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The use of Irinotecan Hydrochloride concentrate for solution for 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 concentrate for solution for 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 few 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 concentrate for solution for injection is used in monotherapy, it is usually prescribed with the every-3-week-dosage schedule. However, the weekly-dosage schedule (see Pharmacology: Pharmacodynamics under Actions) may be considered in patients who may need a closer follow-up or who are at particular risk of severe neutropenia.
Delayed diarrhoea: Patients should be made aware of the risk of delayed diarrhoea occurring more than 24 hours after the administration of Irinotecan Hydrochloride concentrate for solution for 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 concentrate for solution for 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 hyperleucocytosis, those with performance status c≥ 2 and women. If not properly treated, diarrhoea can be life-threatening, especially if the patient is concomitantly neutropenic.
As soon as the first liquid stool occurs, the patient should start drinking large volumes of beverages containing electrolytes and an appropriate antidiarrhoeal therapy must be initiated immediately. This antidiarrhoeal treatment will be prescribed by the department where Irinotecan Hydrochloride concentrate for solution for 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 concentrate for solution for injection when/if diarrhoea is occurring.
The currently recommended antidiarrhoeal 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. ln 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, hospitalisation 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 at previous cycles.
In patients who experienced severe diarrhoea, a reduction in dose is recommended for subsequent cycles (see Dosage & Administration).
Haematology: Weekly monitoring of complete blood cell counts is recommended during Irinotecan Hydrochloride concentrate for solution for injection treatment. 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 broad-spectrum intravenous antibiotics.
In patients who experienced severe haematological events, a dose reduction is recommended for subsequent administration (see Dosage & 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 (see Pharmacology: Pharmacokinetics under Actions) and thus increasing the risk of hematotoxicity in this population. For patients with a bilirubin > 3 times ULN (see Contraindications).
Nausea and vomiting: A prophylactic treatment with antiemetics is recommended before each treatment with Irinotecan Hydrochloride concentrate for solution for injection. Nausea and vomiting have been frequently reported. Patients with vomiting associated with delayed diarrhoea should be hospitalised 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 (see Adverse Reactions).
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 concentrate for solution for 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.
Chronic inflammatory bowel disease and/or bowel obstruction: Patients must not be treated with lrinotecan Hydrochloride concentrate for solution for injection until resolution of the bowel obstruction (see Contraindications).
Patients with impaired renal function: Studies in this population have not been conducted (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Cardiac disorders: Myocardial ischaemic 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).
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. 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.
Patients with reduced UGT1A1 activity: The active metabolite irinotecan, SN-38, metabolized predominantly by UDP-glucuronosyl transferase (UGT). lt has been reported that patients who are homoyzygous (UGT1A1*6/*6 or UGT1A1*28/*28) or heterozygous (UGT1A1*6/*28) in allele UGT1A1*6, UGT1A1*28 of UGT may be at increased risk for serious adverse reactions (especially neutropenia) caused by reduced glucuronidation of SN-38. Added caution should be exercised when administering in such patients.
Other: Since this medicine contains sorbitol, it is unsuitable in hereditary fructose intolerance. lnfrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhea 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.
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 concentrate for solution for injection, and advised not to drive or operate machinery if these symptoms occur.
Use in Elderly: Due to the greater frequency of decreased biological functions, in particular hepatic function, in elderly patients, dose selection with Irinotecan Hydrochloride concentrate for solution for injection should be cautious in this population (see Dosage & Administration).
