Fever (grade 4 neutropenia and ≥ grade 2 fever)	Omit dose until resolved, then ↓ 50 mg/m2	↓ 50 mg/m2	↓ 50 mg/m2
Other Hematologic Toxicities	Dose modifications for leukopenia, thrombocytopenia, and anemia during a course of therapy and at the start of subsequent courses of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.
Diarrhea
1 (2-3 stools/day >pretreatment)	Maintain dose level	Maintain dose level	Maintain dose level
2 (4-6 stools/day >pretreatment)	↓ 25 mg/m2	Maintain dose level	Maintain dose level
3 (7-9 stools/day > pretreatment)	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2	↓ 25 mg/m2	↓ 50 mg/m2
4 (≥10 stools/day > pretreatment)	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2	↓ 50 mg/m2	↓ 50 mg/m2
Other Nonhematologic ToxicitiesC
Grade 1	Maintain dose level	Maintain dose level	Maintain dose level
Grade 2	↓ 25 mg/m2	↓ 25 mg/m2	↓ 50 mg/m2
Grade 3	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2	↓ 25 mg/m2	↓ 50 mg/m2
Grade 4	Omit dose until resolved to ≤ grade 2, then ↓ 5o mg/m2	↓ 50 mg/m2	↓ 50 mg/m2
AAll dose modifications should be based on the worst preceding toxicity.
BNational Cancer Institute Common Toxicity Criteria (version 1.0).
CExcludes alopecia, anorexia, asthenia.

Pregnancy Risk Factor D

• In animal reproduction studies, adverse events were reported. Limited information is available on the use of irinotecan during pregnancy (conventional).
• If administered during pregnancy, may cause harm to the fetus.
• Treatment should be stopped for females with reproductive potential.

Use of irinotecan while breastfeeding

• It is unknown if breast milk contains irinotecan.
• The manufacturer suggests that the mother decide whether to stop breastfeeding or discontinue using the drug.
• This is in consideration of the risk of serious adverse reactions in breastfed babies.

Irinotecan Dose in Kidney Disease:

• Renal impairment:
  • There are no dosage adjustments provided in the drug manufacturer’s labeling (has not been studied); use with caution.
• Dialysis:
  • Use in patients with dialysis is not recommended by the drug manufacturer; however, the literature recommends reducing weekly dose from 125 mg/m² to 50 mg/m² and administer after hemodialysis or on non-dialysis days.

Irinotecan Dose in Liver disease:

• Manufacturer's labeling:
  • Liver metastases with normal hepatic function:
    • No dosage adjustment necessary.
  • Bilirubin >ULN to ≤2 mg/dL: 
    • Reduce initial dose by one dose level
  • Bilirubin >2 mg/dL:
    • Use is not recommended
• Alternate recommendations: The following adjustments have also been recommended:
  • Bilirubin 1.5 to 3 mg/dL:
    • Administer 75% of dose (Floyd 2006)
  • Bilirubin 1.51 to 3 times ULN:
    • Reduce dose from 350 mg/m every 3 weeks to 200 mg/m every 3 weeks.  

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• Frequency of adverse reactions observed for single-agent use of irinotecan only.
• In limited pediatric experience, dehydration (often associated with severe hypokalemia and hyponatremia) was among the most significant grade 3/4 adverse events, with a frequency of up to 29%.
• In addition, grade 3/4 infection was reported in 24% of candidates.

Common Side Effects of Irinotecan:

• Cardiovascular:
  • Vasodilation
• Central Nervous System:
  • Cholinergic Syndrome
  • Pain
  • Dizziness
  • Insomnia
  • Headache
  • Chills
• Dermatologic:
  • Alopecia
  • Diaphoresis
  • Skin Rash
• Endocrine & Metabolic:
  • Weight Loss
  • Dehydration
• Gastrointestinal:
  • Diarrhea
  • Nausea
  • Abdominal Pain
  • Vomiting
  • Abdominal Cramps
  • Anorexia
  • Constipation
  • Mucositis
  • Flatulence
  • Stomatitis
• Hematologic & Oncologic:
  • Anemia
  • Leukopenia
  • Thrombocytopenia
  • Neutropenia
• Hepatic:
  • Increased Serum Bilirubin
  • Increased Serum Alkaline Phosphatase
• Infection:
  • Infection
• Neuromuscular & Skeletal:
  • Weakness
  • Back Pain
• Respiratory:
  • Dyspnea
  • Cough
  • Rhinitis
• Miscellaneous:
  • Fever

Less Common Side Effects of Irinotecan:

• Cardiovascular:
  • Edema
  • Hypotension
  • Thromboembolism
• Central Nervous System:
  • Drowsiness
  • Confusion
• Gastrointestinal:
  • Abdominal Distention
  • Dyspepsia
• Hematologic & Oncologic:
  • Febrile Neutropenia
  • Hemorrhage
  • Neutropenic Infection
• Hepatic:
  • Increased Serum AST
  • Ascites
  • Jaundice
• Respiratory:
  • Pneumonia

Contraindications to Irinotecan:

• Hypersensitivity to irinotecan and any component of the formulation
• Canadian labeling: Additional contraindications not in the US labeling
  • Combination with azole antifungals (ketoconazole or fluconazole),
  • Patients with hereditary fructose intolerance

Warnings and precautions

• Suppression of bone marrow: [US Boxed Warning]
  • Might cause severe myelosuppression.
  • Sepsis-related deaths following severe neutropenia have been reported.
  • Antibiotics should be used immediately for complications secondary to neutropenia.
  • If neutropenic fever is present or the absolute neutrophil count is below 1,000/mm3, the therapy should be stopped temporarily. The dose should then be reduced once the absolute neutrophil counts are >1,000/mm3.
  • Patients who have had previous pelvic/abdominal radiotherapy have a higher risk of severe bone loss.
  • Patients who received weekly irinotecan and had previously received pelvic/abdominal radiotherapy were more likely to develop grade 3 or 4.
  • Based on limited data, concurrent radiation therapy with irinotecan is not recommended.
• Diarrhea:
  • Severe diarrhea can occur, which could be fatal if it is not treated promptly.
  • Early diarrhea occurs within one day of receiving irinotecan. It is characterised by cholinergic symptoms. Atropine can be used to prevent or treat it.
  • Loomeramide should be used immediately to treat late diarrhea, which can be potentially life-threatening.
  • If the patient experiences severe neutropenia, fever, or ileus, antibiotics may be necessary.
  • For severe diarrhea, interrupt treatment and decrease the dose.
  • Early diarrhea is usually temporary and not severe. Cholinergic symptoms include increased salivation and rhinitis.
  • Higher doses of Irinotecan may result in more frequent cholinergic symptoms.
  • Late diarrhea occurs if the treatment is not completed within 24 hours. This can lead to electrolyte imbalance or dehydration.
  • Colitis, ulceration and bleeding may all occur with Late diarrhea. There have been cases of megacolonization and intestinal perforation.
  • Late diarrhea usually begins within 5 days of the last 3-week dose of irinotecan and 11 days after the last weekly dose.
  • For the treatment of late-onset diarrhea, it is important to have Loperamide readily available.
  • Diarrhea patients should be closely monitored and treated immediately.
  • Before resuming weekly irinotecan doses, the bowel function must return to baseline within 24 hours.
  • Diarrhea patients should avoid diuretics or laxatives.
• Extravasation
  • Irinotecan can be irritating.
  • Avoid extravasation. In the event of extravasation, the manufacturer suggests flushing the site with sterile waters and using ice to cool it.
• Gastrointestinal toxicities:
  • Irinotecan can cause moderate emesis.
  • Antiemetics can be used to prevent nausea or vomiting.
• Hypersensitivity
  • There have been severe hypersensitivity reactions, including anaphylaxis.
  • Hypersensitivity can be monitored closely and therapy should be stopped immediately.
• Toxicity in the lungs:
  • Fatal interstitial lung disease (IPD-like) has been reported in patients treated with combination and single-drug therapy.
  • Preexisting lung disease, radiation therapy and colony-stimulating factor are all risk factors for pulmonary poisoning.
  • Patients at high risk should be monitored for symptoms such as cough and difficulty breathing prior to and during treatment with irinotecan.
  • Assess any progressive changes in baseline pulmonary symptoms and any new-onset symptoms promptly (eg, fever, cough, dyspnea).
  • If IPD is confirmed, discontinue chemotherapy.
• Toxicity in the renal system:
  • Acute renal impairment and renal failure have been reported, possibly due to diarrhea.
  • Patients with impaired renal function should be cautious.
  • Patients on dialysis should not be given this medication.
• Thromboembolism
  • Thromboembolic events were reported.
• Bowel obstruction
  • Irinotecan should not be used on patients with bowel obstruction until the obstruction is resolved.
• Hepatic impairment
  • Patients with liver impairment should be cautious
  • The risk of exposure to the active metabolite (SN-38) is increased; toxicities could be exacerbated.
  • Patients with modestly elevated total serum bilirubin levels (from 1 to 2 mg/dL), have a significantly higher chance of experiencing grade 3 or 4 neutropenia, than patients with levels below 1 mg/dL.
  • Patients who have an abnormal bilirubin glucuronidation, such as Gilbert syndrome, could be more at risk for myelosuppression if they receive therapy with irinotecan.
  • Patients with hyperbilirubinemia or hepatic dysfunction should be treated with caution. Dosage adjustments should also be considered.

Irinotecan (conventional): Drug Interaction

Risk Factor C (Monitor therapy)
Aprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Chloramphenicol (Ophthalmic)	May enhance the adverse/toxic effect of Myelosuppressive Agents.
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CloZAPine	Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased.
Coccidioides immitis Skin Test	Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test.
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Denosumab	May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
Duvelisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Eltrombopag	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Fosaprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fosnetupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Gemfibrozil	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. See separate drug interaction monographs for agents listed as exceptions.
Ivosidenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Larotrectinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Mesalamine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Ocrelizumab	May enhance the immunosuppressive effect of Immunosuppressants.
Palbociclib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
P-glycoprotein/ABCB1 Inhibitors	May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).
Pidotimod	Immunosuppressants may diminish the therapeutic effect of Pidotimod.
Promazine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Ranolazine	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Rifabutin	May decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. Rifabutin may decrease the serum concentration of Irinotecan Products.
Rifapentine	May decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. Rifapentine may decrease the serum concentration of Irinotecan Products.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Simeprevir	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Siponimod	Immunosuppressants may enhance the immunosuppressive effect of Siponimod.
Smallpox and Monkeypox Vaccine (Live)	Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live).
Teriflunomide	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
Tertomotide	Immunosuppressants may diminish the therapeutic effect of Tertomotide.
Tobacco (Smoked)	May decrease serum concentrations of the active metabolite(s) of Irinotecan Products.
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Trastuzumab	May enhance the neutropenic effect of Immunosuppressants.
Risk Factor D (Consider therapy modification)
Baricitinib	Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted.
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).
Deferiprone	Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely.
Echinacea	May diminish the therapeutic effect of Immunosuppressants.
Fingolimod	Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections).
Leflunomide	Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly.
Lenograstim	Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy.
Lipegfilgrastim	Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
Nivolumab	Immunosuppressants may diminish the therapeutic effect of Nivolumab.
Palifermin	May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy.
Roflumilast	May enhance the immunosuppressive effect of Immunosuppressants.
Sipuleucel-T	Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy.
Stiripentol	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring.
Tofacitinib	Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants.
Tolvaptan	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
Vaccines (Inactivated)	Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.
Risk Factor X (Avoid combination)
BCG (Intravesical)	Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical).
BCG (Intravesical)	Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).
Cladribine	May enhance the immunosuppressive effect of Immunosuppressants.
Cladribine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Conivaptan	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Strong)	May decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Irinotecan Products.
CYP3A4 Inhibitors (Strong)	May increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Irinotecan Products.
Dipyrone	May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Lasmiditan	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Natalizumab	Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
Pimecrolimus	May enhance the adverse/toxic effect of Immunosuppressants.
St John's Wort	May decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be reduced. St John's Wort may decrease the serum concentration of Irinotecan Products.
Tacrolimus (Topical)	May enhance the adverse/toxic effect of Immunosuppressants.
UGT1A1 Inhibitors	May increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Exceptions: Atazanavir; Ombitasvir, Paritaprevir, and Ritonavir; Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir.
Upadacitinib	Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib.
Vaccines (Live)	Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live)

Monitoring parameters:

• CBC with differential, platelet count, and hemoglobin with each dose;
• bilirubin,
• electrolytes (with severe diarrhea);
• monitor for cholinergic reactions;
• monitor bowel movements and hydration status;
• signs/symptoms of pulmonary toxicity or hypersensitivity reactions;
• monitor the infusion site for signs of inflammation and avoid extravasation

A test is available for genotyping of UGT1A1; however, the use of the test is not widely accepted and a dose reduction is already recommended in patients who have experienced toxicity.   

How to administer Irinotecan?

• IV: IV Infusions are usually administered over a period of one and a half hours.
• Premedications:
  • Irinotecan can cause moderate emesis.
  • Premedication with dexamethasone or a 5-HT1-blocker is recommended for 30 minutes prior to administration.
  • If needed, prochlorperazine could be used for subsequent purposes.
  • As a premedication or treatment for cholinergic symptoms, such as increased salivation, rhinitis or constricted pupils, diaphoresis or abdominal cramping, SubQ or IV atropine 0.25-1 mg can be used.
• Management of Diarrhea:
  • Loperamide 4 mg orally at the onset and 2 mg every two hours thereafter. Or 4 mg every four hours at night until late diarrhea has subsided.
  • If diarrhea persists, repeat the administration.
  • You should not use Loperamide for longer than 48 hours consecutively.

Mechanism of action of Irinotecan:

• Irinotecan, along with its active metabolite (SN-38) reversibly binds to the topoisomerase I DNA complex which inhibits religation on the cleaved DNA strand.
• This causes the accumulation of cleavable compounds and results in the breaking down of double-strand DNA.
• These cell breaks are not easily repaired by mammalian cells, which results in cell death that is consistent with the S-phase cell cycle specificity, and termination of cell replication.

Distribution:

• distributes to pleural fluid, sweat, and saliva.

Protein binding,

• plasma: Predominantly to albumin;
  • Irinotecan: about 30% to 68%,
  • SN-38 (active metabolite): ~95%
• Metabolism:
  • Primarily hepatic by carboxylesterase enzymes to SN-38 (active metabolite); CYP3A4-mediated metabolism to inactive metabolites may also occur (one of which may be hydrolyzed to release SN-38).
  • Conjugation of SN-38 occurs by UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite.
  • SN-38 is raised by UGT1A1*28 polymorphism (10% of North Americans are homozygous for UGT1A1*28 allele).

Bioavailability:

• Median: 9%; increased in presence of gefitinib (median: 42%)

Half-life elimination:

• Children and Adolescents: Irinotecan: about 2.66 hours (range: 1.82 to 4.47 hours); SN38 (active metabolite): about 1.58 hours (range: 0.29 to 8.28 hours)
• Adults: Irinotecan: about 6 to 12 hours; SN-38: ~10 to 20 hours

Time to peak:

• Irinotecan: Oral: Children and Adolescents: about 3 hours
• SN-38: Following 90-minute infusion: ~1 hour

Excretion:

• Urine: Irinotecan (11% to 20%), metabolites (SN-38 <1%, SN-38 glucuronide, 3%)

International Brands of Irinotecan:

• Camptosar
• Actatecan
• Ai Li
• Calmtop
• Campto
• Camptosar
• Camtecan
• Efixano
• Etoniri
• Herocan
• Ican
• Imocam
• Imtus
• Indotecan
• Innocan
• Irenax
• Irican
• Iricip
• Irino
• Irinocan
• Irinocyt
• Irinogen
• Irinokabi
• Irinoll
• Irinotel
• Irinotesin
• Irinox
• Iritecan
• Irnocam
• Irocan
• Irotin
• Itoxaril
• Linatecan
• Lritecin
• Pipetecan
• Romisan
• Terican
• Topotecin
• Trinotecan

Irinotecan Brand Names in Pakistan:

Irinotecan Injection 40 mg
Campto	Pfizer Laboratories Ltd.
Irinotecan	Novartis Pharma (Pak) Ltd
Irinotel	Atco Laboratories Limited

Irinotecan Injection 100 mg
Campto	Pfizer Laboratories Ltd.
Cpt Ii	Medinet Pharmaceuticals
Cytotecan	Consolidated Chemical Laboratories (Pvt) Ltd.
Irinotecan	Novartis Pharma (Pak) Ltd
Irinotel	Atco Laboratories Limited
Kebirtecan	Oncogene Pharmaceuticals Karachi