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irinotecan

( eye-reen-oh-TEE-can )
Funding:
New Drug Funding Program
  • Irinotecan - First Line - Metastatic Colorectal Small Bowel or Appendiceal Cancer
  • Irinotecan - Second Line - Metastatic Colorectal Small Bowel or Appendiceal Cancer
Other Name(s): Camptosar® ()
Appearance: Clear, light-yellow solution mixed into larger bags of fluids
A - Drug Name

irinotecan

SYNONYM(S):   CPT-11

COMMON TRADE NAME(S):   Camptosar® ()

 
B - Mechanism of Action and Pharmacokinetics

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.



Distribution

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);
95% (SN-38) (mainly albumin)

Metabolism

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
Elimination

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)
 
C - Indications and Status
Health Canada Approvals:

  • 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
 
D - Adverse Effects

Emetogenic Potential:  

Moderate

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
Flushing (11%) 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


* "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.
Dose-limiting side effects are underlined.

** 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.

The most common and severe adverse effect of irinotecan is diarrhea. Two distinct types of diarrhea associated with irinotecan have been identified – an early onset cholinergic syndrome and late-onset diarrhea. The early-onset cholinergic effects, usually transient, may arise up to 24 hours after treatment and includes profound warmth, rhinitis, lacrimation, increased salivation, diaphoresis or flushing, followed by abdominal cramping and sudden diarrhea. They are thought to be related to the anticholinesterase activity of irinotecan and are more likely to occur at higher dose levels.  Acute events are managed successfully by administering IV or SC atropine 0.25 to 1 mg. Because of the short half-life of atropine, using it to prevent cholinergic symptoms is controversial; however, prophylactic atropine should be considered (unless contraindicated) in patients experiencing 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.

 

 
E - Dosing

Adequate antiemetic therapy and prophylactic loperamide must be provided. 

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


Adults:

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)

 


Dosage with Toxicity:

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
*This 5-FU infusion dosing has not been approved by Health Canada, but was used in some phase III trials.
# Dose depends on regimen used.
 
Dose Adjustments for Irinotecan in Combination with Fluorouracil:
 

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.



Dosage with Hepatic Impairment:

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



Dosage with Renal Impairment:

No specific studies, but as the kidney is not a major route of excretion, no adjustment anticipated to be required.



Dosage in the elderly:

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.

 



Children:

Safety and efficacy not established.



 
F - Administration Guidelines

  • 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


 
G - Special Precautions
Contraindications:

  • 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

Other Warnings/Precautions:

  • 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.

Pregnancy and Lactation:
  • 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
 
H - Interactions

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
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

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



Suggested Clinical Monitoring

Monitor Type Monitor Frequency

Renal function tests

Periodic

Blood glucose, especially in patients with diabetes

Baseline and as clinically indicated
 
J - Supplementary Public Funding

New Drug Funding Program (

NDFP Website

)
  • Irinotecan - First Line - Metastatic Colorectal Small Bowel or Appendiceal Cancer
  • Irinotecan - Second Line - Metastatic Colorectal Small Bowel or Appendiceal Cancer

 
K - References

Berg D.  Irinotecan Hydrochloride: drug profile and nursing implications of a topoisomerase I inhibitor in patients with advanced colorectal cancer.  ONF 1998;25(3):535-43.
 
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.

Irinotecan. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2018; October 26, 2018

McEvoy GK, editor. AHFS Drug Information 2013.  Bethesda: American Society of Health-System Pharmacists, p. 1089-93.
 
Product Monograph:  Avastin® (bevacizumab).  Hoffmann-La Roche Ltd., February 23, 2012.
 
Product Monograph: Camptosar® (irinotecan).  Pfizer Canada Inc., December 9, 2014.

Product Monograph: Irinotecan. Pfizer Canada Inc., February 11, 2015
 
Product Monograph:  Nexavar® (sorafenib).  Bayer Inc., May 1, 2013.
 
Somasundaram S, Edmund NA, Moore DT, Small GW, Shi YY, Orlowski RZ. Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer.  Cancer Res 2002 Jul 1;62(13):3868-75.
 
Tournigand C, André T, Achile E, et al.  FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.  J Clin Oncol 2004;22(2):229-37.
 
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.


 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

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