Zinotecan

A light yellow coloured solution, free from visible particles solution. Irinotecan is used alone or in combination with other medications to treat colon or rectal cancer (cancer that begins in the large intestine). Irinotecan is in a class of antineoplastic medications. It works by stopping the growth of cancer cells. The Molecular formula of Irinotecan Hydrochloride is C33H38N4O6.HCl.3H2O, molecular weight is 677.18 g/mol. The structural formula is:

ZINOTECAN Injection is indicated as a component of first-line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum. Irinotecan is also indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.

Patients should be carefully monitored for toxicity and doses of Irinotecan should be modified as necessary to accommodate individual patient tolerance to treatment. Recommended Dose Modifications for Single-Agent Schedules. All dose modifications should be based on the worst preceding toxicity.

A new cycle of therapy should not begin until the toxicity has recovered to NCI grade 1 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery from treatment- related toxicity. If the patient has not recovered, consideration should be given to discontinuing this combination therapy. Provided intolerable toxicity does not develop, treatment with additional cycles of Irinotecan may be continued indefinitely as long as patients continue to experience clinical benefit.

Dosage in Patients with Reduced UGT1A1 Activity

When administered in combination with other agents, or as a single-agent, a reduction in the starting dose by at least one level of Irinotecan 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.

• Read the label carefully before use

• Keep out of the reach of children

ZINOTECAN  Injection is administered by intravenous infusion. 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 applications of ice are recommended.

Premedication with  Antiemetics :Irinotecan  is emetigenic. It is recommended that patients receive premedication with  antiemetic agents. In clinical studies of the weekly dosage schedule, the  majority of patients received 10 mg of dexamethasone given in conjunction with  another type of antiemetic agent, such as a 5-HT3 blocker  (e.g., ondansetron or granisetron). 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 (e.g., prochlorperazine) for subsequent use as needed.

Treatment of  Cholinergic Symptoms :Prophylactic  or 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.

Immunosuppressant  Effects/Increased Susceptibility  to  Infections :Administration  of live or live-attenuated vaccines in patients immunocompromised by  chemotherapeutic agents including Irinotecan, may result in serious or fatal  infections. Avoid vaccination with a live vaccine in patients receiving  irinotecan. Killed or inactivated vaccines may be administered; however, the  response to such vaccines may be diminished.

Patients at Particular  Risk : In  patients receiving either irinotecan/5-FU/LV or 5-FU/LV 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. Patients who had previously received  pelvic/abdominal radiation and elderly patients with comorbid conditions should  be closely monitored.

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. 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). 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.

Ketoconazole, enzyme-inducing  anticonvulsants and St. John’s Wort are known to have drug-drug interactions  with irinotecan therapy.

Irinotecan  commonly causes neutropenia, leucopenia, and anemia, any of which may be severe  and therefore should not be used in patients with severe bone marrow failure.  Patients must not be treated with irinotecan until resolution of the bowel  obstruction. Patients with hereditary fructose intolerance should not be given  Irinotecan, as this product contains sorbitol.

Information for Patients : Patients  and patients’ caregivers should be informed of the expected toxic effects of  Irinotecan, particularly of its gastrointestinal complications, such as nausea,  vomiting, abdominal cramping, diarrhea, and infection. Each patient should be  instructed to have loperamide readily available and to begin treatment for late  diarrhea (generally occurring more than 24 hours after administration of  Irinotecan) at the first episode of poorly formed or loose stools or the  earliest onset of bowel movements more frequent than normally expected for the  patient. One dosage regimen for loperamide used in clinical trials consisted of  the following (Note: This dosage regimen exceeds the usual dosage  recommendations for loperamide.): 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. Premedication with  loperamide is not recommended. The use of drugs with laxative properties should  be avoided because of the potential for exacerbation of diarrhea. Patients  should be advised to contact their physician to discuss any laxative use.

Patients  should be instructed to contact their physician or nurse 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;  inability to get diarrhea under control within 24 hours; or fever or evidence  of infection.

Patients  should be warned about the potential for dizziness or visual disturbances which  may occur within 24 hours following the administration of Irinotecan, and  advised not to drive or operate machinery if these symptoms occur.

Patients  should be alerted to the possibility of alopecia.

Laboratory Tests : Careful  monitoring of the white blood cell count with differential, hemoglobin, and  platelet count is recommended before each dose of Irinotecan.

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