Irinotel

Irinotecan hydrochloride trihydrate.

Each mL contains Irinotecan HCl trihydrate 20.0 mg, sorbitol 45.0 mg, lactic acid 0.9 mg and water for injection q.s.
Irinotel (irinotecan) is a semisynthetic derivative of the plant alkaloid camptothecin extracted from the Chinese tree Camptotheca accuminata. Irinotecan is a promising antitumor agent with activity in a broad range of experimental tumor models. It inhibits topoisomerase I function by binding to the topoisomerase I/DNA-cleavable complex.
Irinotecan hydrochloride trihydrate is a pale yellow to yellow crystalline powder with high antitumor activity. Chemically it is (4S)-4, 11-diethyI-4-hydroxy-9-[(4-piperi-dinopiperidino) carbonyloxy]-1 H-pyrano [3', 4':6, 7] indolizino [1,2-b] quinoline-3,14(4H,12H) dione hydrochloride. It is slightly soluble in water and organic solvents. It has an empirical formula of C₃₃H₃₈N₄O₆.HCI.3H₂O and a molecular weight of 677.19.

Pharmacology: Pharmacodynamics: Mechanism of action: Irinotecan exerts antitumor activity by inhibiting the intranuclear enzyme topoisomerase I. This enzyme plays a key role in maintaining the structure of DNA during translation, transcription, and replication by inducing single strand breaks and relieving the torsional strain. Irinotecan and its active metabolite SN-38 bind to the topoisomerase/DNA complex. The formation of topoisomerase I/camptothecin/DNA-cleavable complex effects damage through interference with DNA metabolism and damage to the DNA replication fork. They stabilize topoisomerase I DNA breaks, causing irreversible double-strand breaks through interference with the process of replication. Mammalian cells cannot efficiently repair these double-strand breaks and thus lead to apoptosis or cell death. Since topoisomerase I complexes with DNA only during DNA synthesis, the cytotoxic action of the irinotecan metabolite likely takes place during S-phase. Reduced expression of topoisomerase I is a mechanism of resistance to irinotecan.
Pharmacokinetics: Irinotecan is a relatively inactive prodrug, which is converted by carboxylesterases to SN-38. SN-38 is responsible for the majority of in vivo antitumor activity of the drug. Irinotecan and its active metabolite SN-38 exist both as an active closed ring lactone form and an open ring inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the two forms. An acidic pH promotes formation of the lactone form, whereas a more basic pH yields the hydroxy acid anion form. SN-38 has 100- to 1000- fold greater antitumor activity than irinotecan. SN-38 is responsible for the majority of in vivo antitumor activity of the drug. The drug offers an advantage over camptothecin by virtue of its water - solubility and lesser degree of toxicity and an improved toxicity profile.
After intravenous (IV) infusion of irinotecan hydrochloride injection in humans, plasma concentrations of irinotecan decline in a multiexponential manner with a mean terminal elimination half-life of approximately 6 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 hours. The half-life of the lactone (active) form of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid anion forms are in equilibrium. Although the pharmacokinetics of irinotecan are highly variable over the dose range of 50 mg/m² to 350 mg/m², area under the curve (AUC) of irinotecan increases linearly with dose. Maximum concentrations of the active metabolite SN-38 are generally seen within 1 hour following the end of a 90-minute infusion of irinotecan. Upon intravenous administration, irinotecan shows a bioavailability of 14% and V_d of 141 to 255 L/m². SN-38 and SN-38G (Glucoronide) were found to have availability equal to 3% and 10% of irinotecan, respectively.
Irinotecan exhibits moderate plasma protein binding (30% to 68%). The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and occurs primarily in the liver. SN-38 subsequently undergoes conjugation to form a glucuronide. The disposition of irinotecan has not been fully elucidated in humans. The urinary excretion of irinotecan is 11% to 20%; SN-38, <1%; and SN-38 glucuronide, 3% No change in pharmacokinetic parameters is found in pediatric patients.
Pharmacokinetic parameters for irinotecan and SN-38 following 90-minute infusions of irinotecan at 125 mg/m² were determined in a phase II study in patients with metastatic carcinoma of the colon or rectum and are summarized as follows: See table.

Click on icon to see table/diagram/image

Toxicology: Preclinical and Clinical Studies: As a single agent antitumor activity has been seen in several in vitro and in vivo experimental tumor model, as well as pleiotropically drug - resistant tumor cell lines and human tumor xenografts: including mammary carcinoma MX-1, gastric adenocarcinoma ST-15, colon carcinoma Co-4, and squamous cell lung carcinoma QG-56. In combination tumor activity has been shown to be additive or synergistic with cisplatin, carboplatin, mitomycin C, cytarabine, amsacrine, mitoxantrone, doxorubicin, bleomycin, and etoposide.
Lethality is observed after single IV irinotecan doses of approximately 111 mg/kg in mice and 73 mg/kg in rats (approximately 2.6 and 3.4 times the recommended human dose of 125 mg/m², respectively). Death is preceded by cyanosis, tremors, respiratory distress, and convulsions.
Patients with advanced disease who receive 5-FU-based chemotherapy inevitably experience progressive disease, usually within 6 to 8 months of beginning treatment. Three multicentered, phase II, open-label clinical trials were conducted to evaluate the efficacy of single-agent therapy with irinotecan injection. They involved a total of 304 patients with metastatic colorectal cancer that recurred or progressed following prior 5-FU-based therapy. All three studies used the same dosage schedule. Irinotecan was administered as a 90 minute intravenous infusion once weekly for 4 weeks, followed by a 2-week rest (one course). These studies were designed to evaluate tumor response rate. Based on the intent-to-treat population, the response to therapy was 20.8% (10/48) in the San Antonio study and 13.3% (12/90) in the Mayo/NCCTG study. In the US Multicenter study, the response rate was 14.1% (9/64) for the patients who received the 125 mg/m²; starting dose and 7.8% (8/102) for the patients who received an initial dose of 100 mg/m². In the intent-to-treat analysis of the pooled data across all three studies, 193 of the 304 patients began therapy at the recommended starting dose of 125 mg/m². Among these 193 patients, there were two CRs and 27 PRs for an overall response rate of 15% (29/304).
Response rates to irinotecan Injection were similar in males and females and among patients older and younger than 65 years. Rates were also similar in patients with cancer of the colon or cancer of the rectum and in patients with single and multiple metastatic sites. For all 304 patients, median survival time was 9.0 months. The effect of irinotecan hydrochloride on time to disease progression has not been evaluated in randomized clinical trials.

Irinotecan is indicated for single agent or combination therapy of various type of tumors: Metastatic carcinoma of the colon or rectum that has recurred or progressed following 5‑fluorouracil (5‑FU)‑based therapy; Previously untreated metastatic carcinoma of the colon or rectum; Irinotecan combined with cetuximab is indicated for the treatment of patients with epidermal growth factor receptor (EGFB)‑expressing metastatic colorectal cancer after failure of irinotecan‑including cytotoxic therapy; Irinotecan combined with 5 FU, folinic acid (FA) and bevacizumab is indicated for first‑line treatment of patients with metastatic carcinoma of the colon or rectum; Cervical cancer; Ovarian cancer; Non‑small‑cell lung cancer; Small‑cell lung cancer; Inoperable or recurrence gastric cancer; Esophageal cancer; Malignant Glioma.

Premedication with antiemetics: Since irinotecan is emetogenic agent, it is recommended that patients receive premedication with antiemetic agents. In clinical studies, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HT3 blocker (eg, ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of irinotecan.
Dosage and administration: Irinotecan should be administered as intravenous infusion over 30 to 90 minutes for all doses.
Single‑agent dosage regimen: Weekly dosage regimen: Irinotecan dose is 125 mg/m². A lower starting dose may be considered (e.g. 100 mg/m²) for patients with any of the following conditions prior extensive radiotherapy, performance status of 2, increased bilirubin levels, or gastric cancer. Treatment should be given in repeated 6‑week cycles comprising weekly treatment for 4 weeks, followed by a 2‑week rest.
Once‑every‑2‑week dosage regimen: Irinotecan dose is 250 mg/m² every 2 weeks by intravenous infusion. A lower starting dose may be considered (e.g., 200 mg/m²) for patients with any of the following conditions age 65 years and older, prior extensive radiotherapy, performance status of 2, increased bilirubin levels, or gastric cancer.
Once‑every‑3‑week dosage regimen: Irinotecan for the once‑every‑3‑week dose is 350 mg/m². A lower starting dose may be considered (e.g., 300 mg/m²) for patients with any of the following conditions: age 65 years and older, prior extensive radiotherapy, performance status of 2, increased bilirubin levels, or gastric cancer.
Combination‑agent dosage schedules: Irinotecan combine with 5‑fluorouracil (5‑FU) and Leucovorin: Irinotecan in combination with 5‑FU and leucovorin is recommended for the treatment of metastatic colorectal cancer. The recommended dose is 125 mg/m² of irinotecan, 500 mg/m² of 5‑FU, and 20 mg/m² of leucovorin. Lower starting doses may be considered for irinotecan (e.g., 100 mg/m²) and 5‑FU (e.g. 400 mg/m²) for patients with any of the following conditions: age 65 years and older, prior extensive radiotherapy, performance status of 2, increased bilirubin levels, or gastric cancer. Treatment should be given in repeated 6‑week cycles, comprising weekly treatment for 4 weeks, followed by a 2‑week rest.
Irinotecan in combination with Cetuximab: For dosage & administration of concomitant cetuximab, refer to the full prescribing information of cetuximab. Normally, the same dose of irinotecan is used as administered in the last cycles of the prior irinotecan‑containing regimen. Irinotecan must not be administered earlier than 1 hour after the end of the cetuximab infusion.
Irinotecan in combination with Bevacizumab: For dosage & administration of bevacizumab, refer to the full prescribing information of bevacizumab. Bevacizumab is recommended in combination with irinotecan (125 mg/m²) /bolus 5‑FU (500 mg/m²) folinic acid (20 mg/m²) given once weekly for 4 weeks every 6 weeks. 
Irinotecan in combination with Cisplatin: Irinotecan in combination with cisplatin has been studied for non‑small cell and small cell lung cancer, cervical cancer, gastric cancer, and esophageal cancer. This regimen may be used in the treatment of patients with over indicated cancers, except for colorectal cancer (see Indications).
The recommended dose is 65 mg/m² of irinotecan and 30 mg/m² of cisplatin. A lower dose of irinotecan (e.g., 50 mg/m²) may be considered for patients with any of the following conditions age 65 years and older, prior extensive radiotherapy, performance status of 2, increased bilirubin levels or gastric cancer. Treatment should be given in repeated 6‑week cycles, comprising weekly treatment for 4 weeks, followed by a 2‑week rest.
Delayed Dosing: IRINOTEL should not be administered until the neutrophil count returns to more than 1500 cells/mm³. In patients who experienced severe neutropenia or severe gastrointestinal adverse events, e.g. diarrhea, nausea and vomiting, dosing of IRINOTEL should be delayed until there has been a full recovery of these symptoms, especially diarrhea.
Duration of Treatment: Treatment with IRINOTEL should be continued until there is an objective progression of the disease or an unacceptable toxicity.
In patients with a bilirubin more than 3 times the ULN, patients should not be treated with IRINOTEL.
Patients with Impaired Renal Function: IRINOTEL is not recommended for use in patients with impaired renal function as studies in this population have not been conducted.
Elderly: No specific pharmacokinetic studies have been performed in the elderly. However, the dose should be chosen carefully in this population due to their greater frequency of decreased biological functions, in particular hepatic function. This population therefore requires more intensive surveillance.

In US phase I trials, single doses of up to 345 mg/m² of irinotecan injection were administered to patients with various cancers. Single doses up to 750 mg/m² of irinotecan have been given in non US 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. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.

Patients with a known hypersensitivity to irinotecan, topotecan, or other camptothecin analogues or hypersensitivity to one of the excipients of irinotel.
Pregnancy and lactation.
Patients with chronic inflammatory bowel disease and/or bowel obstruction.
Patients with a bilirubin more than 3 times the upper limit of the normal range.
Patients with severe bone marrow failure; Patients with who performance status more than 2.

Irinotecan injection 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.
Irinotecan Injection can induce both early and late forms of diarrhea that appear to be mediated by different mechanisms. Both forms of diarrhea may be severe. Early diarrhea (occurring during or within 24 hours of administration of irinotecan) may be preceded by complaints of diaphoresis and abdominal cramping and may be ameliorated by atropine. Late diarrhea (occurring more than 24 hours after 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 if severe diarrhea occurs. Severe myelosuppression may occur.

General: Since it is a cytotoxic anticancer drug, procedures for proper handling and disposal should be followed. In case of extravasation, monitor infusion site for signs of inflammation.
Irinotecan Injection can induce both early (less than 24 hour onset after dosing) and late forms (24 hours or longer onset after dosing) of diarrhea that appear to be mediated by different mechanisms.
Myelosuppression.
Temporarily discontinue if neutropenic fever occurs or if the ANC drops below 500/mm³. Reduce subsequent dosing if counts fall as follows: Total WBC count (2000/mm³); neutrophil count (1000/mm³); hemoglobin (8 gm/dl); platelet count (100,000/mm³).
Previous cytotoxic or radiation (abdominal or pelvic) therapy.
Elderly (over 65-years).
Renal impairment.
Hepatic impairment (serum bilurubin > 2 mg/dl, transaminase > 3 times upper limit of normal if no liver metastases or > 5 times upper limit of normal if with liver metastases).
History of bleeding disorders.
Carcinogenesis, Mutagenesis and Impairment of Fertility: No long-term animal studies have been performed to evaluate the carcinogenic potential of irinotecan. Rats were however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per week for 13 weeks. There was a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas.
Neither irinotecan nor SN-38 was mutagenic in the in vitro Ames assay.
No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan in doses of up to 6 mg/kg/day to rats and rabbits.
Drug Interactions: The adverse effects of irinotecan injection, such as myelosuppression and diarrhea, would be expected to be exacerbated by other antineoplastic agents having similar adverse effects.
Patients who have previously received pelvic or abdominal irradiation, or both, are at increased risk of severe myelosuppression following the administration.
Lymphocytopenia has been reported. 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.
Hyperglycemia has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of irinotecan.
The incidence of akathisia in clinical trials was greater in patients (8.5%, 4/47) when prochlorperazine was administration on the same day as irinotecan than when these drugs were given on separate days (1.3%, 1/80).
Patients receiving immunosuppressive chemotherapy should not be vaccinated with live vaccines as there is an increased risk of infection.
Use in Pregnancy & Lactation: Pregnancy: Category D.
Irinotecan hydrochloride injection may cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies in pregnant woman. If the drug is used during pregnancy or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Woman of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with irinotecan.
As many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing/lactation be discontinued when receiving therapy with irinotecan.
Use in Children: Use of irinotecan in children as well as in pediatric patients is not yet established.
Use in the Elderly: The terminal half-life of irinotecan was 6.0 hrs in patients who were 65 years or older and 5.5 hours in patients younger than 65 years.

Blood: Neutropenia is a frequent and dose-limiting toxicity of irinotecan. Neutropenia is observed in most patients, and is grade 3 or 4 in up to 33% treated with 100 mg/m² weekly.
Thrombocytopenia and anemia are generally less frequent and not severe. However, blood transfusions were given in approximately 10% of 304 patients during phase II trials. Leukocyte nadirs have occurred on days 21 to 29 during weekly intravenous administration, and recovery is evident by days 27 to 34.
Eosinophilia is observed in up to one-third of patients during therapy.
Gastrointestinal: Diarrhea is a dose-limiting toxicity during irinotecan therapy. It can induce both early and late forms of diarrhea. Abdominal cramps, nausea, vomiting, diaphoresis and anorexia may precede the onset of diarrhea. Pretreatment with ondansetron plus diphenhydramine may be useful in preventing gastrointestinal symptoms. Early diarrhea may be mediated by a cholinergic mechanism. Increased formation of its active metabolite SN-38 may also contribute to or cause diarrhea. Early diarrhea can be severe but is usually transient, may be ameliorated by administration of atropine. Data suggests that the late-onset diarrhea (can be prolonged, may lead to dehydration and electrolyte imbalance, and can be life threatening) is due to a secretory mechanism, possibly related to drug related alteration of intestinal epithelial cells. Fluid electrolyte replacement is essential. It should be carefully monitored, treated promptly with loperamide as it blocks major secretory mechanisms. If grade III or IV late diarrhea as per NCl criteria occurs, irinotecan injections should be delayed until recovery and subsequent doses have to be reduced.
Cardiovascular System: Flushing is reported but does not generally require treatment.
Central Nervous System: Insomnia and dizziness is reported. Dizziness may represent orthostatic hypotension secondary to dehydration.
Kidney/Genitourinary: Renal failure related to diarrhea-induced renal hypoperfusion has occurred occasionally.
Liver: Elevation of serum transaminases and bilirubin has been observed in up to 25% of patients.
Liver enzyme elevations to NCl grade 3 or 4 is usually seen in < 10% and typically in patients with hepatic metastases.
Respiratory: Pulmonary toxicity, frequently described as pneumonitis, has been reported infrequently in patients with SCLC or NSCLC. Symptoms of dyspnea on exertion may occur.
Corticosteroid therapy has produced equivocal results.
Eosinophilia has preceded the occurrence of pulmonary toxicity in several patients.
General: Alopecia has been observed in 12% to 70% of patients.
Skin rashes and pain are reported at the infusion site.
A constellation of symptoms resembling a cholinergic syndrome has been described in patients treated with irinotecan. Most or all symptoms respond to subcutaneous atropine (0.25 to 0.5mg).
Asthenia, fever & abdominal pain may occur.

Handling and Disposal: Unused portion and all materials that have been utilized for dilution and administration should be disposed of according to standard procedures for anticancer drugs.

Store at controlled room temperature at 15-30°C (59-86°F) protected from light. The vials should remain in the carton until the time of use. The solution is physically and chemically stable for up to 24 hours at room temperature and in ambient fluorescent lighting. Solution diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C, 36° to 46°F), and protected from light are physically and chemically stable for 48 hours. 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 4 hours if kept at room temperature. If reconstitution and dilution are performed under strict aseptic conditions (e.g. on Laminar Air Flow bench), Irinotel Injection solution should be used (infusion completed) within 12 hours at room temperature or 24 hours if refrigerated (2° to 8° C, 36° to 46°F).

Cytotoxic Chemotherapy

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

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