Irinotecan – Uses, Dosage, Side Effects, Interaction

Irinotecan is an antineoplastic enzyme inhibitor primarily used in the treatment of colorectal cancer. Irinotecan is a semisynthetic derivative of camptothecin. Camptothecins interact specifically with topoisomerase I, an enzyme in the cell nucleus that regulates DNA topology and facilitates nuclear processes such as DNA replication, recombination, and repair. During these processes, topoisomerase I relieve torsional strain in DNA by inducing reversible single-strand breaks, allowing single DNA strands to pass through the break. The 3′-DNA terminus of the broken DNA strands binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After the DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the chemically unaltered topoisomers that allow transcription to proceed. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent the religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either Irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks. The precise contribution of SN-38 to the activity of irinotecan in humans is not known. Irinotecan is cell cycle phase-specific (S-phase).

Use in Cancer

Acalabrutinib is approved to treat:

• Chronic lymphocytic leukemia or small lymphocytic lymphoma in adults.
• Mantle cell lymphoma in adults who have received at least one other type of treatment.¹

¹This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, a confirmatory trial(s) must show that acalabrutinib provides a clinical? benefit in these patients. Acalabrutinib is also being studied in the treatment of other types of cancer.

FDA-approved Uses

Colorectal Cancer

• Colorectal cancer is the third most common cause of cancer mortality in the United States. It constitutes about 10% of worldwide cancer deaths.[rx] Irinotecan is combined with 5-fluorouracil (5-FU) and leucovorin for maximum efficacy against colorectal cancer.[rx] It is considered more efficacious in combination with 5-FU/leucovorin than the separate individual use of the agents. This combination is also known as the FOLFIRI regimen.[rx] With therapy regimens like FOLFIRI, the median survival rate of a patient with metastatic colorectal cancer has improved from 8 months to 24 months.[rx]
• Capecitabine, the pro-drug of 5-FU, is also combined with irinotecan for a treatment regimen known as XELIRI. There is insufficient supporting evidence to state whether FOLFIRI or XELIRI works better against colorectal cancer.[rx] Both are considered first-line therapy, and both share similar side effect? profiles.
• Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), is combined with irinotecan for patients with wild-type K-Ras colorectal tumors.[rx]

Pancreatic Cancer

• Pancreatic ductal adenocarcinoma has a poor prognosis? due to its late stage of presentation, increased susceptibility to metastasizing, and resistance to treatments. Nanoliposomal irinotecan, combined with 5-FU/leucovorin, was approved for the treatment of pancreatic cancer in October 2015. Nanoliposomal irinotecan allows for better pharmacokinetics and biodistribution due to the drug’s encapsulation within liposome-based nanoparticles. Because of how aggressive pancreatic cancer is and how recently the approval of this regimen is, there is no set sequencing of therapy to be considered superior. It is up to the provider and the patient’s age and status.[rx]

Non-FDA-approved Uses

Ovarian Cancer

• Ovarian cancer is the second most common gynecologic malignancy in the United States. To treat ovarian cancer, irinotecan is combined with cisplatin, a platinum analog that cross-links DNA. It is still undergoing clinical trials, but early phase I and phase II trials show response rates of 20% to 25% in patients with recurrent or refractory disease.[rx]

Lung Cancer

• The current chemotherapy regimen for small-cell lung cancer is etoposide and cisplatin. Recent studies have been demonstrating the efficacy of irinotecan with cisplatin. Myelosuppression is the most common side effect with either regimen researchers note it to be worse in patients receiving etoposide and cisplatin. Using irinotecan in place of etoposide, a topoisomerase II inhibitor could allow patients to tolerate the regimen longer and thus improve outcomes.

Contraindication?

• dehydration?
• decreased function of bone marrow?
• anemia?
• decreased blood platelets
• low levels of a type of white blood cell called neutrophils
• obstruction of a blood vessel by a blood clot
• a type of inflammation? of the lung called interstitial pneumonitis
• inflammatory bowel disease?
• blocked bowels with decreased peristaltic movement
• liver? problems
• high amount of bilirubin? in the blood
• diarrhea?
• pregnancy
• a patient who is producing milk and breastfeeding
• chronic obstructive pulmonary disease?
• reduced UGT1A1 enzyme activity due to *28 polymorphism
• sepsis?

Dosage

Strengths: 20 mg/mL

Colorectal Cancer

COMBINATION REGIMEN 1:

• 125 mg/m2 IV over 90 minutes on Days 1, 8,15, and 22 with LV 20 mg/m2 IV bolus on Days 1, 8, 15, and 22 followed by 5-FU 500 mg/m2 IV bolus on Days 1, 8, 15, and 22 every 6 weeks

COMBINATION REGIMEN 2:

• 180 mg/m2 IV over 90 minutes on Days 1, 15, and 29 with LV 200 mg/m2 IV over 2 hours on Days 1, 2, 15, 16, 29, and 30 followed by 5-FU 400 mg/m2 IV bolus on Days 1, 2, 15, 16, 29, and 30 and 5-FU 600 mg/m2 IV over 22 hours on Days 1, 2, 15, 16, 29, 30 (NOTE: 5-FU IV follows 5-FU bolus)

SINGLE AGENT REGIMEN 1:

• 125 mg/m2 IV over 90 minutes on Days 1, 8, 15, and 22 then 2-week rest

SINGLE AGENT REGIMEN 2:

• 350 mg/m2 IV over 90 minutes on Day 1 every 3 weeks
• It is recommended that patients receive premedication with antiemetics (e.g., 10 mg dexamethasone given in conjunction with another antiemetic agent, such as a 5-HT 3 blocker [e.g., ondansetron or granisetron]).
• Antiemetic agents should be given at least 30 minutes before this drug.
• Physicians should consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed.
• A similar antiemetic regimen should be used with combination therapy.
• Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms.
• First-line therapy in combination with 5-fluorouracil (5-fu) and leucovorin (LV) for patients with metastatic carcinoma of the colon or rectum
• Patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy

Dose Adjustments

DOSE REGIMEN MODIFICATIONS FOR COMBINATION REGIMEN 1:
IRINOTECAN:

• Starting dose: 125 mg/m2
• Adjusted dose level -1: 100 mg/m2
• Adjusted dose level -2: 75 mg/m2

LV:

• Starting dose: 20 mg/m2
• Adjusted dose level -1: 20 mg/m2
• Adjusted dose level -2: 20 mg/m2

5FU:

• Starting dose: 500 mg/m2
• Adjusted dose level -1: 400 mg/m2
• Adjusted dose level -2: 300 mg/m2

NOTE: Dose beyond dose level -2 by decrements of about 20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely if patients continue to experience clinical benefit.

DOSE REGIMEN MODIFICATIONS FOR COMBINATION REGIMEN 2:
IRINOTECAN:

• Starting dose: 180 mg/m2
• Adjusted dose level -1: 150 mg/m2
• Adjusted dose level -2: 120 mg/m2

LV:

• Starting dose: 200 mg/m2
• Adjusted dose level -1: 200 mg/m2
• Adjusted dose level -2: 200 mg/m2

5FU bolus:

• Starting dose: 400 mg/m2
• Adjusted dose level -1: 320 mg/m2
• Adjusted dose level -2: 240 mg/m2

5FU IV (NOTE: 5-FU IV follows 5-FU bolus):

• Starting dose: 600 mg/m2
• Adjusted dose level -1: 480 mg/m2
• Adjusted dose level -2: 360 mg/m2

NOTE: Dose beyond dose level -2 by decrements of about 20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely if patients continue to experience clinical benefit.

RECOMMENDED DOSE MODIFICATIONS FOR IRINOTECAN HYDROCHLORIDE INJECTION /5-FLUOROURACIL (5-FU)/LEUCOVORIN (LV) COMBINATION SCHEDULES:

• Patients should return to pretreatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to 1500/mm 3 or greater and the platelet count has recovered to 100,000/mm 3 or greater and treatment-related diarrhea is fully resolved.
• Therapy should be delayed 1 to 2 weeks to allow for recovery from therapy-related toxicities.
• If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing therapy.

NEUTROPENIA

• No toxicity: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 1500 to 1999/mm3: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 1000 to 1499/mm3: Decrease by 1 dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 500 to 999/mm3: Omit dose until resolved to Grade 2 or less than decrease by 1 dose level during a cycle of therapy; decrease 1 dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils less than 500/mm3: Omit dose until resolved to Grade 2 or less than decrease by 2 dose levels during a cycle of therapy; decrease 2 dose levels at the start of subsequent cycles relative to the starting dose used in the previous cycle.

NEUTROPENIC FEVER:

• Omit dose until resolved then decrease 2 dose levels.

OTHER HEMATOLOGIC TOXICITIES:

• Dose modifications for leukopenia or thrombocytopenia during a cycle of therapy and at the start of subsequent cycles of therapy are the same as recommended for neutropenia.

DIARRHEA:

• Two to 3 stools/day greater than pretreatment: Delay dose until resolved to baseline, then give same dose; maintenance dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Four to 6 stools/day greater than pretreatment: Omit dose until resolved to baseline, then decrease by 1 dose level; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Seven to 9 stools/day greater than pretreatment: Omit dose until resolved to baseline, then decrease by 1 dose level; decrease by 1 dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Greater than 10 stools/day greater than pretreatment: Omit dose until resolved to baseline, then decrease by 2 dose levels; decrease by 2 dose levels at the start of subsequent cycles relative to the starting dose used in the previous cycle.

OTHER NONHEMATOLOGIC TOXICITIES (excluding alopecia, anorexia, and asthenia):

• First toxicity: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Second toxicity: Omit dose until resolved to Grade 1 or less than decrease by 1 dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Third toxicity: Omit dose until resolved to Grade 2 or less than decrease by 1 dose level during a cycle of therapy; decrease by 1 dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Fourth toxicity: Omit dose until resolved to Grade 2 or less than decrease by 2 dose levels during a cycle of therapy; decrease by 2 dose levels at the start of subsequent cycles relative to the starting dose used in the previous cycle.

* For mucositis/stomatitis decrease only 5-FU, not irinotecan during a cycle of therapy.
* For mucositis/stomatitis decrease only 5-FU, not irinotecan at the start of subsequent cycles relative to the starting dose used in the previous cycle.

DOSE REGIMEN MODIFICATIONS FOR SINGLE AGENT REGIMEN 1:
IRINOTECAN:

• Starting dose: 125 mg/m2
• Adjusted dose level -1: 100 mg/m2
• Adjusted dose level -2: 75 mg/m2

NOTE: Subsequent doses may be adjusted to as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg increments depending on individual patient tolerance. Provided intolerable toxicity does not develop, therapy with additional cycles may be continued indefinitely if patients continue to experience clinical benefit.

DOSE REGIMEN MODIFICATIONS FOR SINGLE AGENT REGIMEN 2:
IRINOTECAN:

• Starting dose: 350 mg/m2
• Adjusted dose level -1: 300 mg/m2
• Adjusted dose level -2: 250 mg/m2

NOTE: Subsequent doses may be adjusted to as low as 200 mg/m2 in 50 mg/m2 decrements depending on individual patient tolerance. Provided intolerable toxicity does not develop, therapy with additional cycles may be continued indefinitely if patients continue to experience clinical benefit.

RECOMMENDED DOSE MODIFICATIONS FOR SINGLE-AGENT SCHEDULES:

• A new cycle of therapy should not begin until the granulocyte count has recovered to 1500/mm3 or greater and the platelet count has recovered to 100,000/mm3 or greater and therapy-related diarrhea is fully resolved.
• Therapy should be delayed 1 to 2 weeks to allow for recovery from therapy-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing this drug.

NEUTROPENIA:
Weekly Schedule:

• No toxicity: Maintain dose level during a cycle of therapy; increase by 25 mg/m2 up to a maximum dose of 150 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 1500 to 1999/mm3: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 1000 to 1499/mm3: Decrease by 25 mg/m2 during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 500 to 999/mm3: Omit dose until resolved to Grade 2 or less then decrease by 25 mg/m2; decrease 25 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils less than 500/mm3: Omit dose until resolved to Grade 2 or less then decrease by 50 mg/m2; decrease 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.

Once Every Three Weeks Schedule:

• No toxicity: Maintain dose level during a cycle of therapy; increase by 25 mg/m2 up to a maximum dose of 150 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 1500 to 1999/mm3: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 1000 to 1499/mm3: Decrease by 25 mg/m2 during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 500 to 999/mm3: Omit dose until resolved to Grade 2 or less then decrease by 25 mg/m2; decrease 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils less than 500/mm3: Omit dose until resolved to Grade 2 or less then decrease by 25 mg/m2; decrease by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.

OTHER HEMATOLOGIC TOXICITIES:

• Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of therapy are the same as recommended for neutropenia.

DIARRHEA:
Weekly Schedule:

• Two to 3 stools/day greater than pretreatment: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Four to 6 stools/day greater than pretreatment: Decrease dose by 25 mg/m2 during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Seven to 9 stools/day greater than pretreatment: Omit dose until resolved to Grade 2 or less, then decrease dose by 25 mg/m2 during a cycle of therapy; decrease dose by 25 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Greater than 10 stools/day greater than pretreatment: Omit dose until resolved to Grade 2 or less, then decrease dose by 50 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.

Once Every Three Weeks Schedule:

• Two to 3 stools/day greater than pretreatment: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Four to 6 stools/day greater than pretreatment: Decrease dose by 25 mg/m2 during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Seven to 9 stools/day greater than pretreatment: Omit dose until resolved to Grade 2 or less, then decrease dose by 25 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Greater than 10 stools/day greater than pretreatment: Omit dose until resolved to Grade 2 or less, then decrease dose by 50 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.

OTHER NONHEMATOLOGIC TOXICITIES (excluding alopecia, anorexia, asthenia):
Weekly Schedule:

• First toxicity: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Second toxicity: Decrease dose by 25 mg/m2 during a cycle of therapy; decrease dose by 25 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Third toxicity: Omit dose until resolved to Grade 2 or less then decrease by 25 mg/m2 during a cycle of therapy; decrease dose by 25 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Fourth toxicity: Omit dose until resolved to Grade 2 or less then decrease by 50 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.

Once Every Three Weeks Schedule:

• First toxicity: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Second toxicity: Decrease dose by 25 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Third toxicity: Omit dose until resolved to Grade 2 or less than decrease by 25 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Fourth toxicity: Omit dose until resolved to Grade 2 or less than decrease by 50 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.

DOSE IN PATIENTS WITH REDUCED UGT1A1 ACTIVITY:

• When administered in combination with other agents, or as a single agent, a reduction in the starting dose by at least one level should be considered for patients known to be homozygous for the UGT1A1 28 alleles; however, the precise dose reduction in this patient population is not known, and subsequent dose modifications should be considered based on individual patient tolerance to therapy.

Side Effects

The Most Common

• nausea
• vomiting
• constipation
• swelling and sores in the mouth
• heartburn
• loss of appetite
• weight loss
• hair loss
• weakness
• sleepiness
• pain, especially back pain
• chest pain
• yellowing of the skin or eyes
• swollen stomach
• unexpected or unusual weight gain
• swelling of the arms, hands, feet, ankles, or lower legs
• rash
• hives
• itching
• difficulty breathing or swallowing

More Common

• severe or ongoing vomiting or diarrhea;
• black or bloody stools;
• nausea or vomiting that keeps you from drinking enough fluids;
• sores or white patches in or around your mouth;
• new or worsening cough or shortness of breath;
• dehydration symptoms–feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin;
• low blood cell counts–fever, tiredness, skin sores, easy bruising, unusual bleeding, pale skin, cold hands, and feet, feeling light-headed;
• symptoms of sepsis–confusion, fever or chills, severe drowsiness, fast heartbeats, rapid breathing, feeling very ill.
• fever, pain, mouth sores, or other signs of infection;
• low blood cell counts, abnormal liver function tests;
• diarrhea, constipation;
• nausea, vomiting, stomach pain;
• loss of appetite, weight loss;
• weakness; or hair loss.

Rare

• loss of appetite,
• constipation,
• cough,
• drowsiness,
• mouth sores,
• weakness,
• trouble sleeping, and
• temporary hair loss.
• hives,
• difficulty breathing,
• swelling of the face, lips, tongue, or throat,
• pain, redness, or swelling at the injection site or arms or legs,
• numbness, tingling, burning of arms or legs,
• back or bloody stools,
• change in the amount of urine,
• shortness of breath,
• cough,
• chest pain,
• weakness on one side of the body,
• trouble speaking,
• confusion,
• rash,
• itching, and
• severe dizziness.

Drug interaction

Pregnancy and Lactation

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

Pregnancy

Available postmarketing and published data reporting the use in pregnant women, are insufficient and confounded by concomitant use of other cytotoxic drugs, to evaluate for any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Verify the pregnancy status in female patients of reproductive potential before initiating therapy

Lactation

Irinotecan and its metabolites are present in human milk; there is no information regarding the effects of the drug on the breastfed infant, or milk production; because of the potential for serious adverse reactions from the drug in a breastfed child, advise lactating women not to breastfeed during treatment and for 7 days after the final dose

References