Irinotecan Hydrochloride 20 mg/ml concentrate for solution for infusion

Irinotecan Hydrochloride 20 mg/ml concentrate for solution for infusion

One millilitre of the concentrate for solution for infusion contains 20 mg irinotecan hydrochloride trihydrate, equivalent to 17.33 mg irinotecan.

Each vial of 2 ml contains 40 mg of irinotecan hydrochloride trihydrate (40 mg/2 ml).

Each vial of 5 ml contains 100 mg of irinotecan hydrochloride trihydrate (100 mg/5 ml).

Excipients:

Sorbitol (E420)

Sodium

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion

Yellowish clear solution

Irinotecan Hydrochloride 20 mg/ml concentrate for solution for infusion 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 advanved disease,

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

Irinotecan Hydrochloride 20 mg/ml concentrate for solution for infusion in combination with cetuximab is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of irinotecan-including cytotoxic therapy.

Irinotecan Hydrochloride 20 mg/ml concentrate for solution for infusion 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.

For adults only.

Irinotecan Hydrochloride 20 mg/ml concentrate for solution for infusion should be infused into a peripheral or central vein.

Recommended dosage

In monotherapy (for previously treated patients):

The recommended dosage of Irinotecan Hydrochloride 20 mg/ml concentrate for solution for infusion is 350 mg/m² administered as an intravenous infusion over 30 to 90 minutes every three weeks (see section 6.6 and section 4.4).

In combination therapy (for previously untreated patients):

The safety and efficacy of irinotecan in combination with 5-fluorouracil (5FU) and folinic acid (FA) has been assessed with the following schedule (see section 5.1):

Irinotecan plus 5 FU/FA in every 2 weeks schedule

The recommended dosage of irinotecan is 180 mg/m² administered once every 2 weeks as an intravenous infusion over 30 to 90 minutes, followed by an 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 product of characteristics.

Dosage adjustments

Irinotecan should be administered after appropriate recovery of all adverse events to grade 0 or 1 of the NCI-CTC grading (National Cancer Institute Common Toxicity Criteria) and when treatment-related diarrhoea is fully resolved.

At the start of a subsequent infusion 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 dosage reduction of 15 to 20% should be applied for irinotecan and/or 5FU when applicable:

● haematological toxicity (neutropenia grade 4, neutropenia with fever (neutropenia grade 3-4 and fever grade 2-4), thrombocytopenia and leucopenia (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.

Refer to the bevacizumab summary of product characteristics for dose modifications of bevacizumab when administered in combination with irinotecan/5FU/FA.

Special populations

Patients with impaired liver function

In monotherapy: Blood bilirubin levels (up to three 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 hyperbilirubinaemia and with a 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 a bilirubin level up to 1.5 times the upper limit of the normal range (ULN) the recommended dosage of irinotecan is 350 mg/m².

● In patients with a bilirubin level ranging from 1.5 to 3 times the ULN, the recommended dosage of irinotecan is 200 mg/m².

● Patients with a bilirubin level of more than 3 times ULN should not be treated with irinotecan (see section 4.3 and section 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 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).

Children

Irinotecan should not be used in children

Method of administration

Irinotecan 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.

Treatment duration

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

● History of severe hypersensitivity to irinotecan hydrochloride trihydrate or one of the excipients;

● Chronic inflammatory bowel disease and/or bowel obstruction (see section 4.4);

● Pregnancy and breast-feeding (see section 4.6 and section 4.4);

● Bilirubin level > 3 times the upper limit of the normal range (see section 4.4);

● Severe bone marrow failure;

● WHO performance status > 2;

● Concomitant use of St. John's Wort preparations (see section 4.5).

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

Given the nature and incidence of adverse events, irinotecan 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 supervision in hospital is recommended for such patients.

When irinotecan is used in monotherapy, it is usually prescribed with the every-3-week-dosage schedule. However, a weekly dosage schedule (see section 5.1) 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 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 the 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 continued for 12 hours after the last liquid stool and should not be modified. In no instance should loperamide be administered for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus, nor for less than 12 hours.

In addition to the anti-diarrhoeal treatment, a prophylactic broad-spectrum antibiotic should be given when diarrhoea is associated with severe neutropenia (neutrophil count < 500 cells/mm³).

In addition to the antibiotic treatment, hospitalisation is recommended for management of the diarrhoea, in the following cases:

● diarrhoea associated with fever;

● severe diarrhoea (requiring intravenous rehydration);

● 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).

Haematology

Weekly 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 neutrophils 1000 cells/mm³) should be urgently treated in 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 infection and haematological toxicity in patients with severe diarrhoea. In patients with severe diarrhoea, complete blood cell count should be performed.

Liver function impairment

Liver function tests should be performed at baseline and before each cycle.

Weekly monitoring of complete blood counts should be conducted in patients with bilirubin ranging from 1.5 to 3 times ULN, due to the decrease of the clearance of irinotecan (see section 5.2) and thus increasing the risk of haematotoxicity in this population . For patients with a bilirubin > 3 times ULN, see section 4.3.

Nausea and vomiting

Prophylactic therapy with anti-emetics 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 syndrome

If acute cholinergic syndrome appears (defined as early diarrhoea and various other symptoms such as sweating, abdominal cramping, lacrimation, 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 disorders

Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Interstitial pulmonary disease can be fatal. Risk factors possibly associated with the development of interstitial pulmonary disease include the use of pneumotoxic drugs, radiotherapy and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during irinotecan therapy.

Elderly

Due to the greater frequency of decreased biological functions, in particular hepatic function, in elderly patients, dose selection with Irinotecan Hydrochloride 20mg/ml Concentrate for Solution for Infusion should be cautious in this population (see section 4.2).

Patients with bowel obstruction

Patients must not be treated with irinotecan until resolution of the bowel obstruction (see section 4.3).

Patients with impaired renal function

Studies in this population have not been conducted (see section 4.2 and section 5.2).

Patients with reduced uridine diphosphate glucuronosyltransferase (UGT) activity

One metabolic pathway to inactivate the active metabolite of irinotecan SN-38 is glucuronidation to the inactive SN-38-glucuronide (SN-38G) by the enzyme uridine diphosphate-glucuronosyltransferase1A1 (UGT1A1). UGT1A1 activity is reduced in individuals with UGT1A1*28 polymorphism or congenital deficiency of UGT1A1 (Crigler-Najjar syndrome type 1 and type 2). Data from a meta analysis indicate that individuals who are homozygous for the UGT1A1*28 allele are at increased risk of haematological toxicity (grade III-IV) from irinotecan administered at moderate or high doses (>150 mg/m²). The relationship between UGT1A1 genotype and the occurrence of irinotecan induced diarrhoea can not be excluded.

If Irinotecan 20 mg/ml is administered in patients known to be homozygous for the UGT1A1*28 polymorphism, the routine starting dose should be applied. However, based on the relationship between genotype and haematologic toxicity, individuals that are known to be homozygous for UGT1A1*28 should be monitored intensively for haematologic toxicity. In case unacceptable haematologic toxicity has occurred during earlier treatment, a reduced dose may be considered for these patients. The precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment.

Other

Since this medicinal product contains sorbitol, patients with rare hereditary problems of 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 by women of child bearing age, and also by male patients, 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 inducers (e.g. rifampicin, carbamazepine, phenobarbital, St John's Wort) of CYP3A4 may alter the metabolism of irinotecan and should be avoided (see section 4.5).

Interaction between irinotecan and neuromuscular muscle relaxants cannot be ruled out. Since irinotecan has anticholinesterase activity, drugs with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarising drugs may be antagonised.

Several studies have shown that concomitant administration of CYP3A4-inducing anticonvulsant drugs (e.g. carbamazepine, phenobarbital or phenytoin) leads to reduced exposure to irinotecan, SN-38 and SN-38 glucuronide and reduced pharmacodynamic effects. The effect of such anticonvulsant drugs was reflected by a decrease in AUC of SN-38 and SN-38G of 50% or more. In addition to induction of cytochrome P450 3A enzymes, enhanced glucuronidation and enhanced biliary excretion may play a role in reducing exposure to irinotecan and its metabolites.

A study has shown that the co-administration of ketoconazole resulted in a decrease in the AUC of APC of 87% and in an increase in the AUC of SN-38 of 109% in comparison to irinotecan given alone.

Caution should be exercised in patients concurrently taking drugs known to inhibit (e.g. ketoconazole) or induce (e.g. rifampicin, carbamazepine, phenobarbital or phenytoin) Cytochrome P450 3A. Concurrent administration of irinotecan with an inhibitor/inducer of this metabolic pathway may alter the metabolism of irinotecan and should be avoided (see section 4.4).

In a small pharmacokinetic study (n=5), in which irinotecan 350 mg/m² was co-administered with St. John's Wort (Hypericum perforatum) 900 mg, a 42% decrease in the active metabolite of irinotecan, SN-38, plasma concentrations was observed. St. John's Wort decreases SN-38 plasma levels. As a result, St. John's Wort should not be administered with irinotecan (see section 4.3).

Co-administration of 5-fluorouracil/folinic acid in the combination regimen does not change the pharmacokinetics of irinotecan.

There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa.

In one study, irinotecan concentrations were similar in patients receiving irinotecan/5FU/FA alone and in combination with bevacizumab. Concentrations of SN-38, the active metabolite of irinotecan, were analyzed in a subset of patients (approximately 30 per treatment arm). Concentrations of SN-38 were on average 33% higher in patients receiving irinotecan /5FU/FA in combination with bevacizumab compared with irinotecan/5FU/FA alone. Due to high inter-patient variability and limited sampling, it is uncertain if the increase in SN-38 levels observed was due to bevacizumab. There was a small increase in diarrhoea and leukopenia adverse events. More dose reductions of irinotecan were reported for patients receiving irinotecan/5FU/FA in combination with bevacizumab.

Patients who develop severe diarrhoea, leukopenia, or neutropenia with the bevacizumab and irinotecan combination should have irinotecan dose modifications as specified in section 4.2.

Pregnancy

There is no information on the use of irinotecan by pregnant women.

Irinotecan has been shown to be embryotoxic, fetotoxic and teratogenic in rabbits and rats. Therefore, irinotecan must not be used during pregnancy (see sections 4.3 and 4.4).

Women of childbearing potential

Women of childbearing potential who are being given irinotecan should be advised not to become pregnant and, should this occur regardless, they should inform the attending physician immediately. Contraceptive measures must be taken by women of child bearing age, and also by male patients, during and for at least three months after cessation of therapy (see sections 4.3 and 4.4).

Lactation

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).

Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of irinotecan, and advised not to drive or operate machinery if these symptoms occur.

Undesirable effects 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 undesirable effects were those expected with cetuximab (such as acneform rash 88%). Therefore, also refer to the product information of cetuximab.

For information on adverse reactions in combination with bevacizumab, refer to the bevacizumab summary of product characteristics.

The following adverse reactions considered to be possibly or probably related to the administration of irinotecan have been reported from 765 patients at the recommended dose of 350 mg/m² in monotherapy, and from 145 patients treated by irinotecan in combination therapy with 5FU/FA in every 2 weeks schedule at the recommended dose of 180 mg/m².

Frequency estimate: 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); very rare (<1/10,000); not known (cannot be estimated from the available data)

Gastrointestinal disorders

Delayed diarrhoea

Diarrhoea (occurring more than 24 hours after administration) is a dose-limiting toxicity of Irinotecan concentrate for solution for infusion.

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 a 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 a 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 the patients, respectively).

Dehydration

Common: Episodes of dehydration associated with diarrhoea and/or vomiting.

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 disorders

Common: Constipation relative to irinotecan and/or loperamide has been observed:

● in monotherapy: in less than 10% of patients

● in combination therapy: in 3.4% of patients

Uncommon: Intestinal obstruction, ileus or gastrointestinal haemorrhage;

Rare: Colitis, including typhlitis, ischaemic and ulcerative colitis, intestinal perforation.

Other mild symptoms include anorexia, abdominal pain and mucositis.

Cases of symptomatic or asymptomatic pancreatitis have been associated with irinotecan therapy.

Blood and lymphatic system disorders

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.

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 1000 cells/mm³, including 7.6% with a neutrophil count below 500 cells/mm³. Total recovery was usually achieved on day 22.

Infectious episodes occurred in about 10.3% of patients and 2.5% of cycles.

Anaemia was reported in about 58.7% of patients (8% with haemoglobin < 8 g/dl and 0.9% with haemoglobin < 6.5 g/dl)

Common: Fever with severe neutropenia was reported in 6.2% of patients and 1.7% of cycles. Infectious episodes were associated with severe neutropenia in about 5.3% of patients and 1.1% of cycles and resulted in death in 2 cases.

Thrombocytopenia (< 100,000 cells/mm³) was observed in 7.4% of patients and 1.8% of cycles with 0.9% with platelet count 50,000 cells/mm³ and 0.2% of cycles. Nearly all 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 1000 cells/mm³, including 2.7% with a neutrophil count below 500 cells/mm³. Total recovery was usually reached within 7-8 days.

Anaemia was reported in 97.2% of patients (2.1% with haemoglobin < 8 g/dl).

Thrombocytopenia (< 100,000/mm³) was observed in 32.6% of patients and 21.8% of cycles. No severe thrombocytopenia (<50,000/mm³) has been observed.

Common: Fever with severe neutropenia was reported in 3.4% of patients and in0.9% 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 the cycles), and resulted in death in 1 case.

Very rare: One case of peripheral thrombocytopenia with anti-platelet antibodies has been reported in the post-marketing experience.

Infections and infestations

Uncommon: Cases of renal insufficiency, hypotension or cardio-circulatory failure have been observed in patients who experienced sepsis.

General disorders and administration site conditions

Very common: Fever in the absence of infection and without concomitant severe neutropenia occurred in 12% of patients treated with monotherapy.

Common: Asthenia was severe in less than 10% of patients treated with monotherapy and in 6.2% of patients treated with combination therapy. The causal relationship with irinotecan has not been clearly established.

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

Uncommon: Mild reactions at the infusion site.

Acute cholinergic syndrome

Common: A severe, transient, acute cholinergic syndrome was observed in 9% of patients treated in monotherapy and 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 disturbance, myosis, lacrimation and increased salivation occurring during or within 24 hours after the infusion of irinotecan. These symptoms disappear after administration of atropine (see section 4.4).

Cardiac disorders

Rare: Hypertension during or following infusion.

Respiratory, thoracic and mediastinal disorders

Uncommon: Interstitial pulmonary disease presenting as pulmonary infiltrates.

Early effects such as dyspnoea have been reported (see section 4.4).

Skin and subcutaneous disorders

Very common: Reversible alopecia.

Uncommon: Mild cutaneous reactions.

Immune system disorders

Uncommon: Mild allergy reactions

Rare: anaphylactic/anaphylactoid reactions.

Musculoskeletal and connective tissue disorders

Rare: Early effects such as muscular contractions or cramps and paraesthesia have been reported.

Investigations

Very common: In combination therapy transient serum levels (grades 1 and 2) of either SGPT, SGOT, alkaline phosphatase or bilirubin were observed in 15%, 11%, 11% and 10% of patients, respectively, in the absence of progressive liver metastases.

Common: In combination therapy, transient grade 3 increase in bilirubin serum levels was observed in 1% of the patients.

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 metastases.

Transient, mild to moderate increases of serum levels of creatinine have been observed in 7.3% of the patients.

Rare: Hypokalaemia and hyponatremia mostly related with diarrhoea and vomiting.

Very Rare: Increases of amylase and/or lipase.

Nervous system disorders

Very rare: Transient speech disorders.

There have been reports of over dosage 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. There is no known antidote for irinotecan. Maximum supportive care should be instituted to prevent dehydration due to diarrhoea and to treat any infectious complications.

Pharmacotherapeutic group: Other antineoplastic agents. ATC Code: L01XX19

Experimental data

Irinotecan is a semisynthetic 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 replication fork and are responsible for the cytotoxicity. This cytotoxic activity was found time-dependent and specific for the S-phase.

In vitro, irinotecan and SN-38 were not found to be significantly recognised by P-glycoprotein MDR, and displays cytotoxic activities on doxorubicin and vinblastine resistant cell lines.

Furthermore, irinotecan has broad anti-tumour activity in vivo against murine tumour models (PO3 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 P-glycoprotein MDR (vincristine- and doxorubicin-resistant P388 leukaemia's).

Besides the anti-tumour activity of irinotecan, the most relevant pharmacological effect of irinotecan is the inhibition of acetylcholinesterase.

Clinical data

In monotherapy:

Clinical phase II/III studies were performed in 980 patients in the every three week dosage schedule with metastatic colorectal cancer who failed a previous 5-fluorouracil regimen. The efficacy of irinotecan was evaluated in 765 patients with documented progression on 5-fluorouracil at study entry.

n.a. = not 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.

Additionaly, non-comparative phase II studies were performed in 304 patients treated with a weekly dosage 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 of 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 therapy:

A 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 the every 2 weeks schedule, on day 1, the administration of irinotecan 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 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 was evaluated in 198 treated patients:

5FU: 5-fluorouracil

FA : folinic acid

NS : not significant

*: as per protocol population analysis

In the weekly schedule, the incidence of severe diarrhoea was 44.4% in patients treated by irinotecan 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 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 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 groups. The evolution of the Global Health Status/Quality of life was slightly better in irinotecan combination group although not significant; showing that efficacy of irinotecan in combination could be reached without affecting the quality of life.

In combination with cetuximab:

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).

In combination with bevazicumab:

A phase III randomised, double-blind, active-controlled clinical trial evaluated bevacizumab in combination with Irinotecan/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/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 summarized in the table below.

^a 5 mg/kg every 2 weeks.

^b Relative to control arm.

Pharmacokinetic/pharmacodynamic data

The intensity of the major toxicities encountered with irinotecan (e.g., leukoneutropenia and diarrhoea) is 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.

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 and the volume of distribution at steady state (Vss): 157 L/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. 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 inter-individual variability in pharmacokinetic parameters is generally observed for SN-38.

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.

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

Mass balance and metabolism studies with 14 C-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) (see section 4.5).

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

Irinotecan clearance is decreased by about 40% in patients with bilirubinemia between 1.5 and 3 times the ULN. 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.

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

Lactic acid

Sorbitol (E420)

sodium hydroxide (for pH adjustment)

hydrochloric acid (for pH adjustment)

water for injection

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Before dilution:

3 years.

After dilution:

The diluted product is physicochemically stable for 48 hours in a refrigerator at 2-8ºC and for 24 hours at room temperature (below 25ºC). From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C.

Do not refrigerate or freeze.

Store in the original package in order to protect from light.

For storage conditions of the diluted medicinal product, see section 6.3.

For 2 ml:

Concentrate for solution for infusion is filled in 4 ml amber coloured glass vial closed with a fluoropolymer coated bromobutyl rubber stopper and aluminum flip off seal.

For 5 ml:

Concentrate for solution for infusion is filled in 7 ml amber coloured glass vial closed with a fluoropolymer coated bromobutyl rubber stopper and aluminum flip off seal.

Pack sizes:

1 × 2 ml vial

1 × 5 ml vial

Not all pack size may be marketed,

Like other anti-neoplastic substances, irinotecan must be prepared and handled with caution. Glasses, a mask and gloves must be used.

If irinotecan solution or infusion solution comes in contact with the skin, wash immediately and thoroughly with soap and water. If irinotecan solution or infusion solution comes in contact with the mucous membranes, rinse immediately with water.

Preparation of the intravenous infusion for administration

Like all drugs that can be administered by injection, irinotecan solution must be prepared aseptically (see section 6.3). If any precipitate is observed in the injection vials or after reconstitution, the product should be discarded according to standard procedures for cytotoxic agents.

Withdraw the required amount of irinotecan solution aseptically from the injection vial with a calibrated syringe and inject into a 250 ml infusion bag or bottle containing either 0.9 % sodium chloride solution or 5 % dextrose solution. The infusion should then be thoroughly mixed by manual rotation.

Disposal

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

Sandoz UK Limited

37 Woolmer Way,

Bordon, Hampshire,

GU35 9QE, UK

PL 04416/1029

22/04/2009

23/09/2009