Topoblock

Each ml contains: Irinotecan Hydrochloride Trihydrate 20 mg, Sorbitol USP 45 mg, Lactic Acid USP 0.9 mg, Water for Injection USP q.s.
TOPOBLOCK (Irinotecan Hydrochloride 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. 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).

Pharmacotherapeutic group: Antineoplastic.
Pharmacology: Pharmacodynamics: Mechanism of action: Irinotecan inhibits Topoisomerase-I, an enzyme involved in DNA replication.
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.
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. Irinotecan has a large mean value of distribution, ranging between 104-211 t/m² after I.V. infusion of 100–350mg/m². Both irinotecan and SN-38 are subject to pH dependent hydrolysis of active closed lactoning structure to an active open ring carboxylate. The AUC ratio of active closed ring form versus total varied from3 3.9% to 44% and from 44.7% to 64% respectively for irinotecan and SN-38.
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 indicated 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-flourouracil and leucovorin for the treatment of colorectal cancer. Irinotecan 125 mg/m² is administered as I.V on 90 min on days 1, 8, 15 & 22 followed by leucovorin 20 mg/m² as I.V bolus on same days. 5-flourouracil 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 doses 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 & 30.
5-FU should be administered immediately after administration of LV at a dose of 400 mg/m² I.V 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

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 diarrhoea 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 diarrhoea that appears to be mediated by different mechanisms. Both form of diarrhoea may be severe. Early diarrhoea 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 diarrhoea and other cholinergic symptoms may be prevented or ameliorated by atropine. Late diarrhoea generally occur 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 diarrhoea should be treated promptly with Loperamide; patients with severe diarrhoea 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 diarrhoea occurs. Severe myelosuppression may occur.
Use in Pregnancy & Lactation: 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.

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 diarrhoea (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 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. 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]; p<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 diarrhoea 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.
Use in Children: The safety and effectiveness of irinotecan in paediatric 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 diarrhoea 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 diarrhoea 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 significently 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 diarrhoea.
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 dypsnea 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.
Drug-Laboratory Test Interactions: There are no interactions between irinotecan and laboratory-tests.

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 tests.
Carcinogenesis, Mutagenesis and Impairment of Fertility: Long-term carcinogenicity studies with irinotecan were not conducted.

Preparation & Administration Precaution: 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. Irinomil 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°C 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. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Store at temperature not exceeding 30°C.

Cytotoxic Chemotherapy

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

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