Irinoll

Irinotecan HCl trihydrate.

Each mL contains irinotecan hydrochloride trihydrate 20 mg, water for injection USP 1 mL.
Irinotecan hydrochloride trihydrate solution for injection is an antineoplastic agent of topoisomerase I inhibitor class. Irinotecan hydrochloride was clinically investigated as CPT-II. It is supplied as a clear colorless to light pale yellow solution.
It is available in a single-dose size of 5 mL-fill vials or 2 mL-fill vials containing 100 mg or 40 mg of irinotecan hydrochloride trihydrate.
The pH of the solution has been adjusted to 3.5 (range 3.0 to 3.8) with sodium-hydroxide or hydrochloric-acid.
Irinotecan is intended for dilution with 5% dextrose injection (USP) or 0.9% sodium-chloride injection (USP) prior to intravenous infusion. The preferred diluent is 5% dextrose injection (USP).

Pharmacology: Pharmacodynamics: Mechanism of Action: Irinotecan inhibits Topoisomerase-I, an enzyme involved in DNA replication.
Clinical Pharmacology: Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase-I which relieves torsional strain in DNA by inducing reversible single-strained breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase-I DNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replicating enzymes interact with the ternary complex formed by topoisomerase-I DNA and either irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-stranded breaks.
Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by carboxylesterase mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 100 times potent as irinotecans an inhibitor of topoisomerase-I purified from human and rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2 to 2000 fold. However, the plasma area under the concentration versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN-38 is 95% bound to plasma proteins compared to approximately 50% bound to plasma proteins for irinotecan. The precise contribution of SN-38 to the activity of irinotecan is thus unknown. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. A pH dependent equilibrium exist between the two forms such that an acid pH promotes the formation of the lactone, while a more basic pH favours the hydroxy acid anion form. Administration of irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types.
Pharmacokinetics: After the intravenous infusion of irinotecan in humans, irinotecan plasma concentrations decline in a multiexponential manner, with a terminal elimination half-life of about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hrs. Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound to human plasma proteins (95%bound). The plasma protein to which irinotecan and SN-38 predominantly binds is albumin.
Metabolism and Excretion: The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and primarily occurs in liver. SN-38 subsequently undergoes conjugation to form a glucuronide metabolite. Mean residence time was generally between 9-12 hrs independent of dose. The elimination of irinotecan was triphasic. The first elimination phase lasting 1.2 to 2.5 hours. SN-38 generally had a longer half-life 7.7 to 17 hours. 10 to 26% of the administered dose of irinotecan and 0.18 to 0.26% of SN-38 were eliminated in the urine over a 24 hours period.

Irinotecan is indicate for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following 5-FU-based therapy.

Combination Therapy: Irinotecan can be administered in two different regimens in combination with 5-fluorouracil and leucovorin for the treatment of colorectal cancer. Irinotecan 125 mg/m² is administered as IV on 90 min on days-1, 8, 15, and 22 followed by leucovorin 20 mg/m² as IV bolus on same days. 5-fluorouracil should be administered immediately after administration of leucovorin at a dose of 500 mg/m² thereafter the additional courses are repeated after every 6 weeks (4 weeks on therapy, 2 weeks off therapy). After initiation of chemotherapy the patient should be carefully monitored for toxicity and dose of irinotecan, LV and 5-FU should be modified as necessary to accommodate individual patient's tolerance to treatment. See Table 1.

Click on icon to see table/diagram/image

Irinotecan 180 mg/m² is administered as IV over 90 minutes on days 1, 15, 29 followed by LV 200 mg/m² over 2 hours on days 1, 2, 15, 16, 29 and 30.
5-FU should be administered immediately after administration of LV at a dose of 400 mg/m² IV bolus. The bolus of 5-FU should be followed by infusional 5-FU at a dose of 600 mg/m² over 22 hours on days 1, 2, 15, 16, 29 and 30. Next course begins on day 43.
After initiation of chemotherapy the patient should be carefully monitored for toxicity and doses of irinotecan, LV and 5-FU should be modified as necessary to accommodate individual patient's tolerance to treatment. See Table 2.

Click on icon to see table/diagram/image

Preparation and Administration: As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from irinotecan injection. The use of gloves is recommended. If a solution of irinotecan contacts the skin, wash the skin immediately and thoroughly with soap and water. If irinotecan contacts the mucous membranes, flush thoroughly with water.
Preparation of Infusion Solution: Inspect vial contents for particulate matter and repeat inspection when drug product is withdrawn from vial into syringe. Irinotecan must be diluted prior to infusion. Irinotecan should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 to 2.8 mg/mL.
The solution is physically and chemically stable for up to 24 hours at room temperature (approximately 25°C) and in ambient fluorescent lighting. Because of possible microbial contamination during dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should be used within 6 hours if kept at room temperature (15°C to 30°C, 59° to 86°F). Other drugs should not be added to the infusion solution.
Refrigeration of admixtures using 0.9% Sodium Chloride Injection is not recommended because of an incidence of visible particulates. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Single doses of up to 750 mg/m² of irinotecan have been given in clinical trials. The adverse events in these patients were similar to those reported with the recommended dosage and regimen.
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 infection.

Irinotecan is contraindicated in patients with a known hypersensitivity to the drug.

Irinotecan injection should be administered only under the supervision of a physician who is experienced in the use of cancer chemo-therapeutic agents. The drug can induce both early and late forms of diarrhea that appears to be medicated by different mechanisms. Both forms of diarrhea may be severe. Early diarrhea occur during or shortly after infusion of irinotecan may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyper peristalsis that can cause abdominal cramping. Early diarrhea and other cholinergic symptoms may be prevented or ameliorated by atropine. Late diarrhea generally occurs more than 24 hours after the administration of irinotecan can be prolonged, may lead to dehydration and electrolyte imbalance, and can be life threatening. Late diarrhea should be treated promptly with loperamide; patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Administration of irinotecan should be interrupted and subsequent doses be reduced if severe diarrhea occurs. Severe myelosuppression may occur.

Care of Intravenous Site: Irinotecan is administered by intravenous infusion so care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site with sterile water and application of ice are recommended.
Pre-medication with Antiemetics: Irinotecan is emetogenic. It is recommended that patients receive pre-medication with antiemetic agents starting at least 30 minutes before administration of irinotecan.
Treatment of Cholinergic Symptoms: Prophylactic and therapeutic administration of 0.25 to 1 mg of intravenous or subcutaneous atropine should be considered (unless clinically contraindicated) in patients experiencing rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping, or diarrhea (occurring during or shortly after infusion of irinotecan). These symptoms are expected to occur more frequently with higher irinotecan doses.
Patients at Particular Risk: Physicians should exercise particular caution in monitoring the effects of irinotecan in the elderly (>65 years) and in patients who had previously received pelvic/abdominal irradiation. The use of irinotecan in patients with significant hepatic dysfunction has not been established. 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. However in clinical trials of the weekly schedule, it has been noted that patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) have had a significantly greater likelihood of experiencing first-course grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL {50.0%[19/38]17.7%[47/226]; <0.001}. Patients with abnormal glucuronidation of bilirubin, such as those with Gilbert's Syndrome, may also be at greater risk of myelosuppression when receiving therapy with irinotecan. An association between baseline bilirubin elevations and an increased risk of late diarrhea has not been observed in studies of the weekly dosage schedule.
Laboratory Tests: Careful monitoring of white blood cell count with differential, haemoglobin, and platelet count is recommended before each dose of irinotecan.
Carcinogenesis, Mutagenesis and Impairment of Fertility: Long-term carcinogenicity studies with irinotecan were not conducted. Rats were, however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per week for 13 weeks (in separate studies the 25 mg/kg dose produced an irinotecan C_max and AUC that were about 7.0 times and 1.3 times the respective values in patients administered 125 mg/m² weekly) and were then allowed to recover for 90 weeks. Under these conditions, there was a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. However, atrophy of male reproductive organs was observed after multiple daily irinotecan doses both in rodents at 20 mg/kg (which in separate studies produced an irinotecan C_max and AUC about 5 and 1 times, respectively, the corresponding values in patients administered 125 mg/m² weekly) and dog at 0.4 mg/kg (which in separate studies produced an irinotecan C_max and AUC about one-half and 1/15, respectively, the corresponding values in patients administered 125 mg/m² weekly).
Use in Children: The use and effectiveness of irinotecan in pediatric patients have not been established.

There are no adequate and well-controlled studies of irinotecan in pregnant women. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be appraised of the potential hazard to the foetus. Women of child bearing potential should be advised to avoid becoming pregnant while receiving the treatment with irinotecan.

Gastrointestinal: Nausea, vomiting and diarrhea are the common adverse events following treatment with irinotecan and can be severe. When observed, nausea and vomiting usually occur during or shortly after infusion of irinotecan. In the clinical studies testing the every 3-week-dosage schedule, the median time to the onset of diarrhea was 5 days after irinotecan infusion.
Hematology: Irinotecan commonly causes neutropenia, leukopenia (including lymphocytopenia), and anaemia. Serious thrombocytopenia is uncommon. When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was significantly higher in patients who received previous pelvic/abdominal irradiation than those who had not received such irradiation.
Body as a whole: Asthenia, fever, and abdominal-pain are generally the most common events of this type.
Cholinergic Symptoms: Patients may have cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing and intestinal hyperperistalsis that can cause abdominal cramping and early diarrhea.
Hepatic: In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4 liver enzyme abnormalities were observed in fewer than 10% of patients. These events typically occur in patients with known hepatic metastasis.
Dermatologic: Alopecia has been reported during treatment with irinotecan. Rashes have also been reported but did not result in discontinuation of treatment.
Respiratory: Severe pulmonary events are infrequent. In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4 dyspnea had lung metastasis; the extent to which malignant pulmonary involvement or other pre-existing lung disease may have contributed to dyspnea in these patients is unknown.
Neurologic: Insomnia and dizziness can occur, but are not usually considered to be directly related to the administration of irinotecan. Dizziness may sometimes represent symptomatic evidence of orthostatic hypotension in patients with dehydration.
Cardiovascular: Vasodilation (flushing) may occur during administration of irinotecan. Bradycardia may also occur, but has not required intervention. These effects have been attributed to the cholinergic syndrome sometimes observed during or shortly after infusion of irinotecan.

The adverse effects of irinotecan, such as myelosuppression and diarrhoea, would be expected to be exacerbated by other antineoplastic agents having similar adverse effects.
Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of irinotecan. The concurrent administration of irinotecan with irradiation has not been adequately studied and is not recommended.
Lymphocytopenia has been reported in patients receiving irinotecan and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of this effect. However, serious opportunistic infections have not been observed, and no complications have specifically been attributed to lymphocytopenia. Hyperglycemia has also been reported in patients receiving irinotecan. Usually, this has been observed in patients with 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.
Drug-Laboratory Test Interactions: There are no known interactions between irinotecan and laboratory test.

Do not store above 25°C. Protect from light. It is recommended that the vial should remain in the carton until the time of use. Do not freeze.

Cytotoxic Chemotherapy

L01CE02 - irinotecan ; Belongs to the class of Topoisomerase 1 (TOP1) inhibitors. Used in the treatment of cancer.

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