IRINOTECAN HYDROCHLORIDE MEDAC 20 MG / ML CONCENTRATE FOR SOLUTION FOR INFUSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Irinotecan medac 20 mg/ml, concentrate for solution for infusion.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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).

Each vial of 15 ml contains 300 mg of irinotecan hydrochloride trihydrate

(300 mg/15 ml).

Each vial of 25 ml contains 500 mg of irinotecan hydrochloride trihydrate

(500 mg/25 ml).

Each vial of 50 ml contains 1000 mg of irinotecan hydrochloride trihydrate (1000 mg/50 ml).

Excipients with known effect

Sorbitol (E 420)

This medicine contains 45 mg sorbitol per ml.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion.

A clear yellow solution.

pH 3.0 – 3.8

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Irinotecan Hydrochloride medac is indicated for the treatment of patients with advanced colorectal cancer

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

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

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

Irinotecan Hydrochloride medac 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 Hydrochloride medac 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________________________________

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.

For adults only.

Posology

In monotherapy (for previously treated patients):

The recommended dose of irinotecan is 350 mg/m2 administered as an intravenous infusion over a 30– to 90-minute period every 3 weeks (see sections 4.4 and 6.6).

In combination therapy (for previously untreated patients):

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

Irinotecan plus 5-FU/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 infusion with folinic acid and 5-fluorouracil.

For 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.

Dose adjustments

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

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

With the following adverse events a dose reduction of 15 – 20 % should be applied for irinotecan and/or 5-FU when applicable:

Haematological toxicity (neutropenia grade 4, febrile neutropenia [neutropenia grade 3 – 4 and fever grade 2 – 4], thrombocytopenia and leukocytopenia [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/5-FU/FA.

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 WHO 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 haematotoxicity is increased. Thus, weekly monitoring of complete blood counts should be conducted in this patient population.

In patients with bilirubin up to 1.5 times the ULN, the recommended dose of irinotecan is 350 mg/m2

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

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

In combination therapy:

No data are available in patients with hepatic impairment treated by 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 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).

Method of administration

After dilution the irinotecan solution for infusion should be infused into a peripheral or central vein.

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

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

Breast-feeding (see section 4.6).

Bilirubin > 3 times the ULN (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, refer to the product information for these medicinal products.

4.4 Special warnings and precautions for use

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 hospital supervision is recommended for such patients.

When irinotecan is used in monotherapy, it is usually prescribed with the every-3-week-dose schedule. However, the weekly-dose 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 appropriate therapy immediately.

Patients with an increased risk of diarrhoea are those who had a previous abdominal/pelvic radiotherapy, those with baseline hyperleukocytosis, those with WHO 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 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 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 (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.

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 haematotoxicity 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. 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 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).

Patients with 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).

Patients with impaired 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.

Further, studies in this population have not been conducted (see sections 4.2 and 5.2).

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 predominantly 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 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.

Excipients

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 hereditary fructose intolerance (HFI). Medicines (containing sorbitol/fructose) given intravenously may be life-threatening and should be contraindicated 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.

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.

Contraceptive measures must be taken during and for at least 3 months after cessation of therapy (see section 4.6).

Concomitant administration of irinotecan with a strong inhibitor (e.g., ketoconazole) or inducer (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, St. John’s wort, apalutamide) of cytochrome P450 3A4 (CYP3A4) may alter the metabolism of irinotecan and should be avoided (see section 4.5).

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).

4.5 Interaction with other medicinal products and other forms of interaction

Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out. Since irinotecan has anticholinesterase activity, the neuromuscular blocking effects of suxamethonium may be prolonged and the neuromuscular blockade of nondepolarising active substances may be antagonised.

Caution should be exercised in patients concurrently taking medicinal products known to inhibit (e.g., ketoconazole) metabolism of the active substance by CYP3A4: A study has shown that the co-administration of ketoconazole resulted in a decrease in the AUC of the principal oxidative metabolite APC of 87 % and in an increase in the AUC of SN-38 of 109 % in comparison to irinotecan given alone.

In a small pharmacokinetic study (n = 5), in which irinotecan 350 mg/m2 was coadministered 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. Therefore, St. John’s wort should not be administered together with irinotecan (see section 4.3).

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

Atazanavir sulphate. Co-administration of atazanavir sulphate, a CYP3A4 and UGT1A1 inhibitor, has the potential to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should take this into consideration when co-administering these medicinal products.

Interactions common to all cytotoxics

The use of anticoagulants is common due to increased risk of thrombotic events in tumoural diseases. If vitamin K antagonist anticoagulants are indicated, an increased frequency in the monitoring of INR (International Normalised Ratio) is required due to their narrow therapeutic index, the high intra-individual variability of blood thrombogenicity and the possibility of interaction between oral anticoagulants and anticancer chemotherapy.

Concomitant use contraindicated (see section 4.3)

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 an inducer 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). Several studies have shown that concomitant administration of CYP3A-inducing anticonvulsant medicinal products (e.g., carbamazepine, phenobarbital, phenytoin, apalutamide) 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-38 glucuronide by 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. Additionally with phenytoin: Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic substances.

Concomitant use to take into consideration

Ciclosporine, tacrolimus: Excessive immunosuppression with risk of lymphoproliferation

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/5-FU/FA alone and in combination with bevacizumab. Concentrations of SN-38, the active metabolite of irinotecan, were analysed in a subset of patients (approximately 30 per treatment arm). Concentrations of SN-38 were on average 33 % higher in patients receiving irinotecan/5-FU/FA in combination with bevacizumab compared with irinotecan/5-FU/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 leukocytopenia adverse events. More dose reductions of irinotecan were reported for patients receiving irinotecan/5-FU/FA in combination with bevacizumab.

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

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.

Other combinations

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

Pregnancy

There are no or limited amount of data from the use of irinotecan in pregnant women.

Studies in animals have shown reproductive toxicity (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 the clinical condition of the woman requires treatment with irinotecan.. The advantages of treatment should be weighed against the possible risk for the foetus in every individual case (see sections 4.3 and 4.4).

Contraception in males and females

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

Breast-feeding

In lactating rats, 14C-irinotecan was detected in milk. It is unknown whether irinotecan is excreted in human milk. Consequently, because of the potential for adverse reactions in nursing infants, irinotecan is contraindicated during breast-feeding (see section 4.3).

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).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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 %). For information on adverse reactions on irinotecan in combination with cetuximab, also refer to their respective summary of product characteristics.

For information on adverse reactions in combination with bevacizumab, refer to the bevacizumab 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 reaction, cardiac ischemia/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 cardiac ischemia/infar­ction. For complete information on adverse reactions of capecitabine and bevacizumab, refer to the respective capecitabine and 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 with irinotecan in combination therapy with 5-FU/FA in every-2-weeks schedule at the recommended dose of 180 mg/m2.

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.

Tabulated list of adverse reactions

Side effects have been summarised in the table below with MedDRA frequencies. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very common: > 1/10

Infection and infestation

Infrequent cases of renal insufficiency, hypotension or cardio-circulatory failure have been observed in patients who experienced sepsis.

Blood 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:

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 < 1,000 cells/mm3 including 7.6 % with a neutrophil count < 500 cells/mm3.

Total recovery was usually reached by day 22.

Fever with severe neutropenia was reported in 6.2 % of patients and in 1.7 % of cycles.

Infectious episodes occurred in about 10.3 % of patients (2.5 % of cycles) and were associated with severe neutropenia in about 5.3 % of patients (1.1 % of cycles), and resulted in death in two 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.

In combination therapy:

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 < 1,000 cells/mm3 including 2.7 % with a neutrophil count < 500 cells/mm3.

Total recovery was usually reached within 7 – 8 days.

Fever with severe neutropenia was reported in 3.4 % of patients and in 0.9 % of cycles.

Infectious episodes occurred in about 2 % of patients (0.5 % of cycles) and were associated with severe neutropenia in about 2.1 % of patients (0.5 % of cycles), and resulted in death in one 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.

One case of peripheral thrombocytopenia with antiplatelet antibodies has been reported in the post-marketing experience.

Immune system disorders

Uncommon mild allergy reactions and rare cases of anaphylactic/a­naphylactoid reactions have been reported.

Nervous system disorders

There have been very rare postmarketing reports of transient speech disorders associated with irinotecan infusions.

Cardiac disorders

Rare cases of hypertension during or following the infusion have been reported.

Respiratory disorders

Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Early effects such as dyspnoea have been reported (see section 4.4).

Gastrointestinal disorders

Delayed diarrhoea

Diarrhoea (occurring more than 24 hours after administration) is a doselimiting toxicity of irinotecan.

In 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.

In 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 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:

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

In combination therapy:

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

Dehydration

Episodes of dehydration commonly associated with diarrhoea and/or vomiting have been reported.

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.

Other gastrointestinal disorders

Constipation relative to irinotecan and/or loperamide has been observed, shared between:

– in monotherapy: in less than 10 % of patients

– in combination therapy: 3.4 % of patients.

Infrequent cases of intestinal obstruction, ileus, or gastrointestinal haemorrhage and rare cases of colitis, including typhlitis, ischemic and ulcerative colitis, were reported. Rare cases of intestinal perforation were reported. Other mild effects include anorexia, abdominal pain and mucositis.

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

Hepatobiliary disorders

There have been postmarketing reports of hepatic steatosis and steatohepatitis (frequencies cannot be estimated from available data).

Skin and subcutaneous tissue disorders

Alopecia was very common and reversible. Mild cutaneous reactions have been reported although uncommonly.

Musculoskeletal disorders

Early effects such as muscular contraction or cramps and paresthesia have been reported.

General disorders and infusion site reactions

Acute cholinergic syndrome

Severe transient acute cholinergic syndrome was observed in 9 % of patients treated in monotherapy and in 1.4 % of patients treated in combination therapy. The main symptoms were defined as early diarrhoea and various other symptoms such as abdominal pain, conjunctivitis, rhinitis, hypotension, vasodilation, sweating, chills, malaise, dizziness, visual disturbances, myosis, lacrimation and increased salivation occurring during or within the first 24 hours after the infusion of irinotecan. These symptoms 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. They disappear after atropine administration (see section 4.4).

Asthenia was severe in less than 10 % of patients treated in monotherapy and in 6.2 % of patients treated in combination therapy. The causal relationship to irinotecan has not been clearly established. Fever in the absence of infection and without concomitant severe neutropenia, occurred in 12 % of patients treated in monotherapy and in 6.2 % of patients treated in combination therapy.

Mild infusion site reactions have been reported although uncommonly.

Investigations

Laboratory tests

In monotherapy, transient and mild to moderate increases in serum levels of either transaminases, alkaline phosphatase or bilirubin were observed in 9.2 %, 8.1 % and 1.8 % of the patients, respectively, in the absence of progressive liver metastasis.

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

In combination therapy transient 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 was 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 hypokalemia and hyponatremia mostly related with diarrhoea and vomiting have been reported.

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.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

5.2 Pharmacokinetic properties

Distribution

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

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

Biotransformation

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 glucuronide 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.

Elimination

In a phase I study in 60 patients with a dose regimen of a 30-minute intravenous infusion of 100 – 750 mg/m2 every 3 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) was 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 |ig/ml and 56 ng/ml, respectively, and the mean area under the curve (AUC) values were 34 Ligf/ml and 451 ng^h/ml, respectively. A large interindividual variability in pharmacokinetic parameters is generally observed for SN-38.

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 and SN-38 exposure increase proportionally with irinotecan administered dose; their pharmacokinetics are independent of the number of previous cycles and of the administration schedule.

Pharmacokinetic/phar­macodynamic relationships

The intensity of the major toxicities encountered with irinotecan (e.g., neutropenia and diarrhoea) is related to the exposure (AUC) to parent substance 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.

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

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. The most well-characterized UGT1A1 genetic variants are UGT1A1*28 and UGT1A1*6. These variants and other congenital deficiencies in UGT1A1 expression (such as Gilbert's syndrome and Crigler-Najjar) are associated with reduced activity of this enzyme.

Patients that are UGT1A1 poor metabolisers (e.g. homozygous for UGT1A1*28 or *6 variants) are at increased risk of severe adverse reactions such as neutropenia and diarrhoea following administration of irinotecan, as a consequence of SN-38 accumulation. According to data from several meta-analyses, the risk is higher for patients receiving irinotecan doses >180 mg/m2 (see section 4.4).

In order to identify patients at increased risk of experiencing severe neutropenia and diarrhoea, UGT1A1 genotyping can be used. Homozygous UGT1A1*28 occurs with a frequency of 8–20% in the European, African, Near Eastern and Latino population. The *6 variant is nearly absent in these populations. In the East Asian population the frequency of 28/28 is about 1–4%, 3–8% for 6/28 and 2–6% for 6/6. In the Central and South Asian population the frequency of 28/28 is around 17%, 4% for 6/28 and 0.2% for 6/6.

5.3 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 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 foetal viability and increase in behavioural abnormalities.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sorbitol (E420)

Lactic acid

Sodium hydroxide (to adjust to pH 3.5)

Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

3 years.

Diluted medicinal product (solution for infusion)

After dilution in 0.9 % sodium chloride solution or 5 % glucose solution, chemical and physical in-use stability has been demonstrated for up to 6 hours at room temperature (approximately 25 °C) and ambient lighting or 48 hours if stored at refrigerated temperatures (approximately 2 °C – 8 °C).

From a microbiological point of view, the solution for infusion 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 6 hours at room temperature or 24 hours if stored at 2 °C – 8 °C unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

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

6.5 Nature and contents of container

Irinotecan medac 40 mg:

2-ml brown glass vial, with a halobutyl rubber closure coated with a layer of an inert fluoropolymer on the inner side. Pack of one vial.

Irinotecan medac 100 mg:

5-ml brown glass vial, with a halobutyl rubber closure coated with a layer of an inert fluoropolymer on the inner side. Pack of one vial.

Irinotecan medac 300 mg:

15-ml brown glass vial, with a halobutyl rubber closure coated with a layer of an inert fluoropolymer on the inner side. Pack of one vial.

Irinotecan medac 500 mg:

25-ml brown glass vial, with a halobutyl rubber closure coated with a layer of an inert fluoropolymer on the inner side. Pack of one vial.

Irinotecan medac 1000 mg:

50-ml brown glass vial, with a halobutyl rubber closure coated with a layer of an inert fluoropolymer on the inner side. Pack of one vial.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

As with other antineoplastic agents, Irinotecan Hydrochloride medac must be prepared and handled with caution.

The use of glasses, mask and gloves is required.

If Irinotecan Hydrochloride medac concentrate for solution for infusion or the prepared solution for infusion should come into contact with the skin, wash immediately and thoroughly with soap and water. If Irinotecan Hydrochloride medac concentrate for solution for infusion or the prepared solution for infusion should come into contact with the mucous membranes, wash immediately with water.

Preparation of the intravenous solution

As with any other injectable medicinal products, the Irinotecan Hydrochloride medac solution for infusion must be prepared aseptically (see section 6.3).

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 Hydrochloride medac concentrate for solution for infusion 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 solution for 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.

For single use only.

7. MARKETING AUTHORISATION HOLDER

medac

Gesellschaft für klinische Spezialpräparate mbH

Theaterstr. 6

22880 Wedel

Germany

8 MARKETING AUTHORISATION NUMBER(S)

PL 11587/0047

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 02 April 2009

Date of latest renewal: 14 February 2014