4.1. Therapeutic indications

Irinotecan 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 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 (see section 5.1).

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

4.2. Posology and method of administration

Posology

For adults only. Diluted irinotecan solution for infusion should be infused into a peripheral or central vein.

Recommended dosage:

Dosages of irinotecan mentioned in this summary of product characteristics refer to mg of irinotecan hydrochloride, trihydrate.

In monotherapy (for previously treated patient)

The recommended dosage of irinotecan is 350 mg/m2 administered as an intravenous infusion over a 30 to 90 minute period every three weeks (see sections 4.4 and 6.6).

In combination therapy (for previously untreated patient)

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

• Irinotecan plus 5FU/FA in every 2 weeks schedule

The recommended dose of irinotecan is 180 mg/m2 administered once every 2 weeks as an intravenous infusion over a 30- to 90-minute period, followed by an infusion of folinic acid and 5-fluorouracil.

For the posology and method of administration of concomitant cetuximab, refer to the product information for this medicinal product.

Normally, the same dose of irinotecan is used as administered in the last cycles of the prior irinotecan-containing regimen. Irinotecan must not be administered earlier than 1 hour after the end of the cetuximab infusion.

For the posology and method of administration of bevacizumab, refer to the bevacizumab summary of product characteristics.

For the posology and method of administration of capecitabine combination, please see section 5.1 and refer to the appropriate sections in the capecitabine summary of product characteristics.

Dosage adjustments:

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

At the start of a subsequent infusion of therapy, the dose of irinotecan, and 5FU when applicable, should be decreased according to the worst grade of adverse events observed in the prior infusion. Treatment should be delayed by 1 to 2 weeks to allow recovery from treatment-related adverse events.

With the following adverse events a dose reduction of 15 to 20% should be applied for irinotecan 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 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. In these patients with hyperbilirubinaemia and prothrombin time greater than 50%, the clearance of irinotecan is decreased (see section 5.2), 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 levels up to 1.5 times the ULN, the recommended dosage of irinotecan is 350 mg/m2.

• In patients with bilirubin levels between 1.5 to 3 times the ULN, the recommended dosage of irinotecan is 200 mg/m2.

• Patients with bilirubin levels beyond 3 times the ULN, should not be treated with irinotecan (see sections 4.3 and 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 sections 4.4 and 5.2).

Elderly

No specific pharmacokinetic studies have been performed in the elderly. However, the dose should be chosen carefully in this population due to their greater frequency of decreased biological functions. This population should require more intense surveillance (see section 4.4).

Paediatric population

The safety and efficacy of irinotecan 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:

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

• Chronic inflammatory bowel disease and/or bowel obstruction (see section 4.4).

• Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

• Breast-feeding (see sections 4.4 and 4.6).

• Bilirubin > 3 times the upper limit of the normal range (see section 4.4).

• Severe bone marrow failure.

• WHO performance status > 2.

• Concomitant use with St John's Wort (see section 4.5).

• Live attenuated vaccines (see section 4.5).

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

4.4. Special warnings and precautions for use

The use of irinotecan should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a physician qualified in the use of anticancer chemotherapy.

Given the nature and incidence of adverse events, irinotecan will only be prescribed in the following cases after the expected benefits have been weighed against the possible therapeutic risks:

• in patients with 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 anti-diarrhoeal treatment combined with high fluid intake at onset of delayed diarrhoea). Strict hospital supervision is recommended for such patients.

When irinotecan is used in monotherapy, it is usually prescribed using the every-3-week dosage schedule. However, the weekly-dosage schedule (see section 5) may be considered in patients who 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 appropriate therapy immediately.

Patients with an increased risk of diarrhoea are those who have had 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 anti-diarrhoeal therapy must be initiated immediately. The anti-diarrhoeal treatment will be prescribed by the department where irinotecan has been administered. After discharge from the hospital, the patients should obtain the prescribed medicinal products so 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 anti-diarrhoeal treatment consists of high doses of loperamide (4 mg at the first intake and then 2 mg every 2 hours). This therapy should continue for 12 hours after the last liquid stool and should not be modified. In no instance should loperamide be administered for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus, nor for less than 12 hours.

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

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

- Diarrhoea associated with fever,

- Severe diarrhoea (requiring intravenous hydration),

- Diarrhoea persisting beyond 48 hours following the initiation of high-dose loperamide therapy.

Loperamide should not be given prophylactically, even in patients who experienced delayed diarrhoea at previous cycles.

In patients who experienced severe diarrhoea, a reduction in dose is recommended for subsequent cycles (see section 4.2).

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 treatment. Patients should be aware of the risk of neutropenia and the significance of fever. Febrile neutropenia (temperature > 38°C and neutrophil count ≤ 1,000 cells/mm3) should be urgently treated in the hospital with broad-spectrum intravenous antibiotics.

In patients who experienced severe haematological events, a dose reduction is recommended for subsequent administration (see section 4.2).

There is an increased risk of infections and haematological toxicity in patients with severe diarrhoea. In patients with severe diarrhoea, complete blood cell counts should be performed.

Patients with reduced UGT1A1 activity

Patients that are UGT1A1 poor metabolisers, such as patients with Gilbert's syndrome (e.g. homozygous for UGT1A1*28 or *6 variants) are at increased risk for severe neutropenia and diarrhoea following irinotecan treatment. This risk increases with the irinotecan dose level.

Although a precise dose reduction in starting dose has not been established, a reduced irinotecan starting dose should be considered for patients that are UGT1A1 poor metabolisers, especially patients who are administered doses > 180 mg/m2 or frail patients. Consideration should be given to applicable clinical guidelines for dose recommendations in this patient population. Subsequent doses may be increased based on individual patient tolerance to treatment.

UGT1A1 genotyping can be used to identify patients at increased risk of severe neutropenia and diarrhoea, however the clinical utility of pre-treatment genotyping is uncertain, since UGT1A1 polymorphism does not account for all the toxicity seen from irinotecan therapy (see section 5.2).

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 (see section 5.2) and thus increasing the risk of hepatotoxicity in this population. For patients with a bilirubin > 3 times the ULN, see section 4.3.

Nausea and vomiting

A prophylactic treatment with antiemetics is recommended before each treatment with irinotecan. Nausea and vomiting have been frequently reported. Patients with vomiting associated with delayed diarrhoea should be hospitalised as soon as possible for treatment.

Acute cholinergic syndrome

If acute cholinergic syndrome appears (defined as early diarrhoea and various other signs and symptoms such as sweating, abdominal cramping, myosis and salivation), atropine sulphate (0.25 mg subcutaneously) should be administered unless clinically contraindicated (see section 4.8).

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. If the patient experiences an acute and severe cholinergic syndrome, the use of prophylactic atropine sulphate is recommended with subsequent doses of irinotecan.

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 should be cautious in this population (see section 4.2).

Chronic inflammatory bowel disease and/or bowel obstruction

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

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 (see section 4.2).

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 (see section 4.8).

Consequently, patients with known risk factors should be closely monitored, and action should be taken to try to minimise 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.

Contraception in women of childbearing potential/men:

Due to the potential for genotoxicity, advise female patients of reproductive potential to use highly effective contraception during treatment and for 6 months after the last dose of irinotecan. Due to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of irinotecan (see section 4.6).

Breast-feeding

Due to the potential for adverse reactions in nursing infants, breast-feeding should be discontinued for the duration of irinotecan therapy (see sections 4.3 and 4.6).

Concomitant administration of irinotecan with a strong inhibitor (e.g. ketoconazole) or inducer (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, apalutamide) of CYP3A4 may alter the metabolism of irinotecan and should be avoided (see section 4.5).

This medicine contains sorbitol (see section 2). Sorbitol is a source of fructose. Patients with hereditary fructose intolerance (HFI) must not be given this medicine unless strictly necessary.

Babies and young children (below 2 years of age) may not yet be diagnosed with HFI. Medicines (containing fructose) given intravenously may have life-threatening effects in individuals with HFI and should not be administered in this population unless there is an overwhelming clinical need and no alternatives are available.

A detailed history with regard to HFI symptoms has to be taken of each patient prior to being given this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Concomitant use contraindicated (see section 4.3)

Saint John's Wort: Decrease in the active metabolite of irinotecan, SN-38, plasma levels. 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. As a result, St. John's Wort should not be administered with irinotecan.

Live attenuated vaccines (e.g. yellow fever vaccine): Risk of generalised reaction to vaccines, possibly fatal. Concomitant use is contraindicated during treatment with irinotecan and for 6 months following discontinuation of chemotherapy. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Concomitant use not recommended (see section 4.4)

Concurrent administration of irinotecan with strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) may alter the metabolism of irinotecan and should be avoided (see section 4.4).

Strong CYP3A4 and/or UGT1A1 inducing medicinal products (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin or apalutamide): Risk of reduced exposure to irinotecan, SN-38 and SN-38 glucuronide and reduced pharmacodynamic effects. Several studies have shown that concomitant administration of CYP3A4-inducing anticonvulsant medicinal products leads to reduced exposure to irinotecan, SN-38 and SN-38 glucuronide and reduced pharmacodynamic effects. The effects of such anticonvulsant medicinal products were reflected by a decrease in AUC of SN-38 and SN-38G by 50% or more. In addition to induction of CYP3A4 enzymes, enhanced glucuronidation and enhanced biliary excretion may play a role in reducing exposure to irinotecan and its metabolites. Additionally with phenytoin: Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic medicinal products.

Strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, protease inhibitors, clarithromycin, erythromycin, telithromycin): 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.

UGT1A1 inhibitors (e.g. atazanavir, ketoconazole, regorafenib): Risk to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should take this into consideration if the combination is unavoidable.

Other CYP3A4 inhibitors (e.g. crizotinib, idelalisib): Risk of increase in irinotecan toxicity, due to a decrease in irinotecan metabolism by crizotinib or idelalisib.

Caution for use

Vitamin K antagonists: Increased risk of haemorrhage and thrombotic events in tumoural diseases. If vitamin K antagonists are indicated, an increased frequency in the monitoring of INR (International Normalised Ratio) is required.

Concomitant use to take into consideration

Immunodepressant agents (e.g. ciclosporine, tacrolimus): Excessive immunosuppression with risk of lymphoproliferation.

Neuromuscular blocking agents: Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out. Since irinotecan has anticholinesterase activity, medicinal products with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarising medicinal products may be antagonised.

Other combinations

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

Bevacizumab: Results from a dedicated drug-drug interaction trial demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38. However, this does not preclude any increase of toxicities due to their pharmacological properties.

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

Antineoplastic agents (including flucytosine as a prodrug for 5-fluorouracil): Adverse effects of irinotecan, such as myelosuppression, may be exacerbated by other antineoplastic agents having a similar adverse-effect profile.

4.6. Fertility, pregnancy and lactation

Contraception

Due to the potential for genotoxicity, advise female patients of reproductive potential to use highly effective contraception during treatment and for 6 months after the last dose of irinotecan (see section 4.4).

Due to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of irinotecan (see section 4.4).

Pregnancy

There are limited data from the use of irinotecan in pregnant women. Irinotecan has been shown to be embryotoxic and teratogenic in animals (see section 5.3). Therefore, based on results from animal studies and the mechanism of action of irinotecan, irinotecan should not be used during pregnancy unless clearly necessary.

Women of childbearing potential should not be started on irinotecan until pregnancy is excluded. Pregnancy should be avoided if either partner is receiving irinotecan.

Breast-feeding

The available data are limited but suggested that irinotecan and its metabolite are excreted in human milk. Consequently, because of the potential for adverse reactions in nursing infants, breast-feeding should be discontinued for the duration of irinotecan therapy (see sections 4.3 and 4.4).

Fertility

There are no human data on the effect of irinotecan on fertility. In animals adverse effects of irinotecan on the fertility of offspring has been documented (see section 5.3). Prior to starting to take irinotecan consider advising patients on the preservation of gametes.

4.7. Effects on ability to drive and use machines

Irinotecan 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, and advised not to drive or operate machinery if these symptoms occur.

4.8. 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. These symptoms disappear after atropine administration (see section 4.4).

Monotherapy

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. 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).

Adverse Reactions Reported with Irinotecan in Monotherapy (350 mg/m2 every 3 weeks schedule)

MedDRA System Organ Class

Frequency Category

Preferred Term

Infections and infestations

Common

Infection

Blood and lymphatic system disorders

Very common

Neutropenia

Very common

Anaemia

Common

Thrombocytopenia

Common

Febrile neutropenia

Metabolism and nutrition disorders

Very common

Decreased appetite

Nervous system disorders

Very common

Cholinergic syndrome

Gastrointestinal disorders

Very common

Diarrhoea

Very common

Vomiting

Very common

Nausea

Very common

Abdominal pain

Common

Constipation

Skin and subcutaneous tissue disorders

Very common

Alopecia (reversible)

General disorders and administration site conditions

Very common

Mucosal inflammation

Very common

Pyrexia

Very common

Asthenia

Investigations

Common

Blood creatinine increased

Common

Transaminases (ALT and AST) increased

Common

Blood bilirubin increased

Common

Blood alkaline phosphatase increased

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.

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 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 of product 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/5FU/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/5FU/FA alone. For other information on adverse reactions in combination with bevacizumab, refer to the bevacizumab summary of product characteristics.

Irinotecan has been studied in combination with 5FU 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 have been reported 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.

Adverse Reactions Reported with Irinotecan in Combination Therapy (180 mg/m2 every 2 weeks schedule)

MedDRA System Organ Class

Frequency Category

Preferred Term

Infections and infestations

Common

Infection

Blood and lymphatic system disorders

Very common

Thrombocytopenia

Very common

Neutropenia

Very common

Anaemia

Common

Febrile neutropenia

Metabolism and nutrition disorders

Very common

Decreased appetite

Nervous system disorders

Very common

Cholinergic syndrome

Gastrointestinal disorders

Very common

Diarrhoea

Very common

Vomiting

Very common

Nausea

Common

Abdominal pain

Common

Constipation

Skin and subcutaneous tissue disorders

Very common

Alopecia (reversible)

General disorders and administration site conditions

Very common

Mucosal inflammation

Very common

Asthenia

Common

Pyrexia

Investigations

Very common

Transaminases (ALT and AST) increased

Very common

Blood bilirubin increased

Very common

Blood alkaline phosphatase increased

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 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 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

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) (see section 4.4).

Post-Marketing Surveillance

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

MedDRA System Organ Class

Preferred Term

Infections and infestations

• Pseudomembranous colitis one of which has been documented bacteriologically (Clostridium difficile)

• Sepsis

• Fungal infections*

• Viral infections†

Blood and lymphatic system disorders

• Thrombocytopenia with antiplatelet antibodies

Immune system disorders

• Hypersensitivity

• Anaphylactic reaction

Metabolism and nutrition disorders

• Dehydration (due to diarrhoea and vomiting)

• Hypovolaemia

Nervous system disorders

• Speech disorder generally transient in nature, in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan

• Paraesthesia

• Muscular contractions involuntary

Cardiac disorders

• Hypertension (during or after infusion)

• Cardio circulatory failure‡

Vascular disorders

• Hypotension‡

Respiratory, thoracic and mediastinal disorders

• Interstitial lung disease presenting as lung infiltration is uncommon during irinotecan therapy; early effects such as dyspnoea have been reported (see section 4.4).

• Dyspnoea (see section 4.4)

• Hiccups

Gastrointestinal disorders

• Intestinal obstruction

• Ileus: cases of ileus without preceding colitis have also been reported

• Megacolon

• Gastrointestinal haemorrhage

• Colitis; in some cases, colitis was complicated by ulceration, bleeding, ileus, or infection.

• Typhlitis

• Colitis ischaemic

• Colitis ulcerative

• Symptomatic or asymptomatic pancreatic enzymes increased

• Intestinal perforation

Hepatobiliary disorders

• Steatohepatitis

• Hepatic steatosis

Skin and subcutaneous tissue disorders

• Skin reaction

Musculoskeletal and connective tissue disorders

• Cramps

Renal and urinary disorders

• Renal impairment and acute renal failure generally in patients who become infected and/or volume depleted from severe gastrointestinal toxicities‡

• Renal insufficiency‡

General disorders and administration site conditions

• Infusion site reaction

Investigations

• Amylase increased

• Lipase increased

• Hypokalaemia

• Hyponatraemia mostly related with diarrhoea and vomiting

• Transaminases increased (i.e. AST and ALT) in the absence of progressive liver metastasis have been very rarely reported.

* e.g. Pneumocystis jirovecii pneumonia, bronchopulmonary aspergillosis, systemic candida.

† e.g. Herpes zoster, influenza, hepatitis B reactivation, cytomegalovirus colitis.

‡ Infrequent 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, or sepsis.

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

4.9. Overdose

Symptoms

There have been reports of overdose, with 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. Maximum supportive treatment should be initiated to prevent dehydration due to diarrhoea and to treat any infectious complications.