Irinotecan-dbl

Overdose

Symptoms

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 diarrhoea.

Management

There is no known antidote for Irinotecan-DBL. Maximum supportive care should be instituted to prevent dehydration due to diarrhoea and to treat any infectious complications.

There are no treatment interventions known to be effective for management of overdosage of Irinotecan-DBL.

Contraindications

- Chronic inflammatory bowel disease and/or bowel obstruction.

-

- Lactation.

- Bilirubin > 3 times the upper limit of the normal range.

- Severe bone marrow failure.

- WHO performance status > 2.

- Concomitant use with St John's Wort.

- Live attenuated vaccines.

For additional contraindications of cetuximab or bevacizumab or capecitabine, refer to the product information for these medicinal products.

Irinotecan-DBL is contraindicated in patients who have experienced a severe hypersensitivity reaction to Irinotecan-DBL or irinotecan HCl.

Incompatibilities

None known.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Undesirable effects

CLINICAL STUDIES

Adverse reaction data have been extensively collected from studies in metastatic colorectal cancer; the frequencies are presented below. The adverse reactions for other indications are expected to be similar to those for colorectal cancer.

The most common (>1/10), dose-limiting adverse reactions of irinotecan are delayed diarrhoea (occurring more than 24 hours after administration) and blood disorders including neutropenia, anaemia and thrombocytopenia.

Neutropenia 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.

Very commonly severe transient acute cholinergic syndrome was observed.

The main symptoms were defined as early diarrhoea and various other symptoms such as abdominal pain, sweating, myosis and increased salivation occurring during or within the first 24 hours after the infusion of Irinotecan-DBL. These symptoms disappear after atropine administration.

MONOTHERAPY

The following adverse reactions considered to be possibly or probably related to the administration of Irinotecan-DBL have been reported from 765 patients at the recommended dose of 350 mg/m2 in monotherapy. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), and very rare (< 1/10,000).

Description of selected adverse reactions (monotherapy)

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-DBL.

Nausea and vomiting were severe in approximately 10% of patients treated with antiemetics.

Constipation has been observed in less than 10% of patients.

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.

Febrile neutropenia was reported in 6.2% of patients and in 1.7% of cycles.

Infections 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 < 8 g/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 the patients showed a recovery by day 22.

Acute cholinergic syndrome severe transient acute cholinergic syndrome was observed in 9 % of patients treated in monotherapy.

Asthenia was severe in less than 10 % of patients treated in monotherapy. The causal relationship to Irinotecan-DBL has not been clearly established.

Pyrexia in the absence of infection and without concomitant severe neutropenia, occurred in 12 % of patients treated in monotherapy.

Laboratory tests 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.

COMBINATION THERAPY

Adverse reactions detailed in this section refer to irinotecan.

There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa. In combination with cetuximab, additional reported adverse reactions were those expected with cetuximab (such as dermatitis acneiform 88%). For information on adverse reactions on irinotecan in combination with cetuximab, also refer to their respective summary of product characteristics.

Adverse drug reactions reported in patients treated with capecitabine in combination with irinotecan in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy include: Very common, all grade adverse drug reactions: thrombosis/embolism; Common, all grade adverse drug reactions: hypersensitivity, myocardial ischaemia/infarction; Common, Grade 3 and Grade 4 adverse drug reactions: febrile neutropenia. For complete information on adverse reactions of capecitabine, refer to the capecitabine summary product of characteristics.

Grade 3 and Grade 4 adverse drug reactions reported in patients treated with capecitabine in combination with irinotecan and bevacizumab in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy include: Common, Grade 3 and Grade 4 adverse drug reactions: neutropenia, thrombosis/embolism, hypertension, and myocardial ischaemia/infarction. For complete information on adverse reactions of capecitabine and bevacizumab, refer to the respective capecitabine and bevacizumab summary of product characteristics.

Grade 3 hypertension was the principal significant risk involved with the addition of bevacizumab to bolus Irinotecan-DBL/5-FU/FA. In addition, there was a small increase in the Grade 3/4 chemotherapy adverse events of diarrhoea and leukopenia with this regimen compared to patients receiving bolus Irinotecan-DBL/5-FU/FA alone. For other information on adverse reactions in combination with bevacizumab, refer to the bevacizumab summary of product characteristics.

Irinotecan-DBL has been studied in combination with 5-FU and FA for metastatic colorectal cancer.

Safety data of adverse reactions from clinical studies demonstrate very commonly observed NCI Grade 3 or 4 possibly or probably-related adverse events in the blood and the lymphatic system disorders, gastrointestinal disorders, and skin and subcutaneous tissue disorders MedDRA System Organ Classes.

The following adverse reactions considered to be possibly or probably related to the administration of Irinotecan-DBL have been reported from 145 patients treated by Irinotecan-DBL in combination therapy with 5FU/FA in every 2 weeks schedule at the recommended dose of 180 mg/m2.

Description of selected adverse reactions (combination therapy)

Severe diarrhoea was observed in 13.1 % of patients who follow recommendations for the management of diarrhoea. Of the evaluable cycles, 3.9 % have a severe diarrhoea.

A lower incidence of severe nausea and vomiting was observed (2.1 % and 2.8 % of patients respectively).

Constipation relative to Irinotecan-DBL and/or loperamide has been observed in 3.4 % of patients.

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 neutrophil count < 500 cells/mm3. Total recovery was usually reached within 7-8 days.

Febrile neutropenia was reported in 3.4% of patients and in 0.9% of cycles.

Infections 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 < 8 g/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.

Acute cholinergic syndrome severe transient acute cholinergic syndrome was observed in 1.4 % of patients treated in combination therapy.

Asthenia was severe in 6.2 % of patients treated in combination therapy. The causal relationship to Irinotecan-DBL has not been clearly established.

Pyrexia in the absence of infection and without concomitant severe neutropenia, occurred in 6.2 % of patients treated in combination therapy.

Laboratory tests Transient serum levels (Grades 1 and 2) of either SGPT, SGOT, 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.

Increases of amylase and/or lipase have been very rarely reported.

Rare cases of hypokalaemia and hyponatraemia mostly related with diarrhoea and vomiting have been reported.

OTHER ADVERSE EVENTS REPORTED IN CLINICAL STUDIES WITH THE WEEKLY REGIMEN FOR Irinotecan-DBL

The following additional drug-related events have been reported in clinical studies with irinotecan: pain, sepsis, anorectal disorder, GI candida infection, hypomagnesaemia, rash, skin signs, gait disturbance, confusion, headache, syncope, flushing, bradycardia, urinary tract infection, breast pain, gamma-glutamyltransferase increased, extravasation, and tumour lysis syndrome, cardiovascular disorders (angina pectoris, cardiac arrest, myocardial infarction, myocardial ischaemia, peripheral vascular disorder, vascular disorder), and thromboembolic events (arterial thrombosis, cerebral infarction, cerebrovascular accident, deep vein thrombosis, peripheral embolism , pulmonary embolism, thrombophlebitis, thrombosis, and sudden death).

POST-MARKETING SURVEILLANCE

Frequencies from post-marketing surveillance are not known (cannot be estimated from available data).

Reporting of suspected adverse reactions

Reporting 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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

By reporting side effects you can help provide more information on the safety of this medicine.

The following adverse drug reactions are discussed in greater detail in other sections of the label:

• Severe Neutropenia
• Severe Diarrhea
• Interstitial Lung Disease
• Severe Hypersensitivity Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Irinotecan-DBL cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice.

The safety data described below are derived from patients with metastatic adenocarcinoma of the pancreas previously treated with gemcitabine-based therapy who received any part of protocol-specified therapy in Study 1, an international, randomized, active-controlled, open-label trial. Protocol-specified therapy consisted of Irinotecan-DBL 70 mg/m² with leucovorin 400 mg/m² and fluorouracil 2400 mg/m² over 46 hours every 2 weeks (Irinotecan-DBL/5-FU/LV; N=117), Irinotecan-DBL 100 mg/m² every 3 weeks (N=147), or leucovorin 200 mg/m² and fluorouracil 2000 mg/m² over 24 hours weekly for 4 weeks followed by 2 week rest (5-FU/LV; N=134). Serum bilirubin within the institutional normal range, albumin ≥ 3 g/dL, and Karnofsky Performance Status (KPS) ≥ 70 were required for study entry. The median duration of exposure was 9 weeks in the Irinotecan-DBL/5-FU/LV arm, 9 weeks in the Irinotecan-DBL monotherapy arm, and 6 weeks in the 5-FU/LV arm.

The most common adverse reactions ( ≥ 20%) of Irinotecan-DBL were diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and pyrexia. The most common, severe laboratory abnormalities ( ≥ 10% Grade 3 or 4) were lymphopenia and neutropenia. The most common serious adverse reactions ( ≥ 2%) of Irinotecan-DBL were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia.

Adverse reactions led to permanent discontinuation of Irinotecan-DBL in 11% of patients receiving Irinotecan-DBL/5-FU/LV; the most frequent adverse reactions resulting in discontinuation of Irinotecan-DBL were diarrhea, vomiting, and sepsis. Dose reductions of Irinotecan-DBL for adverse reactions occurred in 33% of patients receiving Irinotecan-DBL/5-FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia. Irinotecan-DBL was withheld or delayed for adverse reactions in 62% of patients receiving Irinotecan-DBL/5-FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia.

Table 2 provides the frequency and severity of adverse reactions in Study 1 that occurred with higher incidence ( ≥ 5% difference for Grades 1-4 or ≥ 2% difference for Grades 3-4) in patients who received Irinotecan-DBL/5-FU/LV compared to patients who received 5-FU/LV.7

Table 2: Adverse Reactions with Higher Incidence ( ≥ 5% Difference for Grades 1-4* or ≥ 2% Difference for Grades 3 and 4) in the Irinotecan-DBL/5-FU/LV Arm

Irinotecan-DBL can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early onset diarrhea. In Study 1, Grade 1 or 2 cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) Irinotecan-DBL-treated patients. Six of these 12 patients received atropine and in 1 of the 6 patients, atropine was administered for cholinergic symptoms other than diarrhea.

Infusion reactions, consisting of rash, urticaria, periorbital edema, or pruritus, occurring on the day of Irinotecan-DBL administration were reported in 3% of patients receiving Irinotecan-DBL or Irinotecan-DBL/5-FU/LV.

Laboratory abnormalities that occurred with higher incidence in the Irinotecan-DBL/5-FU/LV arm compared to the 5-FU/LV arm ( ≥ 5% difference) are summarized in the following table.

Table 3: Laboratory Abnormalities with Higher Incidence ( ≥ 5% Difference) in the Irinotecan-DBL/5-FU/LV Arm*#

Preclinical safety data

Irinotecan and SN-38 have been shown to be mutagenic in vitro in the chromosomal aberration test on CHO-cells as well as in the in vivo micronucleus test in mice.

However, they have been shown to be devoid of any mutagenic potential in the Ames test.

In rats treated once a week during 13 weeks at the maximum dose of 150 mg/m2 (which is less than half the human recommended dose), no treatment related tumours were reported 91 weeks after the end of treatment.

Single- and repeated-dose toxicity studies with Irinotecan-DBL have been carried out in mice, rats and dogs. The main toxic effects were seen in the haematopoietic and lymphatic systems. In dogs, delayed diarrhoea associated with atrophy and focal necrosis of the intestinal mucosa was reported. Alopecia was also observed in the dog.

The severity of these effects was dose-related and reversible.

Reproduction

Irinotecan was teratogenic in rats and rabbits at doses below the human therapeutic dose. In rats, pups born to treated animals with external abnormalities showed a decrease in fertility. This was not seen in morphologically normal pups. In pregnant rats there was a decrease in placental weight and in the offspring a decrease in fetal viability and increase in behavioural abnormalities

Therapeutic indications

Irinotecan-DBL is indicated for the treatment of patients with advanced colorectal cancer:

- in combination with 5-fluorouracil and folinic acid in patients without prior chemotherapy for advanced disease,

- as a single agent in patients who have failed an established 5-fluorouracil containing treatment regimen.

Irinotecan-DBL in combination with cetuximab is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing RAS wild-type metastatic colorectal cancer, who had not received prior treatment for metastatic disease or after failure of irinotecan-including cytotoxic therapy.

Irinotecan-DBL in combination with 5-fluorouracil, folinic acid and bevacizumab is indicated for first-line treatment of patients with metastatic carcinoma of the colon or rectum.

Irinotecan-DBL in combination with capecitabine with or without bevacizumab is indicated for first-line treatment of patients with metastatic colorectal carcinoma.

Irinotecan-DBL™ is indicated, in combination with fluorouracil and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.

Limitation of Use: Irinotecan-DBL is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Cytostatic topoisomerase I inhibitor. ATC Code : L01XX19

Mechanism of action

Experimental data:

Irinotecan is a semi-synthetic derivative of Irinotecan-DBLthecin. 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 tumours expressing the P-glycoprotein MDR (vincristine- and doxorubicin-resistant P388 leukaemias).

Beside the antitumor activity of Irinotecan-DBL, the most relevant pharmacological effect of irinotecan is the inhibition of acetylcholinesterase.

Clinical data:

In combination therapy for the first-line treatment of metastatic colorectal carcinoma

In combination therapy with Folinic Acid and 5-Fluorouracil

A phase III study was performed in 385 previously untreated metastatic colorectal cancer patients treated with either every 2 weeks schedule or weekly schedule regimens. In the every 2 weeks schedule, on day 1, the administration of Irinotecan-DBL at 180 mg/m2 once every 2 weeks is followed by infusion with folinic acid (200 mg/m2 over a 2-hour intravenous infusion) and 5-fluorouracil (400 mg/m2 as an intravenous bolus, followed by 600 mg/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-DBL at 80 mg/m2 is followed by infusion with folinic acid (500 mg/m2 over a 2-hour intravenous infusion) and then by 5-fluorouracil (2300 mg/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-DBL was evaluated in 198 treated patients:

5FU: 5-fluorouracil

FA: folinic acid

NS: Non Significant

* As per protocol population analysis

In the weekly schedule, the incidence of severe diarrhoea was 44.4% in patients treated by Irinotecan-DBL in combination with 5FU/FA and 25.6% in patients treated by 5FU/FA alone. The incidence of severe neutropenia (neutrophil count < 500 cells/mm3) was 5.8% in patients treated by Irinotecan-DBL in combination with 5FU/FA and in 2.4% in patients treated by 5FU/FA alone.

Additionally, median time to definitive performance status deterioration was significantly longer in Irinotecan-DBL combination group than in 5FU/FA alone group (p=0.046).

Quality of life was assessed in this phase III study using the EORTC QLQ-C30 questionnaire. Time to definitive deterioration constantly occurred later in the Irinotecan-DBL groups. The evolution of the Global Health Status/Quality of life was slightly better in Irinotecan-DBL combination group although not significant, showing that efficacy of Irinotecan-DBL in combination could be reached without affecting the quality of life.

In combination therapy with bevacizumab

A phase III randomised, double-blind, active-controlled clinical trial evaluated bevacizumab in combination with Irinotecan-DBL/5FU/FA as first-line treatment for metastatic carcinoma of the colon or rectum (Study AVF2107g). The addition of bevacizumab to the combination of Irinotecan-DBL/5FU/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 summarised in the table below.

In combination therapy with cetuximab

EMR 62 202-013: This randomised study in patients with metastatic colorectal cancer who had not received prior treatment for metastatic disease compared the combination of cetuximab and irinotecan plus infusional 5-fluorouracil/folinic acid (5-FU/FA) (599 patients) to the same chemotherapy alone (599 patients). The proportion of patients with KRAS wild-type tumours from the patient populations evaluable for KRAS status comprised 64%.

The efficacy data generated in this study are summarised in the table below:

CI = confidence interval; FOLFIRI = irinotecan plus infusional 5-FU/FA; ORR = objective response rate (patients with complete response or partial response); PFS = progression-free survival time

In combination therapy with capecitabine

Data from a randomised, controlled phase III study (CAIRO) support the use of capecitabine at a starting dose of 1,000 mg/m2 for 2 weeks every 3 weeks in combination with irinotecan for the first-line treatment of patients with metastatic colorectal cancer. Eight hundred twenty (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 (1,250 mg/m2 twice daily for 14 days), second-line irinotecan (350 mg/m2 on day 1), and third-line combination of capecitabine (1,000 mg/m2 twice daily for 14 days) with oxaliplatin (130 mg/m2 on day 1). Combination treatment consisted of first-line treatment of capecitabine (1,000 mg/m2 twice daily for 14 days) combined with irinotecan (250 mg /m2 on day 1) (XELIRI) and second-line capecitabine (1,000 mg/m2 twice daily for 14 days) plus oxaliplatin (130 mg/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 800 mg/m2 for 2 weeks every 3 weeks in combination with irinotecan and bevacizumab for the first-line treatment of patients with metastatic colorectal cancer. One hundred fifteen (115) patients were randomised to treatment with capecitabine combined with irinotecan (XELIRI) and bevacizumab: capecitabine (800 mg/m2 twice daily for 2 weeks followed by a 7-day rest period), irinotecan (200 mg/m2 as a 30 minute infusion on day 1 every 3 weeks), and bevacizumab (7.5 mg/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 (1,000 mg/m2 twice daily for two weeks followed by a 7-day rest period), oxaliplatin (130 mg/m2 as a 2 hour infusion on day 1 every 3 weeks), and bevacizumab (7.5 mg/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. The efficacy of Irinotecan-DBL was evaluated in 765 patients with documented progression on 5-FU at study entry.

NA=Non Applicable

* Statistically significant difference

In phase II studies, performed on 455 patients in the every 3-week dosage schedule, the progression- free survival at 6 months was 30 % and the median survival was 9 months. The median time to progression was 18 weeks.

Additionally, non-comparative phase II studies were performed in 304 patients treated with a weekly schedule regimen, at a dose of 125 mg/m2 administered as an intravenous infusion over 90 minutes for 4 consecutive weeks followed by 2 weeks rest. In these studies, the median time to progression was 17 weeks and median survival was 10 months. A similar safety profile has been observed in the weekly-dosage schedule in 193 patients at the starting dose of 125 mg/m2, compared to the every 3-week-dosage schedule. The median time of onset of the first liquid stool was on day 11.

In combination with cetuximab after failure of irinotecan-including cytotoxic therapy

The 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:

CI= confidence interval; DCR= disease control rate (patients with complete response, partial response, or stable disease for at least 6 weeks); ORR= objective response rate (patients with complete response or partial response); OS= overall survival time; PFS= progression-free survival.

The efficacy of the combination of cetuximab with irinotecan was superior to that of cetuximab monotherapy, in terms of objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). In the randomised trial, no effects on overall survival were demonstrated (hazard ratio 0.91, p=0.48).

Patients with Reduced UGT1A1 Activity:

Uridine 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 diarrhoea 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.

There is at present insufficient data to conclude on clinical utility of UGT1A1 genotyping.

Pharmacokinetic properties

Absorption

At the end of the infusion, at the recommended dose of 350 mg/m2, the mean peak plasma concentrations of irinotecan and SN-38 were 7.7 µg/ml and 56 ng/ml, respectively, and the mean area under the curve (AUC) values were 34 µg.h/ml and 451 ng.h/ml, respectively. A large interindividual variability in pharmacokinetic parameters is generally observed for SN-38.

Distribution

The phase I study in 60 patients with a dosage regimen of a 30-minute intravenous infusion of 100 to 750 mg/m2 every three weeks, the volume of distribution at steady state (Vss): 157 L/m2.

In vitro, plasma protein binding for irinotecan and SN-38 was approximately 65% and 95%, respectively.

Biotransformation

Mass balance and metabolism studies with 14C-labelled drug have shown that more than 50% of an intravenously administered dose of irinotecan is excreted as unchanged drug, with 33% in the faeces mainly via the bile and 22% in urine.

Two metabolic pathways account each for at least 12% of the dose:

- Hydrolysis by carboxylesterase into active metabolite SN-38, SN-38 is mainly eliminated by glucuronidation, and further by biliary and renal excretion (less than 0.5% of the irinotecan dose) The SN-38 glucuronite is subsequently probably hydrolysed in the intestine.

- Cytochrome P450 3A enzymes-dependent oxidations resulting in opening of the outer piperidine ring with formation of APC (aminopentanoic acid derivate) and NPC (primary amine derivate).

Unchanged irinotecan is the major entity in plasma, followed by APC, SN-38 glucuronide and SN-38. Only SN-38 has significant cytotoxic activity.

Elimination

In a phase I study in 60 patients with a dosage regimen of a 30-minute intravenous infusion of 100 to 750 mg/m2 every three weeks, irinotecan showed a biphasic or triphasic elimination profile. The mean plasma clearance was 15 L/h/m2. The mean plasma half-life of the first phase of the triphasic model was 12 minutes, of the second phase 2.5 hours, and the terminal phase half-life was 14.2 hours. SN-38 showed a biphasic elimination profile with a mean terminal elimination half-life of 13.8 hours.

Irinotecan clearance is decreased by about 40% in patients with bilirubinemia between 1.5 and 3 times the upper normal limit. In these patients a 200 mg/m2 irinotecan dose leads to plasma drug exposure comparable to that observed at 350 mg/m2 in cancer patients with normal liver parameters.

Linearity/non-linearity

A population pharmacokinetic analysis of irinotecan has been performed in 148 patients with metastatic colorectal cancer, treated with various schedules and at different doses in phase II trials. Pharmacokinetic parameters estimated with a three compartment model were similar to those observed in phase I studies. All studies have shown that irinotecan (CPT-11) and SN-38 exposure increase proportionally with CPT-11 administered dose; their pharmacokinetics are independent of the number of previous cycles and of the administration schedule.

Pharmacokinetic/Pharmacodynamic relationship(s)

The intensity of the major toxicities encountered with Irinotecan-DBL (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.

The plasma pharmacokinetics of total irinotecan and total SN-38 were evaluated in patients with cancer who received Irinotecan-DBL, as a single agent or as part of combination chemotherapy, at doses between 50 and 155 mg/m² and 353 patients with cancer using population pharmacokinetic analysis.

The pharmacokinetic parameters of total irinotecan and total SN-38 following the administration of Irinotecan-DBL 70 mg/m² as a single agent or part of combination chemotherapy are presented in Table 4.

Table 4: Summary of Mean (±Standard Deviation) Total Irinotecan and Total SN-38

Direct measurement of irinotecan liposome showed that 95% of irinotecan remains liposome-encapsulated, and the ratios between total and encapsulated forms did not change with time from 0 to 169.5 hours post-dose. The mean volume of distribution is summarized in Table 4.

Plasma protein binding is < 0.44% of the total irinotecan in Irinotecan-DBL.

Metabolism

The metabolism of irinotecan liposome has not been evaluated. Irinotecan is subject to extensive metabolic conversion by various enzyme systems, including esterases to form the active metabolite SN-38, and UGT1A1 mediating glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several inactive oxidation products, one of which can be hydrolyzed by carboxylesterase to release SN-38. In the population pharmacokinetic analysis using the results of a subset with UGT1A1*28 genotypic testing, in which the analysis adjusted for the lower dose administered to patients homozygous for the UGT1A1*28 allele, patients homozygous (N=14) and non-homozygous (N=244) for this allele had total SN-38 average steady-state concentrations of 1.06 and 0.95 ng/mL, respectively.

Excretion

The disposition of Irinotecan-DBL has not been elucidated in humans. Following administration of irinotecan HCl , the urinary excretion of irinotecan is 11 to 20%; SN-38, < 1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide), over a period of 48 hours following administration of irinotecan HCl in two patients, ranged from approximately 25% (100 mg/m²) to 50% (300 mg/m²).

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Given the nature and incidence of adverse events, Irinotecan-DBL 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-DBL is used in monotherapy, it is usually prescribed with the every-3-week-dosage schedule. However, the weekly-dosage schedule (see section 5) 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-DBL 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-DBL. 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-DBL has been administered. After discharge from the hospital, the patients should obtain the prescribed medicinal products so that they can treat the diarrhoea as soon as it occurs. In addition, they must inform their physician or the department administering Irinotecan-DBL 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 antidiarrhoeal 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.

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 counts is recommended during Irinotecan-DBL 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.

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 the 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 the ULN.

Nausea and vomiting

A prophylactic treatment with antiemetics is recommended before each treatment with Irinotecan-DBL. 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 sulfate (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 sulfate is recommended with subsequent doses of Irinotecan-DBL.

Respiratory disorders

Interstitial lung disease presenting as lung infiltration is uncommon during irinotecan therapy. Interstitial lung disease can be fatal. Risk factors possibly associated with the development of interstitial lung disease include the use of pneumotoxic medicinal products, 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-DBL should be cautious in this population.

Chronic inflammatory bowel disease and/or bowel obstruction

Patients must not be treated with Irinotecan-DBL 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 tumour 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 of treatment with irinotecan). Dosing adjustment may apply to this population.

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).

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.

Others

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.

Women of childbearing potential and men have to use effective contraception during and up to 1 month and 3 months after treatment respectively.

Concomitant administration of irinotecan with a strong inhibitor (e.g. ketoconazole) or inducer (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin) of CYP3A4 may alter the metabolism of irinotecan and should be avoided.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Included as part of the PRECAUTIONS section.

Irinotecan-DBL can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. In Study 1, the incidence of fatal neutropenic sepsis was 0.8% among patients receiving Irinotecan-DBL, occurring in one of 117 patients in the Irinotecan-DBL plus fluorouracil/leucovorin (Irinotecan-DBL/5-FU/LV) arm and one of 147 patients receiving Irinotecan-DBL as a single agent. Severe or life-threatening neutropenia occurred in 20% of patients receiving Irinotecan-DBL/5-FU/LV compared to 2% of patients receiving fluorouracil/leucovorin alone (5-FU/LV). Grade 3 or 4 neutropenic fever/neutropenic sepsis occurred in 3% of patients receiving Irinotecan-DBL/5-FU/LV, and did not occur in patients receiving 5-FU/LV.

In patients receiving Irinotecan-DBL/5-FU/LV, the incidence of Grade 3 or 4 neutropenia was higher among Asian patients [18 of 33 (55%)] compared to White patients [13 of 73 (18%)]. Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of White patients.

Monitor complete blood cell counts on Days 1 and 8 of every cycle and more frequently if clinically indicated. Withhold Irinotecan-DBL if the absolute neutrophil count (ANC) is below 1500/mm³ or if neutropenic fever occurs. Resume Irinotecan-DBL when the ANC is 1500/mm³ or above. Reduce Irinotecan-DBL dose for Grade 3-4 neutropenia or neutropenic fever following recovery in subsequent cycles.

Irinotecan-DBL can cause severe and life-threatening diarrhea. Do not administer Irinotecan-DBL to patients with bowel obstruction.

Severe or life-threatening diarrhea followed one of two patterns: late onset diarrhea (onset more than 24 hours following chemotherapy) and early onset diarrhea (onset within 24 hours of chemotherapy, sometimes occurring with other symptoms of cholinergic reaction). An individual patient may experience both early and late-onset diarrhea.

In Study 1, Grade 3 or 4 diarrhea occurred in 13% receiving Irinotecan-DBL/5-FU/LV compared to 4% receiving 5-FU/LV. The incidence of Grade 3 or 4 late onset diarrhea was 9% in patients receiving Irinotecan-DBL/5-FU/LV, compared to 4% in patients receiving 5-FU/LV. The incidence of Grade 3 or 4 early onset diarrhea was 3% in patients receiving Irinotecan-DBL/5-FU/LV, compared to no Grade 3 or 4 early onset diarrhea in patients receiving 5-FU/LV. Of patients receiving Irinotecan-DBL/5-FU/LV in Study 1, 34% received loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea. Withhold Irinotecan-DBL for Grade 2-4 diarrhea. Initiate loperamide for late onset diarrhea of any severity. Administer intravenous or subcutaneous atropine 0.25 to 1 mg (unless clinically contraindicated) for early onset diarrhea of any severity. Following recovery to Grade 1 diarrhea, resume Irinotecan-DBL at a reduced dose.

Irinotecan HCl can cause severe and fatal interstitial lung disease (ILD). Withhold Irinotecan-DBL in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue Irinotecan-DBL in patients with a confirmed diagnosis of ILD.

Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue Irinotecan-DBL in patients who experience a severe hypersensitivity reaction.

Based on animal data with irinotecan HCl and the mechanism of action of Irinotecan-DBL, Irinotecan-DBL can cause fetal harm when administered to a pregnant woman. Embryotoxicity and teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in irinotecan exposures lower than those achieved with Irinotecan-DBL 70 mg/m² in humans, administered to pregnant rats and rabbits during organogenesis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Irinotecan-DBL and for one month following the final dose.

No studies have been performed to assess the potential of irinotecan liposome for carcinogenicity, genotoxicity or impairment of fertility. Intravenous administration of irinotecan hydrochloride to rats once weekly for 13 weeks followed by a 91-week recovery period resulted in a significant linear trend between irinotecan HCl dosage and the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Irinotecan HCl was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). Neither irinotecan nor its active metabolite, SN-38, was mutagenic in the in vitro Ames assay.

Dedicated fertility studies have not been performed with irinotecan liposome injection. Atrophy of male and female reproductive organs was observed in dogs receiving irinotecan liposome injection every 3 weeks at doses equal to or greater than 15 mg/kg, (approximately 3 times the clinical exposure of irinotecan following administration to Irinotecan-DBL dosed at 70 mg/m² ) for a total of 6 doses. No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan HCl in doses of up to 6 mg/kg/day to rats; however, atrophy of male reproductive organs was observed after multiple daily irinotecan HCl doses both in rodents at 20 mg/kg (approximately 0.007 times the clinical irinotecan exposure following Irinotecan-DBL administration at 70 mg/m²) and in dogs at 0.4 mg/kg (0.0007 times the clinical exposure to irinotecan following administration of Irinotecan-DBL).

Based on animal data with irinotecan HCl and the mechanism of action of Irinotecan-DBL, Irinotecan-DBL can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women. Embryotoxicity and teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in irinotecan exposures lower than those achieved with Irinotecan-DBL 70 mg/m² in humans, administered to pregnant rats and rabbits during organogenesis. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Animal Data

No animal studies have been conducted to evaluate the effect of irinotecan liposome on reproduction and fetal development; however, studies have been conducted with irinotecan HCl. Irinotecan crosses the placenta of rats following intravenous administration. Intravenous administration of irinotecan at a dose of 6 mg/kg/day to rats and rabbits during the period of organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses. In separate studies in rats, this dose resulted in an irinotecan exposure of approximately 0.002 times the exposure of irinotecan based on area under the curve (AUC) in patients administered Irinotecan-DBL at the 70 mg/m² dose. Administration of irinotecan HCl resulted in structural abnormalities and growth delays in rats at doses greater than 1.2 mg/kg/day (approximately 0.0002 times the clinical exposure to irinotecan in Irinotecan-DBL based on AUC). Teratogenic effects included a variety of external, visceral, and skeletal abnormalities. Irinotecan HCl 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 is no information regarding the presence of irinotecan liposome, irinotecan, or SN-38 (an active metabolite of irinotecan) in human milk, or the effects on the breastfed infant or on milk production. Irinotecan is present in rat milk.

Because of the potential for serious adverse reactions in breastfed infants from Irinotecan-DBL, advise a nursing woman not to breastfeed during treatment with Irinotecan-DBL and for one month after the final dose.

Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan HCl and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations.

Females

Irinotecan-DBL can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Irinotecan-DBL and for one month after the final dose.

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with Irinotecan-DBL and for four months after the final dose.

Safety and effectiveness of Irinotecan-DBL have not been established in pediatric patients.

Of the 264 patients who received Irinotecan-DBL as a single agent or in combination with 5-FU and leucovorin in Study 1, 49% were ≥ 65 years old and 13% were ≥ 75 years old. No overall differences in safety and effectiveness were observed between these patients and younger patients.

Effects on ability to drive and use machines

Irinotecan-DBL has moderate influence on the 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-DBL, and advised not to drive or operate machinery if these symptoms occur.

Dosage (Posology) and method of administration

Posology

For adults only. Irinotecan-DBL solution for infusion should be infused into a peripheral or central vein.

Recommended dosage:

In monotherapy (for previously treated patient)

The recommended dosage of Irinotecan-DBL is 350 mg/m2 administered as an intravenous infusion over a 30- to 90- minute period every three weeks.

In combination therapy (for previously untreated patient)

Safety and efficacy of Irinotecan-DBL in combination with 5-fluorouracil (5FU) and folinic acid (FA) have been assessed with the following schedule.

- Irinotecan-DBL plus 5FU/FA in every 2 weeks schedule

The recommended dose of Irinotecan-DBL 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.

Dosage adjustments:

Irinotecan-DBL 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-DBL, 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-DBL 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 duration:

Treatment with Irinotecan-DBL should be continued until there is an objective progression of the disease or an unacceptable toxicity.

Special populations:

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-DBL. In these patients with hyperbilirubinemia and prothrombin time greater than 50%, the clearance of irinotecan is decreased and therefore the risk of hepatotoxicity 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 ULN, the recommended dosage of Irinotecan-DBL is 350 mg/m2.

- In patients with bilirubin ranging from 1.5 to 3 times the ULN, the recommended dosage of Irinotecan-DBL is 200 mg/m2.

- Patients with bilirubin beyond to 3 times the ULN should not be treated with Irinotecan-DBL.

No data are available in patients with hepatic impairment treated by Irinotecan-DBL in combination.

Patients with impaired renal function

Irinotecan-DBL is not recommended for use in patients with impaired renal function, as studies in this population have not been conducted.

Elderly

No specific pharmacokinetic studies have been performed in 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.

Paediatric population

The safety and efficacy of Irinotecan-DBL in children have not yet been established. No data are available.

Method of administration

Precautions to be taken before handling or administering the medicinal product.

DO NOT SUBSTITUTE Irinotecan-DBL for other drugs containing irinotecan HCl.

Administer Irinotecan-DBL prior to leucovorin and fluorouracil.

• The recommended dose of Irinotecan-DBL is 70 mg/m² administered by intravenous infusion over 90 minutes every 2 weeks.
• The recommended starting dose of Irinotecan-DBL in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m² administered by intravenous infusion over 90 minutes. Increase the dose of Irinotecan-DBL to 70 mg/m² as tolerated in subsequent cycles.

There is no recommended dose of Irinotecan-DBL for patients with serum bilirubin above the upper limit of normal.

Administer a corticosteroid and an anti-emetic 30 minutes prior to Irinotecan-DBL infusion.

Table 1: Recommended Dose Modifications for Irinotecan-DBL

For recommended dose modifications of fluorouracil (5-FU) or leucovorin (LV), refer to the Full Prescribing Information; refer to Clinical Studies (14).

Irinotecan-DBL is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

• Withdraw the calculated volume of Irinotecan-DBL from the vial. Dilute Irinotecan-DBL in 500 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP and mix diluted solution by gentle inversion.
• Protect diluted solution from light.
• Administer diluted solution within 4 hours of preparation when stored at room temperature or within 24 hours of preparation when stored under refrigerated conditions [2°C to 8°C (36°F to 46°F)]. Allow diluted solution to come to room temperature prior to administration.
• Do NOT freeze.

Infuse diluted solution intravenously over 90 minutes. Do not use in-line filters. Discard unused portion.

Special precautions for disposal and other handling

As with other antineoplastic agents, Irinotecan-DBL must be prepared and handled with caution. The use of glasses, mask and gloves is required.

If Irinotecan-DBL solution or infusion solution should come into contact with the skin, wash immediately and thoroughly with soap and water. If Irinotecan-DBL solution or infusion solution should come into contact with the mucous membranes, wash immediately with water.

Preparation for the intravenous infusion administration:

As with any other injectable medicinal products, the Irinotecan-DBL solution must be prepared aseptically.

If any precipitate is observed in the vials or after dilution, the product should be discarded according to standard procedures for cytotoxic agents.

Aseptically withdraw the required amount of Irinotecan-DBL solution from the vial with a calibrated syringe and inject into a 250 ml infusion bag or bottle containing either 0.9% sodium chloride solution or 5% glucose solution. The infusion should then be thoroughly mixed by manual rotation.

Disposal:

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.