Therapeutic indications
Irinotecan 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 advanced disease,
• As a single agent in patients who have failed an established 5-fluorouracil
containing treatment regimen.
Irinotecan 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, KRAS wild-type metastatic colorectal cancer, who had
WARNING: DIARRHEA AND MYELOSUPPRESSION
Early and late forms of diarrhea can occur. Early diarrhea may be accompanied by
cholinergic symptoms which may be prevented or ameliorated by atropine. Late diarrhea
can be life threatening and should be treated promptly with loperamide.Monitor patients
with diarrhea and give fluid and electrolytes as needed. Institute antibiotic therapy if
patients develop ileus, fever, or severe neutropenia. Interrupt irinotecan hydrochloride
injection and reduce subsequent doses if severe diarrhea occurs.
Severe myelosuppression may occur.
not received prior treatment for metastatic disease or after failure of irinotecanincluding
cytotoxic therapy (see section 5.1).
Irinotecan 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.
Irinotecan 20 mg/mL concentrate for solution for infusion in combination with
capecitabine with or without bevacizumab is indicated for first-line treatment of
patients with metastatic colorectal carcinoma.

For adults only. Irinotecan 20 mg/mL concentrate for solution for infusion should be
infused into a peripheral or central vein.
Recommended dosage:
In monotherapy (for previously treated patient):
The recommended dosage of irinotecan 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):
Safety and efficacy of Irinotecan in combination with 5-fluorouracil (5FU) and folinic
acid (FA) have been assessed with the following schedule (see section 5.1):
• Irinotecan plus 5FU/FA in every 2 weeks schedule.
The recommended dose of irinotecan is 180 mg/m² administered once every 2 weeks
as an intravenous infusion over a 30- to 90-minute period, followed by infusion with
folinic acid and 5-fluorouracil.
For the posology and method of administration of concomitant cetuximab, refer to the
product information for this medicinal product.
Normally, the same dose of irinotecan is used as administered in the last cycles of the
prior irinotecan-containing regimen. Irinotecan must not be administered earlier than
1 hour after the end of the cetuximab infusion.
For the posology and method of administration of bevacizumab, refer to the
bevacizumab summary product of 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 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 concentrate for
solution for infusion, 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 (UNL)] in patients with performance status ≤ 2, should determine the starting
dose of Irinotecan concentrate for solution for infusion. In these patients with
hyperbilirubinemia and prothrombin time greater than 50%, the clearance of
irinotecan is decreased (see section 5.2) and therefore the risk of hematotoxicity is
increased. Thus, weekly monitoring of complete blood counts should be conducted in
this patient population.
• In patients with bilirubin up to 1.5 times the upper limit of the normal range (ULN),
the recommended dosage of irinotecan is 350 mg/m²,
• In patients with bilirubin ranging from 1.5 to 3 times the ULN, the recommended
dosage of irinotecan is 200 mg/m²,
• Patients with bilirubin beyond to 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 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)

• Chronic inflammatory bowel disease and/or bowel obstruction (see section 4.4) • History of severe hypersensitivity reactions to irinotecan hydrochloride trihydrate or to one of the excipients. • Lactation (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). For additional contraindications of cetuximab or bevacizumab or capecitabine, refer to the product information for these medicinal products.

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 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-dosage schedule. However, the weekly-dosage schedule (see section 5) may be
considered in patients who may need a closer follow-up or who are at particular risk
of severe neutropenia.
Delayed diarrhoea
Patients should be made aware of the risk of delayed diarrhoea occurring more than
24 hours after the administration of irinotecan and at any time before the next cycle.
In monotherapy, the median time of onset of the first liquid stool was on day 5 after
the infusion of irinotecan. Patients should quickly inform their physician of its
occurrence and start appropriate therapy immediately.
Patients with an increased risk of diarrhoea are those who had a previous
abdominal/pelvic radiotherapy, those with baseline hyperleucocytosis, those with
performance status ≥ 2 and women. If not properly treated, diarrhoea can be lifethreatening,
especially if the patient is concomitantly neutropenic.
As soon as the first liquid stool occurs, the patient should start drinking large volumes
of beverages containing electrolytes and an appropriate antidiarrhoeal therapy must be
initiated immediately. This antidiarrhoeal treatment will be prescribed by the
department where irinotecan has been administered. After discharge from the hospital,
the patients should obtain the prescribed drugs so that they can treat the diarrhoea as
soon as it occurs. In addition, they must inform their physician or the department
administering irinotecan when/if diarrhoea is occurring.
The currently recommended antidiarrhoeal treatment consists of high doses of
loperamide (4 mg for the first intake and then 2 mg every 2 hours). This therapy
should continue for 12 hours after the last liquid stool and should not be modified. In
no instance should loperamide be administered for more than 48 consecutive hours at
these doses, because of the risk of paralytic ileus, nor for less than 12 hours.
In addition to the anti-diarrhoeal treatment, a prophylactic broad spectrum antibiotic
should be given, when diarrhoea is associated with severe neutropenia (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
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 ULN, due to decrease of the clearance of
irinotecan (see section 5.2) and thus increasing the risk of hematotoxicity in this
population. For patients with a bilirubin > 3 times ULN (see section 4.3).
Nausea and 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).
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, 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 concentrate for solution
for infusion 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).
Patients with Impaired Renal Function
Studies in this population have not been conducted (see sections 4.2 and 5.2).
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 minimize all modifiable risk factors (e.g. smoking,
hypertension, and hyperlipidaemia)
Immunosuppressant Effects/Increased Susceptibility to Infections
Administration of live or live-attenuated vaccines in patients immunocompromised by
chemotherapeutic agents including irinotecan, may result in serious or fatal infections.
Vaccination with a live vaccine should be avoided in patients receiving irinotecan.
Killed or inactivated vaccines may be administered; however, the response to such
vaccines may be diminished.
Others
Since this medicinal contains sorbitol, it is unsuitable in hereditary fructose
intolerance. Infrequent cases of renal insufficiency, hypotension or circulatory failure
have been observed in patients who experienced episodes of dehydration associated
with diarrhoea and/or vomiting, or sepsis. Contraceptive measures must be taken
during and for at least three months after cessation of therapy.
Concomitant administration of irinotecan with a strong inhibitor (e.g. ketoconazole)
or inducer (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, St John's Wort)
of CYP3A4 may alter the metabolism of irinotecan and should be avoided (see
section 4.5).
 

Interaction between irinotecan and neuromuscular blocking agents 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 CYP3A-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 effects of such anticonvulsant drugs was reflected by a
decrease in AUC of SN-38 and SN-38G 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.
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) drug metabolism by cytochrome P450 3A4. 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.
Atazanavir sulphate. Coadministration of atazanavir sulfate, 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 coadministering
these drugs.
Interactions common to all cytotoxics:
The use of anticoagulants is common due to increased risk of thrombotic events in
tumoral diseases. If vitamin K antagonist anticoagulants are indicated, an increased
frequency in the monitoring of INR (International Normalised Ratio) is required due
to their narrow therapeutic index, the high intra-individual variability of blood
thrombogenicity and the possibility of interaction between oral anticoagulants and
anticancer chemotherapy.
Concomitant use contraindicated
- Yellow fever vaccine: risk of fatal generalised reaction to vaccines
Concomitant use not recommended
- Live attenuated vaccines (except yellow fever): risk of systemic, possible fatal
disease (eg-infections). This risk is increased in subjects who are already
immunosuppressed by their underlying disease.
Use an inactivated vaccine where this exists (poliomyelitis)
- Phenytoin: Risk of exacerbation of convulsions resulting from the decrease of
phenytoin digestive absorption by cytotoxic drug or risk of toxicity enhancement due
to increased hepatic metabolism by phenytoin.
Concomitant use to take into 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.
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.

Pregnancy Category D
There is no data from the use of irinotecan in pregnant women. Irinotecan has been
shown to be embryotoxic and teratogenic in animals. Therefore, based on results from
animal studies and the mechanism of action of irinotecan, Irinotecan concentrate for
solution for infusion should not be used during pregnancy unless clearly necessary.
Women of child-bearing potential
Women of childbearing potential and men have to use effective contraception during
and up to 1 month and 3 months after treatment respectively.
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)
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).

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%). For information on adverse
reactions on irinotecan in combination with cetuximab, also refer to their respective
summaries 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 by
irinotecan in combination therapy with 5FU/FA in every 2 weeks schedule at the
recommended dose of 180 mg/m².
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:
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:
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:
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.
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 below 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 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.
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 below 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 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.
One case of peripheral thrombocytopenia with antiplatelet antibodies has been
reported in the post-marketing experience.
Infection and Infestation
Infrequent cases of renal insufficiency, hypotension or cardio-circulatory failure have
been observed in patients who experienced sepsis.
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, vasodilatation, sweating, chills,
malaise, dizziness, visual disturbances, myosis, lachrimation and increased salivation
occurring during or within the first 24 hours after the infusion of irinotecan. These
symptoms disappear after atropine administration (see section 4.4).
Asthenia was severe in less than 10% of patients treated in monotherapy and in 6.2%
of patients treated in combination therapy. The causal relationship to irinotecan has
not been clearly established. Fever in the absence of infection and without
concomitant severe neutropenia, occurred in 12% of patients treated in monotherapy
and in 6.2% of patients treated in combination therapy.
Mild infusion site reactions have been reported although uncommonly.
Cardiac Disorder
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).
Skin and Subcutaneous Tissue Disorders
Alopecia was very common and reversible. Mild cutaneous reactions have been
reported although uncommonly.
Immune System Disorders
Uncommon mild allergy reactions and rare cases of anaphylactic/anaphylactoid
reactions have been reported.
Musculoskeletal Disorders
Early effects such as muscular contraction or cramps and paresthesia have been
reported.
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 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 hypokalemia and hyponatremia mostly related with diarrhea and
vomiting have been reported.
Nervous System Disorders
There have been very rare postmarketing reports of transient speech disorders
associated with irinotecan infusions

There have been reports of overdosage at doses up to approximately twice the
recommended therapeutic dose, which may be fatal. The most significant adverse
reactions reported were severe neutropenia and severe diarrhoea. 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.

Pharmacodynamic properties
Cytostatic topoisomerase I inhibitor. ATC Code: L01XX19
Experimental data
Irinotecan is a semi-synthetic derivative of camptothecin. It is an antineoplastic agent
which acts as a specific inhibitor of DNA topoisomerase I. It is metabolised by
carboxylesterase in most tissues to SN-38, which was found to be more active than
irinotecan in purified topoisomerase I and more cytotoxic than irinotecan against
several murine and human tumour cell lines. The inhibition of DNA topoisomerase I
by irinotecan or SN-38 induces single-strand DNA lesions which blocks the DNA
replication fork and are responsible for the cytotoxicity. This cytotoxic activity was
found time-dependent and was specific to the S phase.
In vitro, irinotecan and SN-38 were not found to be significantly recognised by the P -
glycoprotein MDR, and displays cytotoxic activities against doxorubicin and
vinblastine resistant cell lines.
Furthermore, irinotecan has a broad antitumor activity in vivo against murine tumour
models (P03 pancreatic ductal adenocarcinoma, MA16/C mammary adenocarcinoma,
C38 and C51 colon adenocarcinomas) and against human xenografts (Co-4 colon
adenocarcinoma, Mx-1 mammary adenocarcinoma, ST-15 and SC-16 gastric
adenocarcinomas). Irinotecan is also active against tumors expressing the Pglycoprotein
MDR (vincristine- and doxorubicin-resistant P388 leukaemia's).
Beside the antitumor activity of irinotecan, the most relevant pharmacological effect
of irinotecan is the inhibition of acetylcholinesterase.
Clinical data
In combination therapy for the first-line treatment of metastatic colorectal carcinoma
In combination therapy with Folinic Acid and 5-Fluorouracil:
A phase III study was performed in 385 previously untreated metastatic colorectal
cancer patients treated with either every 2 weeks schedule (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:

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.
 
Patients with Reduced UGT1A1 Activity
Uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) is involved in the metabolic deactivation of SN-38, the active metabolite of irinotecan to inactive SN-38 glucuronide (SN-38G). The UGT1A1 gene is highly polymorphic, resulting in variable metabolic capacities among individuals. One specific variation of the UGT1A1 gene includes a polymorphism in the promoter region known as the UGT1A1*28 variant. This variant and other congenital deficiencies in UGT1A1 expression (such as Crigler-Najjar and Gilbert's syndrome) are associated with reduced activity of this enzyme. Data from a meta analysis indicate that individuals with Crigler-Najjar syndrome (types 1 and 2) or those who are homozygous for the UGT1A1*28 allele (Gilbert's syndrome) are at increased risk of haematological toxicity (grades 3 and 4) following administration of irinotecan at moderate or high doses (>150 mg/m2). A relationship between UGT1A1 genotype and the occurrence of irinotecan induced diarrhoea was not established.

Patients known to be homozygous for UGT1A1*28 should be administered the normally indicated irinotecan starting dose. However, these patients should be monitored for haematologic toxicities. A reduced irinotecan starting dose should be considered for patients who have experienced prior haematologic toxicity with previous treatment. The exact reduction in starting dose in this patient population has not been established and any subsequent dose modifications should be based on a patient's tolerance of the treatment (see sections 4.2 and 4.4).

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

5.2 Pharmacokinetic properties
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 thriphasic 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 hour s. 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 µ g/ml and 56 ng/ml, respectively, and the mean area under the curve (AUC) values were 34 µ g.h/ml and 451 ng.h/ml, respectively. A large interindividual 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 a nd 3 t imes the upper normal limit. In these patients a 200 m g/m² irinotecan dose leads to plasma drug exposure comparable to that observed at 350 mg/m² in cancer patients with normal liver parameters
 

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 w eeks at the maximum dose of 150 m g/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 fetal viability and increase in behavioural abnormalities.
 

6.1 List of excipients
Sorbitol (E420) Lactic acid Sodium hydroxide Hydrochloric acid Water for injection
 

None known.

Do not admix with other medications.
 

The shelf-life of unopened vials is 24 months. Irinotecan 20 mg/ml concentrate solution for infusion Injection 20 mg/mL is intended for single use only and any unused portion should be discarded. Irinotecan 20 m g/ml concentrate solution for infusion must be diluted prior to infusion. Irinotecan 20 mg/ml concentrate solution for infusion should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 mg/mL to 2.8 mg/mL. Other drugs should not be added to the infusion solution. The solution is physically and chemically stable for up t o 24 hou rs at room temperature and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C, 36° to 46°F), and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates. Freezing Irinotecan 20 mg/ml concentrate solution for infusion and admixtures of Irinotecan 20 mg/ml concentrate solution for infusion may result in precipitation of the drug and should be avoided. The Irinotecan 20 mg/ml concentrate solution for infusion Injection solution should be used immediately after reconstitution as it c ontains no antibacterial preservative. Because of possible microbial contamination during dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° t o 46°F). In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should be used within 4 hour s if kept at room temperature. If reconstitution and dilution are performed under strict aseptic conditions (e.g., on Laminar Air Flow bench), Irinotecan 20 mg/ml concentrate solution for infusion Injection solution should be used (infusion completed) within 12 hour s at room temperature or 24 hours if refrigerated (2° to 8°C, 36° to 46°F).

Store below 30°C.
Protect from light, store in carton. Protect from freezing.
 

Amber glass vial (type I) with rubber stopper and aluminium flip off seal. Pack sizes: 5 ml vial. Available as single pack.

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

If Irinotecan concentrate for solution for infusion should come into contact with the skin, wash immediately and thoroughly with soap and water. If irinotecan solution or infusion solution should come into contact with the mucous membranes, wash immediately with water.
Preparation for the intravenous infusion administration:
As with any other injectable drugs, THE IRINOTECAN CONCENTRATE FOR 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 solution from the vial with a calibrated syringe and inject into a 250 ml infusion bag or bottle containing either 0.9
% sodium chloride solution or 5% glucose solution. The infusion should then be thoroughly mixed by manual rotation.

Disposal:
All materials used for dilution and administration should be disposed of according to hospital standard procedures applicable to cytotoxic agents