Irinocan 40/Irinocan 100 Special Precautions

The use of Irinotecan Hydrochloride Trihydrate Injection should be confined to units specialized in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a physician qualified in the use of anticancer chemotherapy.
Given the nature and incidence of adverse events, Irinotecan Hydrochloride Trihydrate Injection will only be prescribed in the following cases after the expected benefits have been weighted against the possible therapeutic risks: in patients presenting a risk factor, particularly those with a WHO performance status = 2; in the rare instances where patients are deemed unlikely to observe recommendations regarding management of adverse events (need for immediate and prolonged antidiarrhoeal treatment combined with high fluid intake at onset of delayed diarrhoea). Strict hospital supervision is recommended for such patients.
When Irinotecan Hydrochloride Trihydrate Injection is used in monotherapy, it is usually prescribed with the every 3 week dosage schedule. However, the weekly dosage schedule may be considered in patients who may need a closer follow up or who are at particular risk of severe neutropenia.
Delayed diarrhea: Patients should be made aware of the risk of delayed diarrhoea occurring more than 24 hours after the administration of Irinotecan Hydrochloride Trihydrate Injection and at any time before the next cycle. In monotherapy, the median time of onset of the first liquid stool was on day 5 after the infusion of Irinotecan Hydrochloride Trihydrate Injection. Patients should quickly inform their physician of its occurrence and start appropriate therapy immediately.
Patients with an increased risk of diarrhoea are those who had a previous abdominal/pelvic radiotherapy, those with baseline hyper leucocytosis, those with performance status ≥ 2 and women. If not properly treated, diarrhoea can be life threatening, especially if the patient is concomitantly neutropaenic.
As soon as the first liquid stool occurs, the patient should start drinking large volumes of beverages containing electrolytes and an appropriate anti diarrhoeal therapy must be initiated immediately. This anti diarrhoeal treatment will be prescribed by the department where Irinotecan Hydrochloride Trihydrate Injection has been administered. After discharge from the hospital, the patients should obtain the prescribed drugs so that they can treat the diarrhoea as soon as it occurs. In addition, they must inform their physician or the department administering Irinotecan Hydrochloride Trihydrate Injection when/if diarrhoea is occurring.
The currently recommended anti diarrhoeal treatment consists of high doses of Loperamide (4 mg for the first intake and then 2 mg every 2 hours). This therapy should continue for 12 hours after the last liquid stool and should not be modified. In no instance should Loperamide be administered for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus, nor for less than 12 hours.
In addition to the anti diarrhoeal treatment, a prophylactic broad spectrum antibiotic should be given, when diarrhoea is associated with severe neutropenia (neutrophil count < 500 cells/mm³).
In addition to the antibiotic treatment, hospitalization is recommended for management of the diarrhoea, in the following cases: Diarrhoea associated with fever, Severe diarrhoea (requiring intravenous hydration), Diarrhoea persisting beyond 48 hours following the initiation of high dose Loperamide therapy.
Loperamide should not be given prophylactically, even in patients who experienced delayed diarrhoea with previous cycles.
In patients who experienced severe diarrhoea, a reduction in dose is recommended for subsequent cycles.
Haematology: In clinical studies, the frequency of NCI-CTC grade 3 and 4 neutropenia has been significantly higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation. Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more have also 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.
Weekly monitoring of complete blood cell count is recommended during treatment with Irinotecan Hydrochloride Trihydrate Injection. Patients should be aware of the risk of neutropenia and the significance of fever. Febrile neutropenia (temperature >38°C and neutrophil count ≤ 1,000 cells/mm³) should be urgently treated in the hospital with broadspectrum intravenous antibiotics.
In patients who experienced severe haematological events, a dose reduction is recommended for subsequent administration. There is an increased risk of infections and haematological toxicity in patients with severe diarrhoea. In patients with severe diarrhoea, complete blood cell counts should be performed.
Liver impairment: Liver function tests should be performed at baseline and before each cycle. Weekly monitoring of complete blood counts should be conducted in patients with bilirubin ranging from 1.5 to 3 times ULN, due to decrease of the clearance of Irinotecan and thus increasing the risk of hematotoxicity in this population. For patients with a bilirubin >3 times ULN.
Nausea and vomiting: A prophylactic treatment with antiemetic is recommended before each treatment with Irinotecan Hydrochloride Trihydrate Injection. Nausea and vomiting have been frequently reported. Patients with vomiting associated with delayed diarrhoea should be hospitalized as soon as possible for treatment.
Acute cholinergic syndrome: If acute cholinergic syndrome appears (defined as early diarrhoea and various other signs and symptoms such as sweating abdominal cramping, myosis and salivation), atropine sulphate (0.25 mg subcutaneously) should be administered unless clinically contraindicated.
These symptoms may be observed during or shortly after infusion of Irinotecan, are thought to be related to the anticholinesterase activity of the Irinotecan parent compound, and are expected to occur more frequently with higher Irinotecan doses.
Caution should be exercised in patients with asthma. In patients who experienced an acute and severe cholinergic syndrome, the use of prophylactic atropine sulphate is recommended with subsequent doses of Irinotecan Hydrochloride Trihydrate Injection.
Respiratory disorders: Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during Irinotecan therapy. Interstitial pulmonary disease can be fatal. Risk factors possibly associated with the development of interstitial pulmonary disease include the use of pneumotoxic drugs, radiation therapy and colony stimulating factors.
Patients with risk factors should be closely monitored for respiratory symptoms before and during Irinotecan therapy.
Extravasation: While Irinotecan is not a known vesicant, care should be taken to avoid extravasation and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site and application of ice is recommended.
Elderly: Due to the greater frequency of decreased biological functions, in particular hepatic function, in elderly patients, dose selection with Irinotecan Hydrochloride Trihydrate Injection should be cautious in this population.
Chronic inflammatory bowel disease and/or Patients with bowel obstruction: Patients must not be treated with Irinotecan Hydrochloride Trihydrate Injection until resolution of the bowel obstruction.
Renal Function: Increases in serum creatinine or blood urea nitrogen have been observed. There have been cases of acute renal failure. These events have generally been attributed to complications of infection or to dehydration related to nausea, vomiting, or diarrhoea. Rare instances of renal dysfunction due to tumor lysis syndrome have also been reported.
Irradiation therapy: Patients who have previously received pelvic/abdominal irradiation are at increased risk of myelosuppression following the administration of Irinotecan. Physicians should use caution in treating patients with extensive prior irradiation (e.g. >25% of bone marrow irradiated and within 6 weeks prior to start treatment with Irinotecan. Dosing adjustment may apply to this population.
Cardiac Disorders: Myocardial ischemic events have been observed following Irinotecan therapy predominately in patients with underlying cardiac disease, other known risk factors for cardiac disease, or previous cytotoxic chemotherapy consequently, patients with known risk factors should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
Vascular disorders: Irinotecan has been rarely associated with thromboembolic events (pulmonary embolism, venous thrombosis, and arterial thromboembolism) in patients presenting with multiple risk factors in addition to the underlying neoplasm.
Immunosuppressant Effects/Increased Susceptibility to Infections: Administration of live or live-attenuated vaccines in patients, immune compromised by chemotherapeutic agents including Irinotecan, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving Irinotecan. Killed or inactivated vaccines may be administered. However, the response to such vaccines may be diminished.
Others: Since Irinotecan Hydrochloride Trihydrate Injection contains Sorbitol, it is unsuitable in hereditary fructose intolerance. Infrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting, or sepsis.
Contraceptive measures must be taken during and for at least three months after cessation of therapy.
Concomitant administration of Irinotecan with a strong inhibitor (e.g. ketoconazole) or inducer (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, St John's Wort) of CYP3A4 may alter the metabolism of Irinotecan and should be avoided.
This medicinal product contains less than 1 mmol sodium per dose, i.e. essentially 'sodium-free'.
Effects on ability to drive and use machines: Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of Irinotecan Hydrochloride Trihydrate Injection, and advised not to drive or operate machinery if these symptoms occur.