Irinotecan hydrochloride (Camptosar)

Irinotecan hydrochloride (Camptosar)
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]

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Black Box Warning

WARNING: DIARRHEA AND MYELOSUPPRESSION See full prescribing information for complete Boxed Warning. * Early and late forms of diarrhea can occur. Early diarrhea may be accompanied by cholinergic symptoms which may be prevented or ameliorated by atropine. Late diarrhea can be life threatening and should be treated promptly with loperamide. Monitor patients with diarrhea and give fluid and electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe neutropenia. Interrupt irinotecan hydrochloride and reduce subsequent doses if severe diarrhea occurs. Severe myelosuppression may occur.

Overview

Irinotecan hydrochloride (Camptosar) is an antineoplastic agent that is FDA approved for the treatment of metastatic carcinoma of the colon or rectum. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin and alopecia.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indication

• As a component of first-line therapy in combination with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic carcinoma of the colon or rectum.
• For patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.

Dosage

• Colorectal cancer combination regimen 1

• Irinotecan hydrochloride 125 mg/m2 intravenous infusion over 90 minutes on days 1, 8,15, 22 with LV 20 mg/m2 intravenous bolus infusion on days 1, 8, 15, 22 followed by 5-FU intravenous bolus infusion on days 1, 8, 15, 22 every 6 weeks.

• Colorectal cancer combination regimen 2

• Irinotecan hydrochloride 180 mg/m2 intravenous infusion over 90 minutes on days 1, 15, 29 with LV 200 mg/m2 intravenous infusion over 2 hours on days 1, 2, 15, 16, 29, 30 followed by 5-FU 400 mg/m2 intravenous bolus infusion on days 1, 2, 15, 16, 29, 30 and 5-FU 600 mg/m2 intravenous infusion over 22 hours on days 1, 2, 15, 16, 29, 30.

• Colorectal cancer single agent regimen 1

• Irinotecan hydrochloride 125 mg/m2 intravenous infusion over 90 minutes on days 1, 8, 15, 22 then 2-week rest.

• Colorectal cancer single agent regimen 2

• Irinotecan hydrochloride 350 mg/m2 intravenous infusion over 90 minutes on day 1 every 3 weeks.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Irinotecan hydrochloride in adult patients.

Non–Guideline-Supported Use

• Acute lymphoid leukemia
• Acute myeloid leukemia
• Carcinoma of cervix
• Carcinoma of esophagus

• Induction chemotherapy: irinotecan (65 milligrams/square meter (mg/m(2)) and cisplatin (30 mg/m(2)), 2 weeks on and 1 week off, for two 3-week cycles
• Then, 6 weeks of radiotherapy in 180 centigray (cGy) daily fractions to a total dose of 5040 cGy.
• During treatment with radiation, cisplatin was given at a dose of 30 mg/m(2) followed by escalating doses of irinotecan (40, 50, 65, and 80 mg/m(2), once weekly on days 1, 8, 22, and 29 of radiation therapy.

• Colorectal cancer
• First-line treatment of extensive stage small cell lung cancer in combination with carboplatin

• First-line treatment of extensive stage small cell lung cancer in combination with cisplatin

• Irinotecan 60 milligrams/square meter (mg/m(2)) on days 1, 8, and 15 plus cisplatin 60 mg/m(2) on day 1, administered every 4 weeks; or etoposide 100 mg/m(2) on days 1, 2, and 3 plus cisplatin 80 mg/m(2) on day 1, administered every 3 weeks.

• Gastric cancer
• Recurrent or progressive disease of malignant glioma of brain
• Refractory metastatic breast cancer
• Non-Hodgkin's lymphoma
• Non-small cell lung cancer
• Platinum-refractory or platinum-resistant ovarian cancer

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Irinotecan hydrochloride (Camptosar) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Irinotecan hydrochloride in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Irinotecan hydrochloride in pediatric patients.

Contraindications

Irinotecan hydrochloride injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.

Warnings

WARNING: DIARRHEA AND MYELOSUPPRESSION See full prescribing information for complete Boxed Warning. * Early and late forms of diarrhea can occur. Early diarrhea may be accompanied by cholinergic symptoms which may be prevented or ameliorated by atropine. Late diarrhea can be life threatening and should be treated promptly with loperamide. Monitor patients with diarrhea and give fluid and electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe neutropenia. Interrupt irinotecan hydrochloride and reduce subsequent doses if severe diarrhea occurs. Severe myelosuppression may occur.

Diarrhea and Cholinergic Reactions

Early diarrhea (occurring during or shortly after infusion of irinotecan hydrochloride) is usually transient and infrequently severe. It may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Bradycardia may also occur. Early diarrhea and other cholinergic symptoms may be prevented or treated. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). These symptoms are expected to occur more frequently with higher irinotecan doses.

Late diarrhea (generally occurring more than 24 hours after administration of irinotecan hydrochloride) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Grade 3–4 late diarrhea occurred in 23–31% of patients receiving weekly dosing. In the clinical studies, the median time to the onset of late diarrhea was 5 days with 3-week dosing and 11 days with weekly dosing. Late diarrhea can be complicated by colitis, ulceration, bleeding, ileus, obstruction, and infection. Cases of megacolon and intestinal perforation have been reported. Patients should have loperamide readily available to begin treatment for late diarrhea. Begin loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normal. One dosage regimen for loperamide is 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg of loperamide every 4 hours. Monitor and replace fluid and electrolytes. Use antibiotic support for ileus, fever, or severe neutropenia. Subsequent weekly chemotherapy treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without anti-diarrhea medication. Patients must not be treated with irinotecan hydrochloride until resolution of the bowel obstruction. If grade 2, 3, or 4 late diarrhea recurs, subsequent doses of irinotecan hydrochloride should be decreased.

Avoid diuretics or laxatives in patients with diarrhea.

Myelosuppression

Deaths due to sepsis following severe neutropenia have been reported in patients treated with irinotecan hydrochloride. In the clinical studies evaluating the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3% of the patients; 6% of patients received G-CSF for the treatment of neutropenia. Manage febrile neutropenia promptly with antibiotic support. Hold irinotecan hydrochloride if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm3. After recovery to an absolute neutrophil count ≥1000/mm3, subsequent doses of irinotecan hydrochloride should be reduced.

When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation (48% [13/27] versus 24% [67/277]; p=0.04). Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of irinotecan hydrochloride. Based on sparse available data, the concurrent administration of irinotecan hydrochloride with irradiation is not recommended.

Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/266]; p<0.001). Patients with deficient glucuronidation of bilirubin, such as those with Gilbert's syndrome, may be at greater risk of myelosuppression when receiving therapy with irinotecan hydrochloride.

Patients With Reduced UGT1A1 Activity

Individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of irinotecan hydrochloride treatment.

In a study of 66 patients who received single-agent irinotecan hydrochloride (350 mg/m2 once-every-3-weeks), the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 50%, and in patients heterozygous for this allele (UGT1A1 6/7 genotype) the incidence was 12.5%. No grade 4 neutropenia was observed in patients homozygous for the wild-type allele (UGT1A1 6/6 genotype).

In a prospective study (n=250) to investigate the role of UGT1A1*28 polymorphism in the development of toxicity in patients treated with irinotecan hydrochloride (180 mg/m2) in combination with infusional 5-FU/LV, the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 4.5%, and in patients heterozygous for this allele the incidence was 5.3%. Grade 4 neutropenia was observed in 1.8% of patients homozygous for the wild-type allele.

In another study in which 109 patients were treated with irinotecan hydrochloride (100–125 mg/m2) in combination with bolus 5-FU/LV, the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 18.2%, and in patients heterozygous for this allele the incidence was 11.1%. Grade 4 neutropenia was observed in 6.8% of patients homozygous for the wild-type allele.

When administered in combination with other agents or as a single-agent, a reduction in the starting dose by at least one level of irinotecan hydrochloride should be considered for patients known to be homozygous for the UGT1A1*28 allele. 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 treatment.

UGT1A1 Testing

A laboratory test is available to determine the UGT1A1 status of patients. Testing can detect the UGT1A1 6/6, 6/7 and 7/7 genotypes.

Hypersensitivity

Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue irinotecan hydrochloride if anaphylactic reaction occurs.

Renal Impairment/Renal Failure

Renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhea.

Pulmonary Toxicity

Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred in patients receiving irinotecan (in combination and as monotherapy). Risk factors include pre-existing lung disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during irinotecan hydrochloride therapy. In Japanese studies, a reticulonodular pattern on chest x-ray was observed in a small percentage of patients. New or progressive, dyspnea, cough, and fever should prompt interruption of chemotherapy, pending diagnostic evaluation. If IPD is diagnosed, irinotecan hydrochloride and other chemotherapy should be discontinued and appropriate treatment instituted as needed.

Toxicity of the 5 Day Regimen

Outside of a well-designed clinical study, irinotecan hydrochloride Injection should not be used in combination with a regimen of 5-FU/LV administered for 4–5 consecutive days every 4 weeks because of reports of increased toxicity, including toxic deaths.

Increased Toxicity in Patients with Performance Status 2

In patients receiving either irinotecan/5-FU/LV or 5-FU/LV in the clinical trials, higher rates of hospitalization, neutropenic fever, thromboembolism, first-cycle treatment discontinuation, and early deaths were observed in patients with a baseline performance status of 2 than in patients with a baseline performance status of 0 or 1.

Embryofetal Toxicity

irinotecan hydrochloride can cause fetal harm when administered to a pregnant woman. Irinotecan was embryotoxic in rats and rabbits at doses significantly lower than those administered to humans on a mg/m2 basis. In rats, at exposures approximately 0.2 times those achieved in humans at the 125 mg/m2 dose, irinotecan was embryotoxic and resulted in decreased learning ability and female fetal body weight in surviving pups; the drug was teratogenic at lower exposures (approximately 0.025 times the AUC in humans at the 125 mg/m2 dose). There are no adequate and well-controlled studies of irinotecan in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with irinotecan hydrochloride.

Patients with Hepatic Impairment

The use of irinotecan hydrochloride in patients with significant hepatic impairment has not been established. In clinical trials of either dosing schedule, irinotecan was not administered to patients with serum bilirubin >2.0 mg/dL, or transaminase >3 times the upper limit of normal if no liver metastasis, or transaminase >5 times the upper limit of normal with liver metastasis. In clinical trials of the weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) had a significantly greater likelihood of experiencing first-cycle, grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/226]; p<0.001)

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Irinotecan hydrochloride (Camptosar) Clinical Trials Experience in the drug label.

Postmarketing Experience

There is limited information regarding Irinotecan hydrochloride (Camptosar) Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Irinotecan hydrochloride (Camptosar) Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Irinotecan hydrochloride (Camptosar) in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Irinotecan hydrochloride (Camptosar) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Irinotecan hydrochloride (Camptosar) during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Irinotecan hydrochloride (Camptosar) in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Irinotecan hydrochloride (Camptosar) in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Irinotecan hydrochloride (Camptosar) in geriatric settings.

Gender

There is no FDA guidance on the use of Irinotecan hydrochloride (Camptosar) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Irinotecan hydrochloride (Camptosar) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Irinotecan hydrochloride (Camptosar) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Irinotecan hydrochloride (Camptosar) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Irinotecan hydrochloride (Camptosar) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Irinotecan hydrochloride (Camptosar) in patients who are immunocompromised.

Administration and Monitoring

Administration

Intravenous

Monitoring

There is limited information regarding Irinotecan hydrochloride (Camptosar) Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Irinotecan hydrochloride (Camptosar) and IV administrations.

Overdosage

There is limited information regarding Irinotecan hydrochloride (Camptosar) overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Irinotecan hydrochloride (Camptosar) Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Irinotecan hydrochloride (Camptosar) Mechanism of Action in the drug label.

Structure

There is limited information regarding Irinotecan hydrochloride (Camptosar) Structure in the drug label.

Pharmacodynamics

There is limited information regarding Irinotecan hydrochloride (Camptosar) Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Irinotecan hydrochloride (Camptosar) Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Irinotecan hydrochloride (Camptosar) Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Irinotecan hydrochloride (Camptosar) Clinical Studies in the drug label.

How Supplied

There is limited information regarding Irinotecan hydrochloride (Camptosar) How Supplied in the drug label.

Storage

There is limited information regarding Irinotecan hydrochloride (Camptosar) Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Irinotecan hydrochloride (Camptosar) Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Irinotecan hydrochloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Irinotecan hydrochloride (Camptosar) Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Irinotecan hydrochloride (Camptosar) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.