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irinotecan
Irinotecan is a semi-synthetic derivative of camptothecin, an alkaloid extract from camptotheca acuminata. Camptothecin and its analogue belong to the class of topoisomerase I inhibitors. Irinotecan and its active metabolite, SN-38, bind to the topoisomerase DNA complex, preventing religation of the single-strand breaks in the DNA molecule. The drug and its active metabolite are believed to exert their cytotoxic effects during the S-phase of cell cycle.
Peak plasma concentrations of irinotecan are reached by the end of intravenous infusion, whereas those of the SN-38 metabolite occur about 0.5 to 2 hours after the infusion period. Irinotecan exposure increased in a dose-dependent manner over the usual range, where SN-38 increases less than proportionally with dose. No impact of gender on pharmacokinetics.
| Cross blood brain barrier? | No information found |
| PPB |
30–68% (irinotecan); |
Irinotecan is metabolized to its active form, SN38, in the presence of hepatic or gastrointestinal carboxylesterase. Both irinotecan and SN-38 undergo pH-dependent, reversible hydrolysis from the active closed-ring lactone to an open inactive carboxylate form. Irinotecan is also metabolized in part by CYP3A4 and UGT1A1 to inactive metabolites.
| Active metabolites | SN-38 |
| Inactive metabolites | yes |
The complete disposition of irinotecan in human has not been fully elucidated. SN-38 subsequently undergoes conjugation (by UDP glucuronyl transferase – UGT1A1) to form a glucuronide metabolite and is excreted in bile. Approximately 10% of the North American population is homozygous for the wild-type UGT1A1*28 allele, which results in reductions in UGT1A1 enzyme activity and higher SN38 systemic exposure.
| Urine | Low (11-20% unchanged, 5% as metabolites) |
| Half-life | 5.8-11.7 h (irinotecan); 7.7-17 h (SN38) |
- Single-agent treatment for recurrent colorectal cancer after treatment with fluorouracil-based chemotherapy
- As a component of combination first-line chemotherapy for patients with metastatic colorectal cancer
Other Uses:
- Gastrointestinal cancer (gastric, pancreatic, small bowel and appendix)
- Ewing's sarcoma
- Small cell lung cancer
Emetogenic Potential:
Extravasation Potential: None
The adverse effects listed below were reported in > 10% of patients from 3 pooled clinical trials of single-agent, weekly irinotecan in previously treated metastatic colorectal cancer and includes severe or life-threatening events (from these trials or other sources).
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Bradycardia (during infusion) | I | |||
| Hypotension (rare) | E | ||||
| Thromboembolism (5%) | E | ||||
| Dermatological | Alopecia (61%) | E | |||
| Rash (13%) | E | ||||
| Gastrointestinal | Abdominal pain (57%) (severe 16%) | I E | |||
| Anorexia, weight loss (55%) | I E | ||||
| Constipation (30%) | E | ||||
| Diarrhea (51%) (early; late 88%, severe 31%) | I E | ||||
| Dyspepsia (11%) | E | ||||
| Flatulence (12%) | E | ||||
| GI obstruction (rare) | E | ||||
| GI perforation (rare) | E | ||||
| Mucositis (12%) | E | ||||
| Nausea, vomiting (86%) (severe 17%) | I E | ||||
| General | Edema (10%) | E | |||
| Fatigue (76%) (severe 12%) | I | ||||
| Other (28%) (cholinergic symptoms) | I | ||||
| Hematological | Myelosuppression ± infection, bleeding (28%) (grade 3/4) | E | |||
| Hepatobiliary | ↑ LFTs (13%) (4% severe) | E | |||
| Pancreatitis (rare) | E | ||||
| Hypersensitivity | Hypersensitivity (rare) | I | |||
| Metabolic / Endocrine | Hyperglycemia (uncommon) | E | |||
| Tumor lysis syndrome (rare) | I | ||||
| Musculoskeletal | Musculoskeletal pain (15%) | E | |||
| Nervous System | Dizziness (15%) | I E | |||
| Dysarthria (or speech disorder; rare, transient) | I | ||||
| Headache (17%) | I E | ||||
| Insomnia (19%) | I E | ||||
| Renal | Renal failure (rare) | E | |||
| Respiratory | Cough, dyspnea (22%) | I E | |||
| Pneumonitis (infrequent) | I E | ||||
| Rhinitis (16%) | I E | ||||
| Vascular | Flushing (11%) | I | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for irinotecan include nausea, vomiting, fatigue, alopecia, abdominal pain, anorexia, weight loss, diarrhea, constipation, myelosuppression ± infection, bleeding and cholinergic symptoms.
Late diarrhea (occurring more than 24 hours after administration) may lead to dehydration or electrolyte imbalances, and can be life-threatening. The mechanism of late onset diarrhea is not well understood, but it appears to be linked to a secretory process that may be a secondary consequence of an irinotecan cytotoxic effect on the GI mucosa. It occurs in 80% of patients and the median onset time is 5-11 days, depending on the irinotecan dosing schedule. Late diarrhea must be treated promptly with loperamide, 4 mg at the first onset of late diarrhea and then 2mg every 2 hours until the patient is diarrhea-free for at least 12 hours. During the night the patient may take 4mg of loperamide every 4 hours. At these doses, loperamide is not recommended to be used for more than 48 consecutive hours due to the risk of paralytic ileus. Fluid intake should be maintained to avoid dehydration. Premedication with loperamide is not recommended and laxatives should be avoided. Antibiotics should be used in patients with ileus, fever or severe neutropenia.
Irinotecan-induced neutropenia is dose-related, generally brief, and non-cumulative, with a typical onset between days 15 and 21 and recovery between days 28 and 35. The frequency of grade 3 or 4 neutropenia is higher in patients who had prior pelvic or abdominal irradiation, had elevated serum bilirubin or who received the drug over less than 90 minutes. Consider the use of G-CSF in patients experiencing severe neutropenia. An increased risk of neutropenia was observed in patients homozygous for the UGT1A1*28 allele. Consider reducing the irinotecan starting dose (appropriate dose not established) in these patients and those with a history of myelosuppression with previous treatment.
Pneumonitis has been reported infrequently (predominantly in studies from Japan) following administration of irinotecan. This has been described as dyspnea, a non-productive cough, or a diffuse pulmonary infiltrate on chest x-ray. The etiology of these problems is unknown, and it is not clear whether they truly are caused by irinotecan or are actually a manifestation of the disease, primary lung cancer, or lung metastases.
Speech disorders (e.g. dysarthria, stuttering, voice changed) have been reported in post-marketing of irinotecan, with most cases occurring during or shortly after the irinotecan infusion and resolved spontaneously within minutes to hours. The cause of these speech disorders appeared to be unknown; some cases occurred with other neurologic, cholinergic or hypersensitivity symptoms.
Patients should not be treated with irinotecan until they have recovered from prior toxicity: platelets ≥ 100 x 109/L, ANC ≥ 1.5 x 109/L, GI toxicity recovered to baseline (without loperamide for at least 24 hours) and all other toxicities to Grade ≤ 1.
Patients with ileus, fever or febrile neutropenia should receive antibiotics.
Consider a reduction in the starting dose described below for:
- elderly patients (≥ 70 years)
- patients with prior abdominal or pelvic irradiation
- patients with a poor performance status (ECOG of 2)
- patients with mild increases in bilirubin (including Gilbert's syndrome)
- patients homozygous for UGT1A1*28 allele or patients with a history of myelosuppression with previous treatment
For cholinergic adverse effects (early diarrhea):
- Prophylactic atropine may be considered in patients who have experienced cholinergic symptoms
- Diarrhea (including abdominal cramps) may be severe and delayed with irinotecan; use loperamide 4mg at the onset of diarrhea, then 2mg every 2 hours until patient is diarrhea-free for 12 hours. During the night the patient may take 4mg of loperamide every 4 hours
Single agent:
q1w: 125 mg/m2 weekly for 4 weeks with a 2 week rest period.
Dose may be increased to 150mg/m2 in the absence of toxicity.
q3w: ≥ 70 years: 300mg/m2
< 70 years: 350mg/m2
In combination with 5-fluorouracil and leucovorin:
- q2w: 180 mg/m2 (See FOLFIRI regimen)
- 6-week regimen: 125mg/m2 D1, 8, 15 ,22 (IFL regimen)
All dose adjustments should be based on the worst preceding toxicity.
Single Agent:
| Dose Level | Dose (mg/m2) | |
| Weekly Regimen | Q 3 Weeks Regimen | |
| 0 | 125 | 350 |
| -1 | 100 | 300 |
| -2 | 75 | 250 |
| -3 | 50 | 200 |
|
Toxicity grade3
|
Suggested dose
During treatment course
of Weekly schedule2
|
At start of subsequent course1
|
|
|
Weekly schedule2
|
3-weekly schedule2
|
||
|
1
|
No change
|
No change
|
No change
|
|
2
|
↓ 25mg/m2
|
Diarrhea alone – no change
|
Diarrhea alone – no change
|
|
Hematologic alone – no change
|
Hematologic alone – no change
|
||
|
Other 3 : ↓ 25mg/m2
|
Other 3: ↓ 50mg/m2
|
||
|
3
|
Omit, then ↓ 25mg/m2 when ≤ grade 2
|
↓ 25mg/m2
|
↓ 50mg/m2
|
|
4 or febrile neutropenia
|
Omit, then ↓ 50mg/m2 when ≤ grade 2
|
↓ 50mg/m2
|
↓ 50mg/m2
|
| Pneumonitis | Hold; investigate and if confirmed, discontinue. | ||
|
1 Relative to the starting dose used in the previous cycle. Start new cycle when the parameters below are met.
2 Patients should not be retreated until GI toxicity resolved to baseline (without loperamide for at least 24 h), platelets ≥ 100 x 109/L, ANC ≥ 1.5 x 109/L and other toxicities recovered to ≤ grade 1. If no recovery after a 2-week delay, consider discontinuing treatment. 3 Excludes alopecia, anorexia, and fatigue
|
|||
In Combination Treatment:
Dose Levels:
| Regimen | Drug | Starting dose (mg/m2) | Dose level -1 (mg/m2) | Dose Level -2 (mg/m2) |
|
FOLFIRI
|
Irinotecan
|
180
|
150
|
120
|
|
Leucovorin infusion
|
400 or 200#
|
No change
|
No change
|
|
|
5-FU bolus
|
400
|
320
|
240
|
|
|
5-FU infusion* (start day 1 over 46 h)
|
2400
|
2000
|
1600
|
|
|
Alternative schedule for 5-FU infusion (over 22 h on days 1 and 2)
|
600
|
480
|
360
|
|
|
IFL
|
Irinotecan
|
125
|
100
|
75
|
|
Leucovorin bolus
|
20
|
20
|
20
|
|
|
5-FU bolus
|
500
|
400
|
300
|
# Dose depends on regimen used.
|
Toxicity Grade |
During a Cycle of Therapy2 (IFL)
|
At the start of subsequent cycles1, 2 (IFL or FOLFIRI) |
|
|
Hematologic
|
|||
|
Grade 1 |
No change |
No change |
|
|
Grade 2 |
↓ by 1 dose level |
No change |
|
|
Grade 3
|
Omit until ≤ grade 2 , then ↓ by 1 dose level |
↓ by 1 dose level |
|
|
Grade 4 or febrile neutropenia
|
Omit until ≤ grade 2 , then ↓ by 2 dose levels |
↓ by 2 dose levels |
|
|
Diarrhea
|
|||
|
Grade 1: 2-3/day > pre-treatment |
Delay until recovery to baseline then give same dose |
No change |
|
|
Grade 2: 4-6/day > pre-treatment |
Omit until recovery to baseline then ↓ by 1 dose level |
No change |
|
|
Grade 3: 7-9/day > pre-treatment |
Omit until recovery to baseline then ↓ by 1 dose level |
↓ by 1 dose level |
|
|
Grade 4: ≥ 10/day > pre-treatment |
Omit until recovery to baseline then ↓ by 2 dose levels |
↓ by 2 dose levels |
|
|
Other Non-hematologic toxicities (excludes alopecia, anorexia and fatigue). For mucositis/stomatitis, decrease 5FU only, not irinotecan. |
|||
|
Grade 1
|
No change |
No change |
|
|
Grade 2
|
Omit until ≤ grade 1, then ↓ by 1 dose level |
No change |
|
|
Grade 3
|
Omit until ≤ grade 2, then ↓ by 1 dose level |
↓ by 1 dose level |
|
|
Grade 4
|
Omit until ≤ grade 2, then ↓ by 2 dose levels |
↓ by 2 dose levels |
|
|
1 Relative to the starting dose used in the previous cycle. Start new cycle when the parameters below are met. 2 Patients should not be retreated until GI toxicity resolved to baseline (without loperamide for at least 24 h), platelets ≥ 100 x 109/L, ANC ≥ 1.5 x 109/L and other toxicities recovered to ≤ grade 1. If no recovery after a 2-week delay, consider discontinuing treatment. |
|||
Elimination is decreased in hepatic impairment with increased exposure to SN-38. Patients with bilirubin 1-1.5 x ULN or Gilbert’s syndrome are at an increased risk of myelosuppression.
|
Bilirubin 1
|
|
Transaminases
|
Irinotecan dose
|
|
22-35 µmoL/L (1-1.5 x ULN) or with Gilbert’s syndrome |
|
|
Monitor closely; may consider dose reduction
|
|
> 35 µmoL/L
|
or
|
>3 x ULN (without liver metastases) or >5 x ULN (with liver metastases) |
Not recommended.
|
|
1Consider investigating for reversible causes such as biliary obstruction and re-evaluate after stent |
|||
No specific studies, but as the kidney is not a major route of excretion, no adjustment anticipated to be required.
Monitor patients ≥ 65 years closely for increased risk of diarrhea. Patients ≥ 70 years of age using the q3w schedule should receive 300mg/m2 or 100 mg/m2 if using weekly dosing.
Safety and efficacy not established.
- Mix in 500mL bag (D5W-preferred or NS) in a concentration range between 0.12 to 3 mg/mL; infuse IV over 90 minutes
- Do not refrigerate admixtures in NS (may result in precipitation)
- Avoid freezing irinotecan and its admixtures since this may result in drug precipitation
- Do not admix with other drugs
- Protect from light
- Prior to the initial irinotecan treatment, patients should be given a sufficient supply of loperamide and instructed on its appropriate use
- Avoid grapefruit, starfruit, Seville oranges, their juices or products during irinotecan treatment
- Patients with a known hypersensitivity to the product or any of its ingredients
- Irinotecan should not be co-administered with azole antifungals (ketoconazole etc, see Interactions section)
- Avoid in patients with hereditary fructose intolerance since the product contains sorbitol
- Avoid the use of live or live attenuated vaccines
- Not recommended for use in patients with ECOG performance status 3 or 4, or in patients with moderate or severe increases in bilirubin.
- Carefully monitor and consider dose reduction for elderly patients, patients with poor performance status (= 2), limited marrow reserve, 3rd space accumulation, Gilbert’s syndrome and patients with reduced UGT1A1 activity; they may be more susceptible to the toxic effects of irinotecan.
- Concurrent administration of irinotecan with irradiation is not recommended. Patients with prior pelvic or abdominal irradiation are at an increased risk of severe myelosuppression following irinotecan therapy.
Other Drug Properties:
-
Carcinogenicity:
Unknown
The long-term carcinogenic potential of irinotecan has not been studied.
-
Embryotoxicity:
Yes
-
Teratogenicity:
Yes
Irinotecan is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.
-
Excretion into breast milk:
Documented in animals
Breastfeeding is not recommended. -
Fertility effects:
Unknown
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Dexamethasone | Lymphocytopenia | Additive | Monitor blood count |
| Dexamethasone | Hyperglycemia (especially in patients with glucose intolerance) | Lowers glucose tolerance | Monitor blood glucose |
| Prochlorperazine | ↑ akathisia observed when given on same day as irinotecan weekly | Unknown | Caution; avoid on same day of irinotecan treatment |
| Diuretics | ↑ dehydration | Additive | Monitor or Avoid |
| Azole antifungals | ↑ irinotecan toxicity | ↑ exposure of SN38 (110%) | CONTRAINDICATED. (Discontinue ≥ 1 week before first dose of irinotecan) |
| Other inhibitors of CYP3A4 (ciprofloxacin, clarithromycin, verapamil, grapefruit juice, etc) | ↑ irinotecan toxicity | ↑ exposure; increased formation of SN38 | Avoid concomitant use or adjust irinotecan dose |
| CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) | ↓ irinotecan effects | ↓ exposure because of lower SN38 levels | Avoid concomitant use – switch to non-enzyme inducing anticonvulsants; discontinue St. John's Wort ≥ 1 week prior to irinotecan. |
| Curcumin (tumeric) | may reduce effect of irinotecan | inhibits Irinotecan induced apoptosis | Avoid concomitant use |
| Atazanavir | ↑ effect of irinotecan | inhibits UGT1A1 and CYP3A4 | Avoid concomitant use |
| Bevacizumab | Unclear. Potential increased toxicity of irinotecan | Some pharmacokinetic studies have suggested ↑ SN38 levels with coadministration of bevacizumab | Caution |
| Neuromuscular blocking agents (ie. suxamethonium, succinylcholine) | Prolonged neuromuscular blocking effects | Additive anticholinesterase activity | Caution |
| UGT1A1 inhibitors (i.e. sorafenib, protease inhibitors) | ↑ effect of irinotecan | Inhibition of UGT1A1 (up to 120% ↑ exposure in SN-38) | Caution. Monitor for signs and symptoms of irinotecan toxicity. |
| laxatives | Worsens diarrhea | Additive | Avoid |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and before each dose |
Liver function tests |
Baseline and before each cycle (q 3 week regimen) or monthly (weekly x 4 regimen) |
Toxicity rating of diarrhea and other GI effects, cholinergic symptoms, pneumonitis, neurological, bleeding, infection, dehydration, fatigue, pancreatitis, thromboembolism |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
Renal function tests |
Periodic |
Blood glucose, especially in patients with diabetes |
Baseline and as clinically indicated |
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Drengler RL, Kuhn JG, Schaaf LJ et al. Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumor. J Clin Oncol 1999: 17(2):685-96.
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McEvoy GK, editor. AHFS Drug Information 2013. Bethesda: American Society of Health-System Pharmacists, p. 1089-93.
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Product Monograph: Camptosar® (irinotecan). Pfizer Canada Inc., December 9, 2014.
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Wiseman LR, Markham A. Irinotecan: a review of its pharmacological properties and clinical efficacy in the management of advanced colorectal cancer. Drugs 1996;52(4):606-23.
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