irinotecan (Camptosar)

Dosing and uses of Camptosar (irinotecan)

• Adult
• Pediatric

 

Adult dosage forms and strengths

injectable solution

• 20mg/mL

 

Colorectal Cancer

Indicated as first-line therapy (with 5-fluorouracil and leucovorin) for metastatic colorectal cancer (CRC); it is also indicated for CRC that has recurred or progressed following intial fluorouracil-based therapy

Monotherapy

• Patients should be premedicated with antiemetic agents
• Atropine treatment should be considered in patients that experience cholinergic symptoms
• Regimen 1 (Weekly): 125 mg/m² IV infusion over 90 minutes on days 1, 8, 15, 22, then 2 weeks off, then repeat
• Regimen 2 (Once Every 3 Weeks): 350 mg/sq.meter IV infusion over 30-90 minutes q3Weeks
• Adjust dose per protocol

Combination therapy

• Patients should be premedicated with antiemetic agents
• Atropine treatment should be considered in patients that experience cholinergic symptoms
• Regimen 1 (6 week cycle with infusional 5-fluorouracil/ leucovorin): 180 mg/m² IV infusion over 30-90 minutes once on days 1, 15, and 29 IV (infuse over 30-90 min), followed by infusion with leucovorin and 5-fluorouracil; next cycle begins on day 43
• Regimen 2 (6 week cycle with bolus 5-fluorouracil/ leucovorin): 125 mg/sq.meter on days 1, 8, 15, and 22 (infuse over 90 min), followed by bolus doses of leucovorin and 5-fluorouracil
• Adjust dose per protocol

 

Pancreatic Cancer (Orphan)

Stable nanotherapeutic encapsulated irinotecan (MM-398; pegirinotecan)

Orphan indication sponsor

• Merrimack Pharmaceuticals, Inc., 1 Kendall Square; Cambridge, MA 02139-1670

 

Ovarian Cancer (Orphan)

Peg-irinotecan: Treatment of ovarian cancer

Orphan indication sponsor

• Nektar Theraeputics; 455 Mission Bay Blvd; South San Francisco, CA 94158

 

Other Indications & Uses

Off-label: advanced ovarian cancer, glioblastoma multiforme, NSCLC

 

Pediatric dosage forms and strengths

Not recommended

 

Camptosar (irinotecan) adverse (side) effects

>10%

Anemia (>90%)

Leukopenia (>90%)

Neutropenia (>90%)

Thrombocytopenia (>90%)

Elevated bilirubin (88%)

Diarrhea (85%)

Nausea (79%)

Asthenia (70%)

Abdominal pain (63%)

Vomiting (60%)

Alopecia (43%)

Fever (42%)

Constipation (41%)

Anorexia (34%)

Mucositis (32%)

Pain (31%)

Dyspnea (28%)

Cough (27%)

Dizziness (23%)

Infection (22%)

Rash (19%)

 

1-10%

Abdominal fullness (10%)

AST increased (10%)

Dyspepsia (10%),

Edema (10%)

Ascites/jaundice (9%)

Vasodilation (9%)

Thromboembolism (9%)

Hypotension (6%)

Neutropenic fever (2-6%)

 

Frequency not defined

Headache

Insomnia

Orthostatic hypotension

 

Warnings

Black box warnings

The drug should be administered under the supervision of an experienced cancer chemotherapy physician in facility with appropriate personnel and equipment to diagnose and manage the complications resulting from the therapy.

Early & late forms of severe diarrhea that may be mediated by different mechanisms have been reported. Following the irinotecan infusion, atropine can be used to treat or ameliorate the early diarrhea (occurring shortly after the infusion), which may be accompanied by cholinergic symptoms, including intestinal hyperperistalsis. Late diarrhea (after 24 hr of irinotecan infusion) can be life threatening because it can lead to dehydration, electrolyte imbalance, or sepsis. It should be treated promptly with loperamide, and patients should be given fluid and electrolytes if they become dehydrated or antibiotics if they develop fever.

Severe myelosuppression may occur

 

Contraindications

Hypersensitivity

Pregnancy

Hereditary fructose intolerance (d/t sorbitol)

 

Cautions

Hyperbilirubinemia, elderly, receiving radiation therapy, abdominal/pelvic radiation history

Not for use in combination with a regimen of 5-FU/LV administered for 4-5 consecutive days every 4 weeks outside of a clinical study

Interstitial pulmonary disease (IPD)-like events, including fatalities, have been reported (in combination and as monotherapy) for treatment of colorectal cancer and other advanced solid tumors

Diarrhea

• Risk of both early and late forms of diarrhea (by different mechanisms)
• Early form may be treated with atropine (0.25 mg to 1 mg of intravenous or subcutaneous atropine; unless clinically contraindicated)
• Late form should be promptly treated with loperamide; also give fluid and electrolytes if necessary

Risk of severe myelosuppression; manage febrile neutropenia promptly with antibiotic support; interrupt therapy and reduce subsequent doses if necessary

Drug is subject to photodegradation, especially in neutral & alkaline solutions

Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of therapy; consider dose reduction by at least 1 level for pts homozygous in the enzyme UDP-glucuronosyl transferase 1A1*28 (UGT1A1*28) variant

Avoid pregnancy

 

Pregnancy and lactation

Pregnancy category: d

Lactation: not known if excreted in breast milk, do not nurse

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Camptosar (irinotecan)

Mechanism of action

Binds to topoisomerase I to produce double-strand breaks in DNA

 

Pharmacokinetics

Half-Life: 6-12 hr; SN-38 10-20 hr

Pleak Plasma Concentration: 1660 ng/mL; SN-38 26.3 ng/mL

Protein Bound: 30-68%; SN-38 95%

Vd: 110-234 L/m²

Metabolism: hepatic, to SN-38; SN-38 is further metabolized by UGT1A1

Metabolites: SN-38

Clearance: 13-14 L/hr/m²

Excretion: urine, feces

 

Pharmacogenomics

Converted to SN-38 active metabolite; SN-38 is subsequently conjugated predominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite

UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism

Reduced UGT1A1 activity increases risk for neutropenia

~10% of North American population is homozygous for UGT1A1*28 variant; consider dose reduction in these patients

Genetic testing laboratories

• Genotyping tests are available through the following companies
• ARUP Laboratories (https://www.aruplab.com/)
• LabCorp (https://www.labcorp.com/)
• Genzyme Genetics (https://www.genzymegenetics.com/)

 

Administration

IV Incompatibilities

Additive: methylprednisolone sodium succinate (10% loss in 3 hr)

Y-site: gemcitabine

 

IV Preparation

Dilute in D5W to a final concentration of 0.12-2.8 mg/mL (most commonly in 500 mL D5W)

NS can be used, but precipitation under refrigeration is more likely with NS, so D5W is generally preferred

 

IV Administration

Irritant

Infuse over 90 min

If administered in combination with fluorouracil & leucovorin, administer leucovorin immediately after irinotecan, & administer fluorouracil immediately after leucovorin

Premedication with antiemetics (dexamethasone plus ondansetron/granisetron) is recommended, at least 30 min prior to infusion

Atropine should be considered in pts experiencing cholinergic symptoms

 

Storage

Store at controlled room temp

Protect from light