- irinotecan hydrochloride trihydrate
POM: Prescription only medicine
This information is intended for use by health professionals
Method of administration
Precautions to be taken before handling or administering the medicinal productIrinotecan is cytotoxic, for information regarding dilution, and special precautions for disposal and other handling see section 6.6. Irinotecan should not be delivered as an intravenous bolus or an intravenous infusion shorter than 30 minutes or longer than 90 minutes.
In monotherapy (for previously treated patient)The recommended dosage of Irinotecan is 350 mg/m2 administered as an intravenous infusion over a 30 to 90 minute period every three weeks (see sections 4.4 &6.6).
In combination therapy (for previously untreated patient):Safety and efficacy of irinotecan in combination with 5-fluorouracil (5FU) and folinic acid (FA) have been assessed with the following schedule (see section 5.1): Irinotecan plus 5FU/FA in every 2 weeks schedule.The recommended dose of irinotecan hydrochloride trihydrate is 180 mg/m2 administered once every 2 weeks as an intravenous infusion over a 30 to 90 minute period, followed by infusion with folinic acid and 5-fluorouracil.For the posology and method of administration of concomitant cetuximab, refer to the product information for this medicinal product.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. For the posology and method of administration of bevacizumab, refer to the bevacizumab summary of product characteristics.For the posology and method of administration of capecitabine combination, please see section 5.1 and refer to the appropriate sections in the capecitabine summary of product characteristics.
Dosage adjustmentsIrinotecan should be administered after appropriate recovery of all adverse events to grade 0 or 1 NCI-CTC grading (National Cancer Institute Common Toxicity Criteria) and when treatment-related diarrhoea is fully resolved.At the start of a subsequent infusion of therapy, the dose of Irinotecan, and 5FU when applicable, should be decreased according to the worst grade of adverse events observed in the prior infusion. Treatment should be delayed by 1 to 2 weeks to allow recovery from treatment-related adverse events.With the following adverse events a dose reduction of 15 to 20 % should be applied for irinotecan hydrochloride trihydrate and/or 5FU when applicable: - haematological toxicity (neutropenia grade 4, febrile neutropenia (neutropenia grade 3-4 and fever grade 2-4), thrombocytopenia and leukopenia (grade 4)),- non haematological toxicity (grade 3-4).Recommendations for dose modifications of cetuximab when administered in combination with irinotecan must be followed according to the product information for this medicinal product. In combination with capecitabine for patients 65 years of age or more, a reduction of the starting dose of capecitabine to 800 mg/m2 twice daily is recommended according to the summary of product characteristics for capecitabine. Refer also to the recommendations for dose modifications in combination regimen given in the summary of product characteristics for capecitabine.
Treatment DurationTreatment with irinotecan should be continued until there is an objective progression of the disease or an unacceptable toxicity.
Patients with impaired hepatic function:In monotherapy: Blood bilirubin levels (up to 3 times the upper limit of the normal range (ULN)) in patients with performance status ≤ 2, should determine the starting dose of Irinotecan. In these patients with hyperbilirubinemia and prothrombin time greater than 50%, the clearance of irinotecan is decreased (see section 5.2) and therefore the risk of haematotoxicity is increased. Thus, weekly monitoring of complete blood counts should be conducted in this patient population. - In patients with bilirubin up to 1.5 times the upper limit of the normal range (ULN), the recommended dosage of irinotecan hydrochloride trihydrate is 350 mg/m2- In patients with bilirubin ranging from 1.5 to 3 times the ULN, the recommended dosage of irinotecan hydrochloride trihydrate is 200 mg/m2- Patients with bilirubin beyond 3 times the ULN should not be treated with irinotecan (see sections 4.3 & 4.4).No data are available in patients with hepatic impairment treated with irinotecan in combination.
Patients with impaired renal function:Irinotecan is not recommended for use in patients with impaired renal function, as studies in this population have not been conducted. (See section 4.4 and section 5.2).
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. This population should require more intense surveillance (see section 4.4).Paediatric population: Irinotecan should not be used in children.
Delayed diarrhoeaPatients should be made aware of the risk of delayed diarrhoea occurring more than 24 hours after the administration of irinotecan 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. 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 ≥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 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 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. 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 (neutrophils 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 section 4.2).
HaematologyWeekly monitoring of complete blood cell counts is recommended during Irinotecan 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 section 4.2).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 impairmentLiver 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 section 5.2) and thus increasing the risk of hematotoxicity in this population. For patients with a bilirubin> 3 times ULN (see section 4.3).
Nausea and vomitingA prophylactic treatment with antiemetics is recommended before each treatment with irinotecan. 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 syndromeIf acute cholinergic syndrome appears (defined as early diarrhoea and various other symptoms such as sweating, abdominal cramping, myosis and salivation), atropine sulphate (250 micrograms subcutaneously) should be administered unless clinically contraindicated (see section 4.8). 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.
Respiratory disordersInterstitial 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.
ExtravasationWhile 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.
ElderlyDue to the greater frequency of decreased biological functions, in particular hepatic function, in elderly patients, dose selection with Irinotecan should be cautious in this population (see section 4.2).
Chronic inflammatory bowel disease and/or bowel obstructionPatients must not be treated with Irintoecan until resolution of the bowel obstruction (see section 4.3).
Patients with Impaired Renal FunctionStudies in this population have not been conducted. (see sections 4.2 & 5.2).
Cardiac disordersMyocardial 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 (see section 4.2 and section 5.2). 8).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.
OthersSince this medicine 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 (see section 4.6)..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 (see section 4.5).
Interactions common to all cytotoxicsThe use of anticoagulants is common due to increased risk of thrombotic events in tumoral diseases. If vitamin K antagonist anticoagulants are indicated, an increased frequency in the monitoring of INR (International Normalised Ratio) is required due to their narrow therapeutic index, the high intra-individual variability of blood thrombogenicity and the possibility of interaction between oral anticoagulants and anticancer chemotherapy.
Concomitant use contraindicated• Yellow fever vaccine; risk of fatal generalised reaction to vaccines
Concomitant use not recommended• Live attenuated vaccines (except yellow fever); risk of systemic, possible fatal disease (e.g. infections). This risk is increased in subjects who are already immunosuppressed by their underlying diseaseUse inactivated vaccine where this exists (poliomyelitis)• Phenytoin; Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic drug or risk of toxicity enhancement due to increased hepatic metabolism by phenytoin
Concomitant use to take into considerationCiclosporin, Tacrolimus; Excessive immunosuppression with risk of lymphoproliferationThere is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa.Results from a dedicated drug-drug interaction trial demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38. However this does not preclude any increase of toxicities due to their pharmacological properties.
PregnancyThere is no information on the use of irinotecan in pregnant women. Irinotecan has been shown to be embryotoxic and teratogenic in animals.Therefore, Irinotecan based on results from animal studies and the mechanism of action of irinotecan, Irinotecan Seacross should not be used during pregnancy unless clearly necessary.
Women of child-bearing potentialWomen of child-bearing potential and men have to use effective contraception during and up to 1 month and 3 months after treatment respectively.Breastfeeding In lactating rats, 14C-irinotecan was detected in milk. It is not known whether irinotecan is excreted in human milk. Consequently, because of the potential for adverse reactions in nursing infants, breast-feeding must be discontinued for the duration of irinotecan therapy (see section 4.3).
FertilityThere are no human data on the effect of Irinotecan on fertility. In animals adverse effects of irinotecan on the fertility of offspring have been documented (see section 5.3).
Delayed diarrhoeaDiarrhoea (occurring more than 24 hours after administration) is a dose-limiting toxicity of Irinotecan.In monotherapy:Very Common: Severe diarrhoea was observed in 20 % of patients who follow recommendations for the management of diarrhoea. Of the evaluable cycles, 14 % have severe diarrhoea. The median time of onset of the first liquid stool was on day 5 after the infusion of irinotecan.
In combination therapy:Very Common: Severe diarrhoea was observed in 13.1 % of patients who follow recommendations for the management of diarrhoea. Of the evaluable cycles, 3.9 % have severe diarrhoea.Uncommon cases of pseudo-membranous colitis have been reported, one of which has been documented bacteriologically (Clostridium difficile).
Nausea and vomiting
In monotherapy:Very Common: Nausea and vomiting were severe in approximately 10 % of patients treated with antiemetics.
In combination therapy:Common: A lower incidence of severe nausea and vomiting was observed (2.1 % and 2.8 % of patients respectively).
DehydrationCommon: Episodes of dehydration commonly associated with diarrhoea and/or vomiting have been reported. Uncommon: Cases of renal insufficiency, hypotension or cardio-circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting.
Other gastrointestinal disordersCommon: Constipation relative to irinotecan and/or loperamide has been observed, shared between : in monotherapy : in less than 10% of patients in combination therapy : 3.4% of patients.Uncommon: Intestinal obstruction, ileus, or gastrointestinal haemorrhage Rare: Colitis, including typhlitis, ischemic and ulcerative colitis and intestinal perforation. Other mild effects include anorexia, abdominal pain and mucositis..Rare cases of symptomatic or asymptomatic pancreatitis have been associated with irinotecan therapy.
Blood disordersNeutropenia is a dose-limiting toxic effect. Neutropenia was reversible and not cumulative; the median day to nadir was 8 days whatever the use in monotherapy or in combination therapy.
In monotherapy:Very Common: Neutropenia was observed in 78.7% of patients and was severe (neutrophil count <500 cells/mm3) in 22.6% of patients. Of the evaluable cycles, 18% had a neutrophil count below 1,000 cells/mm3 including 7.6% with a neutrophil count <500 cells/mm3. Total recovery was usually reached by day 22. Common: Fever with severe neutropenia was reported in 6.2% of patients and in 1.7% of cycles. Infectious episodes occurred in about 10.3% of patients (2.5% of cycles) and were associated with severe neutropenia in about 5.3% of patients (1.1% of cycles), and resulted in death in 2 cases.Anaemia was reported in about 58.7% of patients (8% with haemoglobin <8g/dl and 0.9% with haemoglobin <6.5 g/dl).Thrombocytopenia (≤ 100,000 cells/mm3) was observed in 7.4% of patients and 1.8% of cycles with 0.9% with platelets count ≤ 50,000 cells/mm3 and 0.2% of cycles. Nearly all of the patients showed a recovery by day 22.
In combination therapy:Very Common: Neutropenia was observed in 82.5% of patients and was severe (neutrophil count <500 cells/mm3) in 9.8 % of patients. Of the evaluable cycles, 67.3 % had a neutrophil count below 1,000 cells/mm3 including 2.7% with a neutrophils count <500 cells/mm3. Total recovery was usually reached within 7-8 days. Common: Fever with severe neutropenia was reported in 3.4% of patients and in 0.9% of cycles.Infectious episodes occurred in about 2% of patients (0.5% of cycles) and were associated with severe neutropenia in about 2.1% of patients (0.5% of cycles), and resulted in death in 1 case.Anaemia was reported in 97.2% of patients (2.1% with haemoglobin <8g/dl). Thrombocytopenia (<100,000 cells/mm3) was observed in 32.6% of patients and 21.8% of cycles. No severe thrombocytopenia (<50,000 cells/mm3) has been observed. Very Rare: One case of peripheral thrombocytopenia with antiplatelet antibodies has been reported in the post-marketing experience.
Infections and InfestationsUncommon: Insufficiency, hypotension or cardio-circulatory failure have been observed in patients who experienced sepsis.
General disorders and infusion site reactions
Acute cholinergic syndromeSevere transient acute cholinergic syndrome was observed in 9% of patients treated in monotherapy and in 1.4% of patients treated in combination therapy. The main symptoms were defined as early diarrhoea and various other symptoms such as abdominal pain, conjunctivitis, rhinitis, hypotension, vasodilatation, sweating, chills, malaise, dizziness, visual disturbances, myosis, lachrimation and increased salivation occurring during or within the first 24 hours after the infusion of irinotecan. These symptoms disappear after atropine administration (see section 4.4).Asthenia was severe in less than 10% of patients treated in monotherapy and in 6.2% of patients treated in combination therapy. The causal relationship to irinotecan has not been clearly established.Fever in the absence of infection and without concomitant severe neutropenia, occurred in 12% of patients treated in monotherapy and in 6.2% of patients treated in combination therapy.Uncommon: Mild infusion site reactions have been reported.
Cardiac disordersRare cases of hypertension during or following the infusion has been reported.
Respiratory disordersUncommon: Interstitial pulmonary disease presenting as pulmonary . Early effects such as dyspnoea have been reported (see section 4.4).
Skin and subcutaneous tissue disordersVery common: Reversible alopecia. Uncommon: Mild cutaneous reactions.
Immune system disordersUncommon: Mild allergic reactions Rare: Anaphylactic/anaphylactoid reactions.
Musculoskeletal disordersRare: Early effects such as muscular contraction or cramps and paresthesia have been reported.
Laboratory tests:Common: In monotherapy, transient and mild to moderate increases in serum levels of either transaminases, alkaline phosphatase or bilirubin were observed in 9.2%, 8.1% and 1.8% of the patients, respectively, in the absence of progressive liver metastasis. Transient and mild to moderate increases of serum levels of creatinine have been observed in 7.3% of the patients. In combination therapy, transient grade 3 serum levels of bilirubin were observed in 1% of the patients, respectively.Very Common: In combination therapy transient serum levels (grades 1 and 2) of either, SGPT (serum glutamic pyruvic transaminase), SGOT (serum glutamic oxaloacetic transaminase), alkaline phosphatase or bilirubin were observed in 15%, 11%, 11% and 10% of the patients, respectively, in the absence of progressive liver metastasis. Transient grade 3 were observed in 0%, 0%, 0% and 1% of the patients, respectively. No grade 4 was observed. Very Rare: Increases of amylase and/or lipase Rare: Hypokalemia and hyponatremia mostly related with diarrhoea and vomiting
Nervous system disordersVery Rare: Transient speech disorders associated with infusion of irinotecan.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:Yellow Card SchemeWebsite: www.mhra.gov.uk/yellowcard
Experimental dataIrinotecan is a semi-synthetic derivative of camptothecin. It is an antineoplastic agent which acts as a specific inhibitor of DNA topoisomerase I. It is metabolised by carboxylesterase in most tissues to SN-38, which was found to be more active than irinotecan in purified topoisomerase I and more cytotoxic than irinotecan against several murine and human tumour cell lines. The inhibition of DNA topoisomerase I by irinotecan or SN-38 induces single-strand DNA lesions which blocks the DNA replication fork and are responsible for the cytotoxicity. This cytotoxic activity was found time-dependent and was specific to the S phase. In vitro, irinotecan and SN-38 were not found to be significantly recognised by the P-glycoprotein MDR, and displays cytotoxic activities against doxorubicin and vinblastine resistant cell lines.Furthermore, irinotecan has a broad antitumor activity in vivo against murine tumour models (P03 pancreatic ductal adenocarcinoma, MA16/C mammary adenocarcinoma, C38 and C51 colon adenocarcinomas) and against human xenografts (Co-4 colon adenocarcinoma, Mx-1 mammary adenocarcinoma, ST-15 and SC-16 gastric adenocarcinomas). Irinotecan is also active against tumors expressing the P-glycoprotein MDR (vincristine- and doxorubicin-resistant P388 leukaemia's).Beside the antitumor activity, the most relevant pharmacological effect of irinotecan is the inhibition of acetylcholinesterase.
In combination therapy for the first-line treatment of metastatic colorectal carcinoma
In combination therapy with Folinic Acid and 5-FluorouracilA phase III study was performed in 385 previously untreated metastatic colorectal cancer patients treated with either every 2 weeks schedule (see Section 4.2) or weekly schedule regimens. In every 2 week schedule, on day 1, the administration of irinotecan at 180mg/m2 once every 2 weeks is followed by infusion with folinic acid (200 mg/m2 over a 2-hour intravenous infusion) and fluorouracil (400 mg/m2 as an intravenous bolus, followed by 600mg/m2 over a 22-hour intravenous infusion). On day 2, folinic acid and 5-fluorouracil are administered at the same doses and schedules. In the weekly schedule, the administration of irinotecan at 80mg/m2 is followed by infusion with FA (500mg/m2 over a 2-hour intravenous infusion) and then by 5-FU (2300mg/m2 over a 24-hour intravenous infusion) over 6 weeks.In the combination therapy trial with the 2 regimens described above, the efficacy of irinotecan was evaluated in 198 treated patients.
|Combined regimens (n=198)||Weekly schedule (n=50)||Every 2 weeks schedule (n=148)|
|Irinotecan +5FU/FA||5FU/FA||Irinotecan +5FU/FA||5FU/FA||Irinotecan +5FU/FA||5FU/FA|
|Response rate (%)||40.8*)||23.1*)||51.2*)||28.6*)||37.5*)||21.6*)|
|Median time to progression (months)||6.7||4.4||7.2||6.5||6.5||3.7|
|Median duration of response (months)||9.3||8.8||8.9||6.7||9.3||9.5|
|Median duration of response and stabilisation (months)||8.6||6.2||8.3||6.7||8.5||5.6|
|Median time to treatment failure (months)||5.3||3.8||5.4||5.0||5.1||3.0|
|Median survival (months)||16.8||14.0||19.2||14.1||15.6||13.0|
In combination therapy with bevacizumab:A phase III randomised, double-blind, active-controlled clinical trial evaluated bevacizumab in combination with irinotecan/5-FU/FA as first-line treatment for metastatic carcinoma of the colon or rectum (study AVF2107g). The addition of bevacizumab to the combination of irinotecan/5-FU/FA resulted in a statistically significant increase in overall survival. The clinical benefit, as measured by overall survival, was seen in all pre-specified patient subgroups, including those defined by age, sex, performance status, location of primary tumour, number of organs involved, and duration of metastatic disease. Refer also to the bevacizumab summary of product characteristics. The efficacy results of Study AVF2107g are summarized in the table below.
|Arm 1 Irinotecan /5FU/FA Placebo||Arm 2 Irinotecan/5FU/FA Avastina|
|Number of Patients||411||402|
|Median time (months)||15.6||20.3|
|95% confidence Interval||14.29-16.99||18.46 24.18|
|Median time (months)||6.2||10.6|
|Overall response rate|
|95% CI||30.2 39.6||39.9 49.8|
|Duration of response|
|Median time (months)||7.1||10.4|
|25-75 percentile (months)||4.7 11.8||6.7 15.0|
|Overall Population||KRAS wild-type population|
|Variable/ static||Cetuximab plus FOLFIRI (n=599)||FOLFIRI (n=599)||Cetuximab plus FOLFIRI (n=172)||FOLFIRI (n=176)|
|%(95% CI)||46.9 (42.9, 51.0)||38.7 (34.8, 42.8)||59.3 (51.6, 66.7)||43.2 (35.8, 50.9)|
|Hazard ratio (95% CI)||0.85 (0.726, 0.998)||0.68 (0.501, 0.934)|
In combination therapy with capecitabineData from a randomised, controlled phase III study (CAIRO) support the use of capecitabine at a starting dose of 1000mg/m2 for 2 weeks every 3 weeks in combination with irinotecan for the first-line treatment of patients with metastatic colorectal cancer. 820 patients were randomised to receive either sequential treatment (n=410) or combination treatment (n=410). Sequential treatment consisted of first-line treatment with capecitabine (1250 mg/m2 twice daily for 14 days), second-line irinotecan (350 mg/m2 on day 1) and third-line combination of capecitabine (1000mg/m2 twice daily for 14 days) with oxaliplatin (130mg/m2 on day 1). Combination treatment consisted of first-line treatment of capecitabine (1000mg/m2 twice daily for 14 days) combined with irinotecan (250mg/m2 on day 1) (XELIRI) and second line capecitabine (1000mg/m2 twice daily for 14 days) plus oxaliplatin (130mg/m2 on day 1). All treatment cycles were administered at intervals of 3 weeks. In first line treatment the median progression-free survival in the intent-to-treat population was 5.8 months (95% CI, 5.1 6.2 months) for capecitabine monotherapy and 7.8 months (95% CI, 7.0 8.3 months) for XELIRI (p=0.0002).Data from an interim analysis of a multicentre, randomised, controlled phase II study (AIO KRK 0604) support the use of capecitabine at a starting dose of 800mg/m2 for 2 weeks every 3 weeks in combination with irinotecan and bevacizumab for the first-line treatment of patients with metastatic colorectal cancer. 115 patients were randomised to treatment with capecitabine combined with irinotecan (XELIRI) and bevacizumab: capecitabine (800mg/m2 twice daily for 2 weeks followed by a 7-day rest period), irinotecan (200mg/m2 as a 30 minute infusion on day 1 every 3 weeks), and bevacizumab (7.5mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks): a total of 118 patients were randomised to treatment with capecitabine combined with oxaliplatin plus bevacizumab: capecitabine (1000mg/m2 twice daily for 2 weeks followed by a 7-day rest period), oxaliplatin (130mg/m2 as a 2 hour infusion on day 1 every 3 weeks), and bevacizumab (7.5mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks). Progression free survival at 6 months in the intent-to-treat population was 80% (XELIRI plus bevacizumab) versus 74% (XELOX plus bevacizumab). Overall response rate (complete response plus partial response) was 45% (XELOX plus bevacizumab) versus 47% (XELIRI plus bevacizumab).
In monotherapy for the second-line treatment of metastatic colorectal carcinoma:Clinical phase II/III studies were performed in more than 980 patients in the every 3 week dosage schedule with metastatic colorectal cancer who failed a previous 5-FU regimen. Efficacywas evaluated in 765 patients with documented progression on 5-FU at study entry.
|Irinotecan versus supportive care||Irinotecan versus 5FU|
|Irinotecan||Supportive care||p values||Irinotecan||5FU||p values|
|Progression Free Survival at 6 months (%)||NA||NA||33.5*||26.7||p=0.03|
|Survival at 12 months (%)||36.2*||13.8||p=0.0001||44.8*||32.4||p=0.0351|
|Median survival (months)||9.2*||6.5||p=0.0001||10.8*||8.5||p=0.0351|
In combination with cetuximab after failure of irinotecan-including cytotoxic therapyThe efficacy of the combination of cetuximab with irinotecan was investigated in two clinical studies. A total of 356 patients with EGFR-expressing metastatic colorectal cancer who had recently failed irinotecan-including cytotoxic therapy and who had a minimum Karnofsky performance status of 60, but the majority of whom had a Karnofsky performance status of ≥ 80 received the combination treatment. EMR 62 202-007: This randomised study compared the combination of cetuximab and irinotecan (218 patients) with cetuximab monotherapy (111 patients).IMCL CP02-9923: This single arm open-label study investigated the combination therapy in 138 patients.The efficacy data from these studies are summarised in the table below:
|Study||N||ORR||DCR||PFS (months)||OS (months)|
|N (%)||95% CI||N (%)||95% CI||Median||95% CI||Median||95% CI|
|Cetuximab + irinotecan|
|EMR 62 202-007||218||50 (22.9)||17.5, 29.1||121 (55.5)||48.6, 62.2||4.1||2.8, 4.3||8.6||7.6, 9.6|
|IMCL CP02-9923||138||21 (15.2)||9.7, 22.3||84 (60.9)||52.2, 69.1||2.9||2.6, 4.1||8.4||7.2, 10.3|
|EMR 62 202-007||111||12 (10.8)||5.7, 18.1||36 (32.4)||23.9, 42.0||1.5||1.4, 2.0||6.9||5.6, 9.1|
Pharmacokinetic/Pharmacodynamic dataThe intensity of the major toxicities encountered with irinotecan (e.g. leukoneutropenia and diarrhoea) are related to the exposure (AUC) to parent drug and metabolite SN-38. Significant correlations were observed between haematological toxicity (decrease in white blood cells and neutrophils at nadir) or diarrhoea intensity and both irinotecan and metabolite SN-38 AUC values in monotherapy.Patients with Reduced UGT1A1 ActivityUridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) is involved in the metabolic deactivation of SN-38, the active metabolite of Irinotecan to inactive SN-38 glucuronide (SN-38G). The UGT1A1 gene is highly polymorphic, resulting in variable metabolic capacities among individuals. One specific variation of the UGT1A1 gene includes a polymorphism in the promoter region known as the UGT1A1*28 variant. This variant and other congenital deficiencies in UGT1A1 expression (such as Crigler-Najjar and Gilbert's syndrome) are associated with reduced activity of this enzyme. Data from a meta- analysis indicate that individuals with Crigler-Najjar syndrome (types 1 and 2) or those who are homozygous for the UGT1A1*28 allele (Gilbert's syndrome) are at increased risk of haematological toxicity (grades 3 and 4) following administration of irinotecan at moderate or high doses (>150 mg/m2). A relationship between UGT1A1 genotype and the occurrence of irinotecan induced diarrhea was not established.Patients known to be homozygous for UGT1A1*28 should be administered the normally indicated irinotecan starting dose. However, these patients should be monitored for haematologic toxicities. A reduced irinotecan starting dose should be considered for patients who have experienced prior haematologic toxicity with previous treatment. The exact reduction in starting dose in this patient population has not been established and any subsequent dose modifications should be based on a patient's tolerance of the treatment (see sections 4.2 and 4.4).There is at present insufficient data to conclude on clinical utility of UGT1A1 genotyping.
After openingThe contents of the vial should be used immediately after the breakage of the vial.
After dilutionChemical and physical in-use stability of the drug product after dilution in the recommended solutions for infusion (see section 6.6) has been demonstrated for 6 hours at 25°C±2°C and for 24 hours at 2°C -8°C.From a microbiological point of view, unless the methods of opening and dilution preclude the risk of microbial contamination, the product should be used immediately after dilution. If not used immediately, in-use storage times and conditions are the responsibility of the user.
Pack sizes1 x 2 ml vial1 x 5 ml vial1x 15 ml vial1 x 25ml vialNot all pack sizes may be marketed.Vials may be sheathed in appropriate sleeve.
Disposal:All materials used for dilution and administration should be disposed according to hospital standard procedures applicable to cytotoxic agents.
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