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

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.  

• 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

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: