Camptosar (Irinotecan HCl Trihydrate)

CAMPTOSAR™

Pharmacia & Upjohn

Irinotecan HCl Trihydrate

Antineoplastic

Caution: Irinotecan should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.

Irinotecan can cause both an early and late form of diarrhea. Both forms of diarrhea may be severe. Early diarrhea (occurring during or within 24 hours of irinotecan administration) may be preceded by sweats and abdominal cramping. Late diarrhea (occurring more than 24 hours after irinotecan administration) can be prolonged. It may lead to dehydration and electrolyte imbalance, and can be life-threatening.

Irinotecan can cause severe myelosuppression, usually resulting in neutropenia.

Action And Clinical Pharmacology: Irinotecan HCl trihydrate is an antineoplastic agent of the topoisomerase I inhibitor class. Irinotecan HCl is a semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata. Camptothecins interact specifically with the enzyme topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-strand breaks.

Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38, which is formed from irinotecan primarily by liver carboxylesterase enzymes. The SN-38 metabolite is approximately 1 000 times more potent than irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumor cell lines. The precise contribution of SN-38 to the activity of irinotecan in humans has not been completely defined. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. An acidic pH promotes the formation of the lactone whereas a basic pH favors the hydroxy acid anion form.

Pharmacokinetics: After i.v. infusion of irinotecan in humans, irinotecan plasma levels decline in a multiexponential manner. A summary of mean irinotecan and SN-38 pharmacokinetic parameters in 64 patients with metastatic carcinoma of the colon and rectum (dosed at 125 mg/m is tabulated below.

Over the dose range of 50 to 350 mg/m the AUC of irinotecan increases linearly with dose. The AUC of SN-38 increases less than proportionally with dose. Irinotecan exhibits moderate plasma protein binding (30 to 68% bound). SN-38 is approximately 95% bound to human plasma proteins, mainly albumin.

The complete disposition of irinotecan in humans has not been fully elucidated. The metabolic conversion of irinotecan to SN-38 is mediated by carboxylesterase enzymes primarily in the liver. SN-38 subsequently undergoes conjugation to form a glucuronide metabolite (SN-38 glucuronide).

The terminal half-life of irinotecan was 6 hours in patients who were 65 years or older, and 5.5 hours in patients younger than 65 years. Dose-normalized AUC0-24 for SN-38 in patients who were at least 65 years old was 11% higher than in patients younger than 65 years. The influence of renal or hepatic insufficiency on the pharmacokinetics of irinotecan has not been formally studied. Patients with hepatic metastases had somewhat higher irinotecan and SN-38 AUC values than patients without liver metastases.

There is no clinically important gender influence on the pharmacokinetics of irinotecan; the influence of race has not been studied.

Clinical Trials: Data from 3 single-agent studies, involving a total of 304 patients support the use of irinotecan in the treatment of patients with metastatic cancer of the colon or rectum that has recurred or progressed following treatment with 5-FU-based therapy. All of the patients had a performance status (PS) of 0 to 2, with the majority at 0 or 1. In each study, irinotecan was administered in repeated 6-week courses as a once weekly dose for 4 weeks, followed by a 2-week rest period. In these trials, the starting doses of irinotecan were 100, 125 or 150 mg/m

Across all 3 studies, 193 of the 304 patients began therapy at the recommended starting dose of 125 mg/m Among these 193 patients, 2 complete and 27 partial responses were observed for an overall response rate of 15.0% (95% confidence interval (CI), 10.0 to 20.1%). The majority of responses were observed within the first 2 courses of therapy. The median duration of response for patients beginning therapy at 125 mg/mwas 5.8 months (range, 2.6 to 15.1 months). An additional 53.4% (103/193) of the patients treated at a starting dose of 125 mg/machieved a best response of stable disease by formal response criteria.

Response to irinotecan was seen in both males and females of all ages. These patients responded to irinotecan regardless of whether prior 5-FU had been given as adjuvant therapy or for metastatic disease. Patients with cancer of the colon or rectum responded to the drug, and these responses occurred both in patients with single and multiple metastatic sites.

The Kaplan-Meier estimate of median survival time for patients on the 125 mg/mstarting dose was 8.9 months (range, 0.3 to 33.4 months). The majority of patients treated with irinotecan had an increase in, or stabilization of body weight, and an improvement or maintenance of performance status. Among responding patients with tumor-related symptoms, the majority experienced amelioration of these symptoms during irinotecan treatment.

Indications And Clinical Uses: For the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following 5-fluorouracil-based therapy.

Contra-Indications: Patients with a known hypersensitivity to the product.

Manufacturers’ Warnings In Clinical States: Irinotecan should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Diarrhea: Irinotecan can induce both an early and a late form of diarrhea that appear to be mediated by different mechanisms. Early onset diarrhea (occurring during or within 24 hours of irinotecan administration) is cholinergic in nature. It can be severe but is usually transient. It may be preceded by complaints of diaphoresis and abdominal cramping. Early diarrhea may be alleviated by the use of atropine (see Precautions and Dosage).

Late onset diarrhea (occurring more than 24 hours after irinotecan administration) can be prolonged. It may lead to dehydration and electrolyte imbalance and can be life-threatening. Late diarrhea should be treated promptly with loperamide (see Precautions). Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. If National Cancer Institute (NCI) grade 3 or 4 late diarrhea occurs, irinotecan administration should be delayed until the patient recovers. Subsequent doses should be decreased (see Dosage).

Myelosuppression: Therapy with irinotecan should be temporarily discontinued if neutropenic fever occurs or if the absolute neutrophil count drops below 0.5´10L. The dose of irinotecan should be reduced if there is a clinically significant decrease in the total white blood cell count.

Pregnancy : Irinotecan has been shown to be embryotoxic in rats and rabbits at a dose of 6 mg/kg/day. It is teratogenic in rats at doses greater than 1.2 mg/kg/day, and in rabbits at 6 mg/kg/day.

Treatment-related changes in the fetuses included external and visceral abnormalities, skeletal variations and abnormalities. Irinotecan may cause fetal harm when administered to a pregnant woman. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be informed of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving irinotecan.

Lactation : It is not known whether irinotecan is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving therapy with irinotecan.

Children: The safety and effectiveness in the pediatric population have not been established.

Precautions: General: Careful monitoring of the white blood cell count with differential, hemoglobin, and platelet count is recommended before each dose of irinotecan. Physicians should use caution in particular when monitoring the effects of irinotecan in patients of 65 years or older as these patients may be more susceptible to the toxic effects of the drug.

The 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.

Irinotecan is emetogenic. Premedication with antiemetic agents is recommended for patients receiving irinotecan. In clinical studies, this premedication has mostly consisted of 10 mg dexamethasone given in conjunction with another type of antiemetic agent. Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of irinotecan. Physicians should also consider providing patients with an antiemetic regimen for subsequent use as needed.

Irinotecan is administered by i.v. infusion. Care should be taken to avoid extravasation. The infusion site should be monitored for signs of inflammation or other adverse effects. If extravasation occurs, flushing the site with sterile water and/or applying ice to the area are recommended.

Treatment of Diarrhea: For the management of irinotecan-induced early onset diarrhea, the use of 0.25 to 1 mg of i.v. atropine should be considered (unless contraindicated) for patients experiencing diaphoresis, abdominal cramping, or diarrhea that occurs during or within 24 hours following administration of irinotecan.

For the management of irinotecan-induced late onset diarrhea (occurring more than 24 hours after irinotecan administration), the prompt use of oral loperamide for controlling and treating the diarrhea, is recommended. The median onset time for late diarrhea is 11 days following the first dose of irinotecan. The dosage of loperamide used in this situation is higher than the usual dosage recommendation. Pretreatment with loperamide before the onset of late diarrhea is not recommended. Instead, at the first episode of late-onset diarrhea (i.e., poorly formed stools or more frequent bowel movement), patients are to take 4 mg loperamide, followed by 2 mg loperamide every 2 hours until they are free of diarrhea for at least 12 hours. During the night, the dose of loperamide may be 4 mg administered every 4 hours.

Information to Be Conveyed to Patients and Care Givers: Patients and/or their care givers should be informed about the expected toxic effects of irinotecan, particularly its gastrointestinal side effects such as diarrhea, nausea and vomiting. Early onset diarrhea can be accompanied by sweating and abdominal cramping. Since this type of diarrhea can occur when the patient arrives home after the irinotecan dose, the patient and/or their care giver should be advised about this. They are to inform the physician promptly if diarrhea occurs.

For the treatment of late onset diarrhea, each patient should be instructed to have loperamide on hand. Premedication with loperamide is not recommended. Instead, the patient is instructed to begin treatment for late diarrhea at the first episode of poorly formed or loose stools; or at the earliest onset of more frequent than normally expected bowel movements for the patient. The dose and frequency of the loperamide regimen should be clearly explained to the patient. Once again, the patient and/or care giver should notify the physician about the occurrence of this late onset diarrhea.

Laxatives should be avoided. Patients are to consult their physician to discuss any laxative use.

Patients are to consult their physician if vomiting, fever or evidence of infection occurs; or if symptoms of dehydration such as fainting, light-headedness, or dizziness are noted following therapy with irinotecan.

Patients are to be alerted to the possibility of alopecia.

Drug Interactions: Adverse events due to irinotecan, such as myelosuppression and diarrhea, would be expected to be enhanced by combination with other antineoplastic agents having similar adverse effects.

Lymphocytopenia has been reported in patients receiving irinotecan. It is possible that the administration of dexamethasone as an antiemetic prophylaxis may have enhanced the likelihood of this effect.

Hyperglycemia has been reported in patients receiving irinotecan. This has usually been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of irinotecan. It is probable that dexamethasone, given as antiemetic prophylaxis, contributed to hyperglycemia in some patients.

The incidence of akathisia in clinical trials was greater (8.5%, 4 of 47 patients) when prochlorperazine was administered on the same day as irinotecan than when these drugs were given on separate days (1.3%, 1 of 80 patients). However, the 8.5% incidence of akathisia is within the range reported for use of prochlorperazine when given as premedication for other chemotherapies.

It would be expected that laxative use during irinotecan therapy may worsen the incidence or severity of diarrhea.

The use of diuretics should be carefully monitored because of the potential risk of dehydration secondary to vomiting and/or diarrhea induced by irinotecan. The physician may wish to withhold diuretics during irinotecan dosing, and certainly during periods of active vomiting or diarrhea.

Laboratory Test Interactions : There are no known interactions between irinotecan and laboratory tests.

Adverse Reactions: In 3 clinical studies, 304 patients with metastatic carcinoma of the colon or rectum that had recurred or progressed following 5-FU-based therapy were treated with irinotecan.

Seventeen of the patients died within 30 days of the administration of irinotecan. In 5 cases (1.6%, 5/304), the deaths were potentially drug-related. These 5 patients experienced a constellation of medical events that included known effects of irinotecan. One of these patients died of neutropenic sepsis without fever. Neutropenic fever, defined as NCI grade 4 neutropenia and grade 2 or greater fever, occurred in 9 (3%) other patients. These patients recovered with supportive care. Thirteen (4.3%) patients discontinued irinotecan treatment because of medical events.

The adverse events in Table II are based on the experience of the 304 patients enrolled in the 3 studies.

Gastrointestinal: Diarrhea, nausea and vomiting were common adverse events following treatment with irinotecan and could be severe. These events occurred early (during or within 24 hours of irinotecan administration) or late (more than 24 hours after irinotecan administration). The median time to onset of late diarrhea was 11 days following administration of irinotecan. For patients on the 125 mg/mstarting dose, the median duration of grades 1 to 4 diarrhea was 3 days. The median duration was 7 days for those patients reporting grades 3 or 4 diarrhea on this same starting dose.

Hematology: Typical adverse hematologic events of irinotecan included neutropenia, leukopenia (including lymphocytopenia) and anemia. Serious thrombocytopenia was uncommon. The frequency of grade 3 or 4 neutropenia was significantly increased in patients who had prior pelvic or abdominal irradiation. Neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3% of the patients. Only 5.6% of patients received G-CSF for the treatment of neutropenia. NCI grade 3 or 4 anemia was noted in 6.9% of the patients. Blood transfusions were given to 9.9% of the patients.

Whole Body: Asthenia, fever and abdominal pain were the most common events of this type.

Hepatic: NCI grade 3 or 4 liver enzyme abnormalities were observed in less than 10% of patients. These events typically occurred in patients with known hepatic metastases.

Dermatologic: Alopecia was reported during treatment with irinotecan. Rashes have also been reported but did not result in discontinuation of treatment.

Respiratory: Severe pulmonary events were infrequent. Over half the patients with dyspnea had lung metastases. The extent to which malignant pulmonary involvement or other pre-existing lung disease may have contributed to dyspnea in these patients is unknown. In the early Japanese trials, there is some information that patients with considerable ascites or pleural effusions were at increased risk for neutropenia or diarrhea.

A potentially life-threatening pulmonary syndrome, consisting of dyspnea, fever and reticulonodular pattern on chest x-ray, was observed in a small percentage of patients in these Japanese studies. The contribution of irinotecan to these preliminary events was difficult to assess because these patients also had lung tumors and some had pre-existing non-malignant pulmonary disease.

Neurologic: Insomnia and dizziness were observed, but were not usually considered to be directly related to the administration of irinotecan. Dizziness may sometimes have represented symptomatic evidence of orthostatic hypotension in patients with dehydration.

Cardiovascular: Vasodilation (flushing) has been observed during administration of irinotecan but has not required intervention.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In phase I trials, single doses of up to 345 mg/mof irinotecan were administered to patients with various cancers. Single doses of up to 750 mg/mof irinotecan have been given in some trials. There are reports of patients who received higher than recommended doses. The adverse events noted in these patients were similar to those reported from patients on the recommended dose, except for a worse level of severity. There is no known antidote for overdosage of irinotecan. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.

Dosage And Administration: Patients should be monitored for toxicity. Careful monitoring of the white blood cell count with differential, hemoglobin and platelet count is recommended before each dose of irinotecan. It is recommended that patients receive pre-medication with antiemetic agents before each irinotecan dose.

Starting Dose: The recommended starting dose of irinotecan is 125 mg/m All doses should be administered as an i.v. infusion over 90 minutes. The recommended treatment regimen (one treatment course) is 125 mg/madministered once weekly for 4 weeks, followed by a 2-week rest period. Thereafter, additional courses of treatment may be repeated every 6 weeks (4 weeks on therapy followed by 2 weeks off therapy).

Dose Modifications: It is recommended that subsequent doses be adjusted to as high as 150 mg/mor to as low as 50 mg/m in increments of 25 to 50 mg/mdepending upon individual patient tolerance of treatment. Provided intolerable toxicity does not develop, treatment with additional courses of irinotecan may be continued indefinitely in patients who attain a response or in patients whose disease remains stable.

Table III describes the recommended dose modifications during a course of therapy, and at the start of each subsequent course of therapy. Therapy with irinotecan should be interrupted when grade 3 or 4 late diarrhea occurs or when other intolerable toxicity is observed. All dose modifications should be based on the worst preceding toxicity. A new course of therapy should not begin until the granulocyte count has recovered to at least 1.5´10L, and the platelet count has recovered to at least 100´10L, and treatment-related diarrhea is fully resolved. If the patient has not recovered after a 2-week delay, discontinuing irinotecan should be considered.

Hepatic Impairment: For patients having liver metastases without decreased hepatic function, no change in dosage and administration is recommended (see Pharmacology). The use of irinotecan in patients with significant hepatic dysfunction has not been established. In clinical trials, irinotecan was not administered to patients with serum bilirubin >35 mol/L, or transaminase >3 times the upper limit of normal if no liver metastases, or transaminase >5 times the upper limit of normal with liver metastases.

Renal Impairment: The influence of renal insufficiency on the pharmacokinetics of irinotecan has not been evaluated. However, since renal excretion does not represent a major route of elimination for irinotecan and its metabolites, alterations in renal function would not be expected to have a major influence on the pharmacokinetics.

Geriatrics: No change in dosage and administration is recommended for geriatric patients (see Pharmacology and Precautions).

Management of Early Onset Diarrhea: The use of i.v. atropine is recommended (unless contraindicated) for the management of this (see Precautions).

Management of Late Onset Diarrhea: Besides the dosage modification, prompt use of oral loperamide is recommended in order to control and treat the diarrhea (see Precautions).

Management of Extravasation: Flushing the infusion site with sterile water and/or applying ice to the area are recommended.

Special Instructions for Preparation and Handling: As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions containing irinotecan. Preparation of irinotecan should be done in a vertical laminar flow hood. The use of gloves, safety glasses and protective clothing is recommended. If irinotecan solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If irinotecan contacts the mucous membranes, flush thoroughly with water. All waste material that has come in contact with irinotecan should be properly segregated, sealed and incinerated.

Parenteral Products: The vial is for single use only. Unused portions must be discarded. Irinotecan must be diluted prior to infusion, using 5% Dextrose Injection USP (preferred) or 0.9% Sodium Chloride Injection USP to a final concentration range of 0.12 to 1.1 mg/mL. Other drugs should not be added to the infusion solution.

The infusion solution is physically and chemically stable for up to 24 hours at controlled room temperature (15 to 30°C) and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection USP and stored at refrigerated temperatures (2 to 8°C) and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection USP, is not recommended due to a low and sporadic incidence of visible particulates. Freezing irinotecan and admixtures of irinotecan may result in precipitation of the drug and should be avoided.

Because of possible microbial contamination during dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection within 24 hours if refrigerated (2 to 8°C). In the case of admixtures prepared with 5% Dextrose Injection or 0.9% Sodium Chloride Injection, the solution should be used within 6 hours when kept at controlled room temperature (15 to 30°C).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Availability And Storage: Each mL of sterile, pale yellow, clear, aqueous solution contains: irinotecan HCl trihydrate 20 mg. Nonmedicinal ingredients: lactic acid, sorbitol and water for injection. Sodium hydroxide and/or hydrochloric acid may be used to adjust the pH to 3.0 to 3.8. Single use vials of 5 mL. Store at controlled room temperature (15 to 30°C). Protect from light. The product is available in an amber glass vial that is packaged in plastic blister to protect from breakage. It is recommended that the vial (and plastic blister) remain in the carton until time of use. The vial should be inspected for damage and visible signs of leaks before removing the plastic blister. If there are signs of breakage or leakage from the vial, do not open the plastic blister. Incinerate the unopened package.

CAMPTOSAR™ Pharmacia & Upjohn Irinotecan HCl Trihydrate Antineoplastic Caution: Irinotecan should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Irinotecan can cause both an early and late form of diarrhea. Both forms of diarrhea may be severe. Early diarrhea (occurring during or within 24 hours of irinotecan administration) may be preceded by sweats and abdominal cramping. Late diarrhea (occurring more than 24 hours after irinotecan administration) can be prolonged. It may lead to dehydration and electrolyte imbalance, and can be life-threatening. Irinotecan can cause severe myelosuppression, usually resulting in neutropenia.

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