Irinotecan

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• atazanavir (Reyataz)
• medications for seizures such as carbamazepine (Carbatrol, Epitol, Tegretol), phenobarbital (Luminal), phenytoin (Dilantin, Phenytek)
• rifabutin (Mycobutin)
• rifampin (Rifadin, Rimactane, in Rifamate and Rifater)
• St. John's wort
• ketoconazole (Nizoral)
• other chemotherapy medications for cancer
• diuretics ('water pills')
• laxatives such as bisacodyl (Dulcolax) or senna (in Correctol, Ex-Lax, Peri-Colace, Senokot)

This is not a complete list of all drug interactions. Ask your doctor or pharmacist for more information.

Serious side effects have occurred with use of irinotecan.

• You may experience the following symptoms while you are receiving a dose of irinotecan or for up to 24 hours afterward: runny nose, increased saliva, shrinking pupils (black circles in the middle of the eyes), watery eyes, sweating, flushing, diarrhea (sometimes called 'early diarrhea'), and stomach cramps. Tell your doctor if you experience any of these symptoms. Your doctor can give you medication to prevent or treat these symptoms.
• You may also experience severe diarrhea (sometimes called ''late diarrhea'') more than 24 hours after you receive irinotecan. This type of diarrhea can be life threatening since it can last a long time and lead to dehydration, infection, kidney failure, and other problems. Tell your doctor if you have or have ever had a bowel obstruction (blockage in your intestine). Tell your doctor and pharmacist if you are taking any of the following medications: other chemotherapy medications for cancer; diuretics ('water pills'); or laxatives such as bisacodyl (Dulcolax) or senna (in Correctol, Ex-Lax, Peri-Colace, Senokot).
• Before you begin your treatment with irinotecan, talk to your doctor about what to do if you have late diarrhea. Your doctor will probably tell you to keep loperamide (Imodium AD) on hand so that you can begin to take it right away if you develop late diarrhea. Your doctor will probably tell you to take loperamide at regular intervals throughout the day and night. Be sure to follow your doctor's directions for taking loperamide; these will be different than the directions printed on the package label of loperamide. Your doctor will also tell you which foods you should eat and which foods you should avoid to control diarrhea during your treatment. Drink plenty of fluids and follow this diet carefully.
• Call your doctor right away the first time you have diarrhea during your treatment. Also call your doctor immediately if you experience any of the following symptoms: fever (temperature higher than 100.4°F); shaking chills; black or bloody stools; diarrhea that does not stop within 24 hours; lightheadedness, dizziness, or fainting; or severe nausea and vomiting that stops you from drinking anything. Your doctor will watch you carefully and may treat you with fluids or antibiotics if needed.
• Irinotecan may cause a decrease in the number of blood cells made by your bone marrow. Tell your doctor if you have or have ever had a blood disease or Gilbert's syndrome (decreased ability to break down bilirubin, a natural substance in the body) and if you are being treated with radiation to your stomach or pelvis (area between the hip bones) or if you have ever been treated with this type of radiation. If you experience any of the following symptoms, call your doctor immediately: fever, chills, cough, or other signs of infection; shortness of breath; fast heartbeat; headache; dizziness;pale skin; confusion; extreme tiredness, or unusual bleeding or bruising.

Do not take irinotecan if you are allergic to it or to any of the inactive ingredients.

Keep all appointments with your doctor and the laboratory. Your doctor will order certain tests to check your body's response to irinotecan.

Before you are treated with irinotecan, tell your doctor about all other cancer medicines you have recently used.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• nefazodone;

• St. John's wort;

• an antibiotic--clarithromycin, erythromycin, telithromycin;

• antifungal medicine--itraconazole, ketoconazole, voriconazole;

• seizure medicine--carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone; or

• antiviral medicine to treat hepatitis or HIV/AIDS--atazanavir, boceprevir, cobicistat (Stribild, Tybost), delavirdine, efavirenz, fosamprenavir, indinavir, nelfinavir, nevirapine, ritonavir, saquinavir, telaprevir.

This list is not complete. Other drugs may interact with irinotecan, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

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

Diarrhea and Cholinergic Reactions

Early diarrhea (occurring during or shortly after infusion of Irinotecan hydrochloride injection) 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 injection) 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 until resolution of the bowel obstruction. If grade 2, 3, or 4 late diarrhea recurs, subsequent doses of Irinotecan hydrochloride injection should be decreased [see Dosage and Administration (2) ].

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 injection. 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 [see Warnings and Precautions (5.2) ]. Hold Irinotecan hydrochloride injection 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 injection should be reduced [see Dosage and Administration(2)].

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 injection. Based on sparse available data, the concurrent administration of Irinotecan hydrochloride injection 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 injection.

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 injection treatment.

In a study of 66 patients who received single-agent Irinotecan hydrochloride injection (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).

When administered as a single-agent, a reduction in the starting dose by at least one level of Irinotecan hydrochloride injection 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 [see Dosage and Administration (2) ].

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 injection 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 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 and other chemotherapy should be discontinued and appropriate treatment instituted as needed [see Adverse Reactions (6.1) ].

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. Irinotecan hydrochloride injection should be used as recommended [see Dosage and Administration (2) ].

Increased Toxicity in Patients with Performance Status 2

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 injection 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/m2dose, 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 injection.

Patients with Hepatic Impairment

The use of Irinotecan hydrochloride injection 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) [see Dosage and Administration (2), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ].

Irinotecan Hydrochloride Injection USP is available in single-dose amber glass vials in the following individual package sizes:

2mL NDC  50742-401-02

5mL NDC  50472-402-05

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light. Protect from freezing. Keep the vials in the carton until the time of use.

Inspect the vial for damage and visible signs of leaks before removing from the carton. If damaged, incinerate the unopened package.

• Patients and caregivers should be informed of gastrointestinal complications, such as nausea, vomiting, abdominal cramping, and diarrhea. Patients should have loperamide readily available to begin treatment for late diarrhea (generally occurring more than 24 hours after administration of Irinotecan hydrochloride injection). 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. Patients should contact their physician if any of the following occur: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; or inability to get diarrhea under control within 24 hours.
• Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of Irinotecan hydrochloride injection.
• Explain the significance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever or infection.
• Irinotecan hydrochloride injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug.
• Patients should be alerted to the possibility of alopecia.
• Contains sorbitol.

Manufactured for:

Ingenus Pharmaceuticals, LLC

Orlando, FL 32839-6408

Customer toll free number: 1-877-748-1970

Manufactured by:

Ingenus Pharmaceuticals, GmbH

Ticino 6917, Switzerland  

Revised: 06/2017

Use of irinotecan for the treatment of patients with significant liver dysfunction has not been established.