Generic Name : Irinotecan injections

Each ml contains:

Irinotecan Trihydrate …………….20mg

Excipients …………………………………………………………q.s.

Irinotecan is a derivative of camptothecin. 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. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks.

Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN38 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 1000 times as potent as irinotecan as 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 (see Pharmacokinetics). The precise contribution of SN-38 to the activity of ZINOTECANis thus unknown. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the two forms such that an acid pH promotes the formation of the lactone, while a more basic pH favors 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.

After intravenous infusion of irinotecan in humans, irinotecan plasma concentrations decline in a multiexponential manner, with a mean 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 hours. The half-lives of the lactone (active) forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid forms are in equilibrium.

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 (seeCLINICAL PHARMACOLOGYandWARNINGS). 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.

Preparation & Administration Precautions

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from ZINOTECAN 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. Several published guidelines for handling and disposal of anticancer agents are available.1-7

• General :Outside  of a well-designed clinical study, ZINOTECAN Injection should not be used in  combination with the “Mayo Clinic” regimen of 5-FU/LV (administration  for 4-5 consecutive days every 4 weeks) because of reports of increased  toxicity, including toxic deaths. Irinotecan should be used as recommended (seeIn  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.Diarrhea :Irinotecan  can induce both early and late forms of diarrhea that appear to be mediated by  different mechanisms. Early diarrhea (occurring during or shortly after  infusion of Irinotecan) is cholinergic in nature. It is usually transient and  only infrequently is severe. It may be accompanied by symptoms of rhinitis,  increased salivation, meiosis, lacrimation, diaphoresis, flushing, and  intestinal hyperperistalsis that can cause abdominal cramping. Early diarrhea  and other cholinergic symptoms may be prevented or ameliorated by  administration of atropine (see PRECAUTIONS, GENERAL, for  dosing recommendations for atropine).Late diarrhea (generally occurring more  than 24 hours after administration of Irinotecan) can be life threatening since  it may be prolonged and may lead to dehydration, electrolyte imbalance, or  sepsis. Late diarrhea should be treated promptly with loperamide (see PRECAUTIONS, INFORMATION FOR PATIENTS, for  dosing recommendations for loperamide). Patients with diarrhea should be  carefully monitored, should be given fluid and electrolyte replacement if they  become dehydrated, and should be given antibiotic support if they develop  ileus, fever, or severe neutropenia. After the first treatment, subsequent  weekly chemotherapy treatments should be delayed in patients until return of  pretreatment bowel function for at least 24 hours without need for  anti-diarrhea medication. If grade 2, 3, or 4 late diarrhea occurs subsequent  doses of Irinotecan should be decreased within the current cycle (see DOSAGE AND ADMINISTRATION).Neutropenia :Deaths  due to sepsis following severe neutropenia have been reported in patients  treated with Irinotecan. Neutropenic complications should be managed promptly  with antibiotic support. Therapy with Irinotecan should be temporarily omitted  during a cycle of therapy if neutropenic fever occurs or if the absolute  neutrophil count drops <1000/mm3. After the  patient recovers to an absolute neutrophil count ≥1000/mm3, subsequent doses of Irinotecan should be reduced  depending upon the level of neutropenia observed (see DOSAGE AND ADMINISTRATION).

  Routine  administration of a colony-stimulating factor (CSF) is not necessary, but  physicians may wish to consider CSF use in individual patients experiencing  significant neutropenia.

  Patients with Reduced UGT1A1 Activity :

  Individuals  who are homozygous for the UGT1A1*28 allele  (UGT1A1 7/7 genotype) are at increased risk for neutropenia following  initiation of Irinotecan treatment.

  In a  study of 66 patients who received single-agent Irinotecan (350 mg/m2 once-every-3-weeks),  the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 50%, and in patients heterozygous for  this allele (UGT1A1 6/7 genotype) the incidence was 12.5%. No grade 4 neutropenia  was observed in patients homozygous for the wild-type allele (UGT1A1 6/6  genotype).

  In a  prospective study (n=250) to investigate the role of UGT1A1*28 polymorphism in the development of toxicity in  patients treated with Irinotecan (180 mg/m2) in combination with infusional 5-FU/LV, the  incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 4.5%, and in patients heterozygous  for this allele the incidence was 5.3%. Grade 4 neutropenia was observed in  1.8% of patients homozygous for the wild-type allele.

  In  another study in which 109 patients were treated with Irinotecan (100-125 mg/m2) in combination with bolus 5-FU/LV, the incidence  of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 18.2%, and in patients heterozygous  for this allele the incidence was 11.1%. Grade 4 neutropenia was observed in  6.8% of patients homozygous for the wild-type allele.

  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 (see DOSAGE AND ADMINISTRATION and PRECAUTIONS, LABORATORY TESTS).

  Hypersensitivity :

  Hypersensitivity  reactions including severe anaphylactic or anaphylactoid reactions have been  observed.

  Colitis/Ileus :

  Cases  of colitis complicated by ulceration, bleeding, ileus, and infection have been  observed. Patients experiencing ileus should receive prompt antibiotic support  (see PRECAUTIONS).

  Renal Impairment/Renal Failure :

  Rare  cases of renal impairment and acute renal failure have been identified, usually  in patients who became volume depleted from severe vomiting and/or diarrhea.

  Thromboembolism :

  Thromboembolic  events have been observed in patients receiving irinotecan-containing regimens;  the specific cause of these events has not been determined.

  Pulmonary Toxicity :

  Interstitial  Pulmonary Disease (IPD)-like events, including fatalities, have been reported  in patients receiving irinotecan (in combination and as monotherapy) for  treatment of colorectal cancer and other advanced solid tumors. In the event of  an acute onset of new or progressive, unexplained pulmonary symptoms such as  dyspnea, cough, and fever, irinotecan and other co-prescribed chemotherapeutic  agents should be interrupted pending diagnostic evaluation. If IPD is  diagnosed, irinotecan and other chemotherapy should be discontinued and  appropriate treatment instituted as needed (see ADVERSE REACTIONS: OVERVIEW OF ADVERSE EVENTS:  RESPIRATORY).

  Pregnancy :

  Irinotecan  may cause fetal harm when administered to a pregnant woman. Radioactivity  related to 14C-irinotecan crosses the placenta of rats  following intravenous administration of 10 mg/kg (which in separate studies  produced an irinotecan Cmax and AUC about 3 and 0.5 times,  respectively, the corresponding values in patients administered 125 mg/m2). Administration of 6 mg/kg/day intravenous  irinotecan to rats (which in separate studies produced an irinotecan Cmax and AUC about 2 and 0.2 times, respectively,  the corresponding values in patients administered 125 mg/m2) and rabbits (about one-half the recommended human  weekly starting dose on a mg/m2 basis) during the period of  organogenesis, is embryotoxic as characterized by increased post-implantation  loss and decreased numbers of live fetuses. Irinotecan was teratogenic in rats  at doses greater than 1.2 mg/kg/day (which in separate studies produced an  irinotecan Cmax and AUC about 2/3 and 1/40th,  respectively, of the corresponding values in patients administered 125 mg/m2) and in rabbits at 6.0 mg/kg/day (about one-half  the recommended human weekly starting dose on a mg/m2 basis).  Teratogenic effects included a variety of external, visceral, and skeletal  abnormalities. Irinotecan administered to rat dams for the period following  organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning  ability and decreased female body weights in the offspring. 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 apprised of the potential hazard to  the fetus. Women of childbearing potential should be advised to avoid becoming  pregnant while receiving treatment with Irinotecan.

• 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). (Also see CLINICAL PHARMACOLOGY: PHARMACOKINETICS IN SPECIAL  POPULATIONS: Hepatic Insufficiency). 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. (See Drug-Drug Interactions sub-section under CLINICAL PHARMACOLOGY)

  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 (See WARNINGS).

First-Line Combination Therapy

A total of 955 patients with metastatic colorectal cancer received the recommended regimens of irinotecan in combination with 5-FU/LV, 5-FU/LV alone, or irinotecan alone. In the two phase 3 studies, 370 patients received irinotecan in combination with 5-FU/LV, 362 patients received 5-FU/LV alone, and 223 patients received irinotecan alone.

In Study 1, 49 (7.3%) patients died within 30 days of last study treatment: 21 (9.3%) received irinotecan in combination with 5-FU/LV, 15 (6.8%) received 5-FU/LV alone, and 13 (5.8%) received irinotecan alone. Deaths potentially related to treatment occurred in 2 (0.9%) patients who received irinotecan in combination with 5-FU/LV (2 neutropenic fever/sepsis), 3 (1.4%) patients who received 5-FU/LV alone (1 neutropenic fever/sepsis, 1 CNS bleeding during thrombocytopenia, 1 unknown) and 2 (0.9%) patients who received irinotecan alone (2 neutropenic fever). Deaths from any cause within 60 days of first study treatment were reported for 15 (6.7%) patients who received irinotecan in combination with 5-FU/LV, 16 (7.3%) patients who received 5FU/ LV alone, and 15 (6.7%) patients who received irinotecan alone. Discontinuations due to adverse events were reported for 17 (7.6%) patients who received irinotecan in combination with 5FU/LV, 14 (6.4%) patients who received 5-FU/LV alone, and 26 (11.7%) patients who received irinotecan alone.

The adverse effects of Irinotecan, 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/ 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 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.

OVERDOSAGE

In U.S. phase 1 trials, single doses of up to 345 mg/m2 of irinotecan were administered to patients with various cancers. Single doses of up to 750 mg/m2 of irinotecan have been given in non-U.S. trials. The adverse events in these patients were similar to those reported with the recommended dosage and regimen. There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhea. 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.

CONTRAINDICATIONS

ZINOTECANInjection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.

Store protected from light at a temperature not exceeding 25degree Celsius.

40MG/2ML (SINGLE USE VIAL)

100MG/5ML (SINGLE USE VIAL)