Irinotecan Hydrochloride 20 MGML, Concentrate For Solution For Infusion SMPC - Taj Pharmaceuticals

Irinotecan Hydrochloride 20 mg/ml, concentrate for solution for infusion SMPC, Taj Pharma ceutical s
IRINO TECA N Taj Phar ma : Us es, Side E ffe cts, Intera ctions, Picture s, Warning s, IRI NOTE CAN Dosage & Rx I nfo | IRIN OTECA N Uses, Side Effects -: Indications, Side E ffe cts, War nings, I RINO TECA N - Drug I nformation - Taj P harma, I RIN OTECA N dos e Taj phar mace uticals I RIN OTECAN i nteractions, Taj Phar mace utical IRI NOTE CAN contraindications, IRI NOTE CAN pri ce, IRI NOTE CAN Taj Phar ma Cancer, oncologyIrinotecan Hydrochloride 20 mg/ ml, concentrate for solution for infusion. SMPC- Taj Pharma . Stay conne cted to all updated on I RIN OTECAN Taj P harma ceutical s Taj phar mace uticals Hyderabad.
RX 4. CLINICAL PARTICULARS
IRINOTECAN 4.1 Therapeutic indications

Irinotecan Hydrochloride is indicated for the
HYDROCHLORIDE treatment of patients with advanced colorectal
cancer
20MG/ML, CONCENTRATE
• as a single agent in patients who have failed an
FOR SOLUTION FOR established 5-fluorouracil containing treatment
regimen.
INFUSION
• in combination with 5-fluorouracil and folinic
1.NAME OF THE MEDICINAL acid in patients without prior chemotherapy for
PRODUCT advanced disease.
Irinotecan Hydrochloride 20 mg/ml, concentrate Irinotecan Hydrochloride in combination with

for solution for infusion. cetuximab is indicated for the treatment of
patients with epidermal growth factor receptor
2. QUALITATIVE AND (EGFR)-expressing metastatic colorectal cancer
QUANTITATIVE COMPOSITION after failure of irinotecan-including cytotoxic
therapy.
One millilitre of the concentrate for solution for
infusion contains 20 mg irinotecan Irinotecan Hydrochloride in combination with 5-
hydrochloride trihydrate, equivalent to 17.33 mg fluorouracil, folinic acid and bevacizumab is
irinotecan. indicated for first-line treatment of patients with
metastatic carcinoma of the colon or rectum.
Each vial of 2 ml contains 40 mg of irinotecan
hydrochloride trihydrate (40 mg/2 ml). 4.2 Posology and method of administration
Each vial of 5 ml contains 100 mg of irinotecan For adults only. After dilution the irinotecan
hydrochloride trihydrate (100 mg/5 ml). solution for infusion should be infused into a
peripheral or central vein.
Each vial of 15 ml contains 300 mg of irinotecan
hydrochloride trihydrate (300 mg/15 ml). Recommended dosage
Each vial of 25 ml contains 500 mg of irinotecan In monotherapy (for previously treated
hydrochloride trihydrate (500 mg/25 ml). patients):
Each vial of 50 ml contains 1000 mg of The recommended dosage of irinotecan is 350
irinotecan hydrochloride trihydrate (1000 mg/50 mg/m² administered as an intravenous infusion
ml). over a 30- to 90-minute period every 3 weeks
(see sections 4.4 and 6.6).
Excipients: Sorbitol (E420).
In combination therapy (for previously untreated
For a full list of excipients, see section 6.1
patients):
3. PHARMACEUTICAL FORM Safety and efficacy of irinotecan in combination
Concentrate for solution for infusion. with 5-fluorouracil (5-FU) and folinic acid (FA)
have been assessed with the following schedule
A clear yellow solution. (see section 5.1).
pH 3.0 – 3.8 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 Treatment with irinotecan should be continued
and 5-fluorouracil. until there is an objective progression of the
disease or an unacceptable toxicity.
For the posology and method of administration
of concomitant cetuximab, refer to the product Special populations
information for this medicinal product.
Patients with impaired hepatic function
Normally, the same dose of irinotecan is used as
administered in the last cycles of the prior In monotherapy:
irinotecan-containing regimen. Irinotecan must
not be administered earlier than 1 hour after the Blood bilirubin levels (up to 3 times the upper
end of the cetuximab infusion. limit of the normal range [ULN]) in patients
with WHO performance status ≤ 2, should
For the posology and method of administration determine the starting dose of irinotecan. In
of bevacizumab, refer to the bevacizumab these patients with hyperbilirubinaemia and
summary of product characteristics. prothrombin time greater than 50 %, the
Dosage adjustments clearance of irinotecan is decreased (see section
5.2) and therefore the risk of haematotoxicity is
Irinotecan should be administered after increased. Thus, weekly monitoring of complete
appropriate recovery of all adverse events to blood counts should be conducted in this patient
grade 0 or 1 NCI-CTC grading (National Cancer population.
Institute Common Toxicity Criteria) and when
treatment-related diarrhoea is fully resolved. • In patients with bilirubin up to 1.5 times the
ULN, the recommended dosage of irinotecan is
At the start of a subsequent infusion of therapy, 350 mg/m².
the dose of irinotecan, and 5-FU when
applicable, should be decreased according to the • In patients with bilirubin ranging from 1.5 to 3
worst grade of adverse events observed in the times the ULN, the recommended dosage of
irinotecan is 200 mg/m².
prior infusion. Treatment should be delayed by 1
– 2 weeks to allow recovery from treatment- • Patients with bilirubin beyond 3 times the ULN
related adverse events. should not be treated with irinotecan (see
sections 4.3 and 4.4).
With the following adverse events a dose
reduction of 15 – 20 % should be applied for In combination therapy:
irinotecan and/or 5-FU when applicable:
No data are available in patients with hepatic
• Haematological toxicity (neutropenia grade 4, impairment treated by irinotecan in combination.
febrile neutropenia [neutropenia grade 3 – 4 and
fever grade 2 – 4], thrombocytopenia and Patients with impaired renal function
leukocytopenia [grade 4]). Irinotecan is not recommended for use in
• Non-haematological toxicity (grade 3 – 4). patients with impaired renal function, as studies
in this population have not been conducted (see
Recommendations for dose modifications of sections 4.4 and 5.2).
cetuximab when administered in combination
with irinotecan must be followed according to Elderly
the product information for this medicinal No specific pharmacokinetic studies have been
product. performed in elderly. However, the dose should
Refer to the bevacizumab summary of product be chosen carefully in this population due to
characteristics for dose modifications of their greater frequency of decreased biological
bevacizumab when administered in combination functions. This population should require more
with irinotecan/5-FU/FA. intense surveillance (see section 4.4).
Treatment duration
4.3 Contraindications on day 5 after the infusion of irinotecan. Patients

Chronic inflammatory bowel disease and/or should quickly inform their physician of its
bowel obstruction (see section 4.4). occurrence and start appropriate therapy
immediately.
• History of severe hypersensitivity to irinotecan
hydrochloride trihydrate or to any of the Patients with an increased risk of diarrhoea are
excipients of Irinotecan Hydrochloride. those who had a previous abdominal/pelvic
radiotherapy, those with baseline
• Lactation (see sections 4.4 and 4.6). hyperleukocytosis, those with WHO
• Bilirubin > 3 times the ULN (see section 4.4). performance status ≥ 2 and women. If not
properly treated, diarrhoea can be life-
• Severe bone marrow failure. threatening, especially if the patient is
• WHO performance status > 2. concomitantly neutropenic.
• Concomitant use with St. John's wort (see As soon as the first liquid stool occurs, the
section 4.5). patient should start drinking large volumes of
beverages containing electrolytes and an
For additional contraindications of cetuximab or appropriate antidiarrhoeal therapy must be
bevacizumab, refer to the product information initiated immediately. This antidiarrhoeal
for these medicinal products. treatment will be prescribed by the department
where irinotecan has been administered. After
4.4 Special Warnings and precautions for discharge from the hospital, the patients should
use obtain the prescribed drugs so that they can treat
Given the nature and incidence of adverse the diarrhoea as soon as it occurs. In addition,
events, irinotecan will only be prescribed in the they must inform their physician or the
following cases after the expected benefits have department administering irinotecan when/if
been weighted against the possible therapeutic diarrhoea is occurring.
risks:
The use of irinotecan should be confined to units
• In patients presenting a risk factor, particularly specialised in the administration of cytotoxic
those with a WHO performance status = 2. chemotherapy and it should only be administered
• In the few rare instances where patients are under the supervision of a physician qualified in the
deemed unlikely to observe recommendations use of anticancer chemotherapy.
regarding management of adverse events (need The currently recommended antidiarrhoeal
for immediate and prolonged antidiarrhoeal treatment consists of high doses of loperamide
treatment combined with high fluid intake at (4 mg for the first intake and then 2 mg every 2
onset of delayed diarrhoea). Strict hospital hours). This therapy should continue for 12
supervision is recommended for such patients. hours after the last liquid stool and should not be
modified. In no instance should loperamide be
When irinotecan is used in monotherapy, it is administered for more than 48 consecutive hours
usually prescribed with the every-3-week- at these doses, because of the risk of paralytic
dosage schedule. However, the weekly-dosage ileus, nor for less than 12 hours.
schedule (see section 5.1) may be considered in
patients who may need a closer follow-up or In addition to the antidiarrhoeal treatment, a
who are at particular risk of severe neutropenia. prophylactic broad-spectrum antibiotic should
be given, when diarrhoea is associated with
Delayed diarrhoea severe neutropenia (neutrophil count < 500
Patients should be made aware of the risk of cells/mm³).
delayed diarrhoea occurring more than 24 hours In addition to the antibiotic treatment,
after the administration of irinotecan and at any hospitalisation is recommended for management
time before the next cycle. In monotherapy, the of the diarrhoea, in the following cases:
median time of onset of the first liquid stool was
• Diarrhoea associated with fever A prophylactic treatment with antiemetics is

recommended before each treatment with
• Severe diarrhoea (requiring intravenous irinotecan. Nausea and vomiting have been
hydration)
frequently reported. Patients with vomiting
• Diarrhoea persisting beyond 48 hours associated with delayed diarrhoea should be
following the initiation of high-dose loperamide hospitalised as soon as possible for treatment.
therapy Acute cholinergic syndrome
Loperamide should not be given If acute cholinergic syndrome appears (defined
prophylactically, even in patients who as early diarrhoea and various other signs and
experienced delayed diarrhoea at previous
symptoms such as sweating, abdominal
cycles.
cramping, myosis and salivation), atropine
In patients who experienced severe diarrhoea, a sulphate (0.25 mg subcutaneously) should be
reduction in dose is recommended for administered unless clinically contraindicated
subsequent cycles (see section 4.2). (see section 4.8). Caution should be exercised in
patients with asthma. In patients who
Haematology experienced an acute and severe cholinergic
Weekly monitoring of complete blood cell syndrome, the use of prophylactic atropine
counts is recommended during irinotecan sulphate is recommended with subsequent doses
treatment. Patients should be aware of the risk of of irinotecan.
neutropenia and the significance of fever. Respiratory disorders
Febrile neutropenia (temperature > 38 °C and
neutrophil count ≤ 1,000 cells/mm³) should be Interstitial pulmonary disease presenting as
urgently treated in the hospital with broad- pulmonary infiltrates is uncommon during
spectrum intravenous antibiotics. irinotecan therapy. Interstitial pulmonary disease
can be fatal. Risk factors possibly associated
In patients who experienced severe with the development of interstitial pulmonary
haematological events, a dose reduction is disease include the use of pneumotoxic drugs,
recommended for subsequent administration radiation therapy and colony stimulating factors.
(see section 4.2). Patients with risk factors should be closely
There is an increased risk of infections and monitored for respiratory symptoms before and
haematological toxicity in patients with severe during irinotecan therapy.
diarrhoea. In patients with severe diarrhoea, Extravasation
complete blood cell counts should be performed.
While irinotecan is not a known vesicant, care
Liver impairment should be taken to avoid extravasation and the
Liver function tests should be performed at infusion site should be monitored for signs of
baseline and before each cycle. inflammation. Should extravasation occur,
flushing the site and application of ice is
Weekly monitoring of complete blood counts recommended.
should be conducted in patients with bilirubin
ranging from 1.5 to 3 times the ULN, due to Elderly
decrease of the clearance of irinotecan (see Due to the greater frequency of decreased
section 5.2) and thus increasing the risk of biological functions, in particular hepatic
haematotoxicity in this population. For patients function, in elderly patients, dose selection with
with a bilirubin > 3 times the ULN see section irinotecan should be cautious in this population
4.3. (see section 4.2).
Nausea and vomiting Patients with chronic inflammatory bowel
disease and/or bowel obstruction
Patients must not be treated with irinotecan until (e.g., rifampicin, carbamazepine, phenobarbital,
resolution of the bowel obstruction (see section phenytoin, St. John's wort) of cytochrome P450
4.3). 3A4 (CYP3A4) may alter the metabolism of
irinotecan and should be avoided (see section
Patients with impaired renal function 4.5).
Studies in this population have not been
conducted (see sections 4.2 and 5.2).
4.5 Interaction with other medicinal
products and other forms of interaction
Cardiac disorders
Interaction between irinotecan and
Myocardial ischaemic events have been neuromuscular blocking agents cannot be ruled
observed following irinotecan therapy out. Since irinotecan has anticholinesterase
predominantly in patients with underlying activity, the neuromuscular blocking effects of
cardiac disease, other known risk factors for suxamethonium may be prolonged and the
cardiac disease, or previous cytotoxic neuromuscular blockade of non-depolarising
chemotherapy (see section 4.8). drugs may be antagonised.
Consequently, patients with known risk factors Several studies have shown that concomitant
should be closely monitored, and action should administration of CYP3A-inducing
be taken to try to minimize all modifiable risk anticonvulsant drugs (e.g., carbamazepine,
factors (e.g. smoking, hypertension, and phenobarbital, phenytoin) leads to reduced
hyperlipidaemia). exposure to irinotecan, SN-38 and SN-38
glucuronide and reduced pharmacodynamic
Immunosuppressant effects/increased
effects. The effects of such anticonvulsant drugs
susceptibility to infections
were reflected by a decrease in AUC of SN-38
Administration of live or live-attenuated and SN-38 glucuronide by 50 % or more. In
vaccines in patients immunocompromised by addition to induction of cytochrome P450 3A
chemotherapeutic agents including irinotecan enzymes, enhanced glucuronidation and
may result in serious or fatal infections. enhanced biliary excretion may play a role in
Vaccination with a live vaccine should be reducing exposure to irinotecan and its
avoided in patients receiving irinotecan. Killed metabolites.
or inactivated vaccines may be administered;
A study has shown that the co-administration of
however, the response to such vaccines may be
ketoconazole resulted in a decrease in the AUC
diminished.
of the principal oxidative metabolite APC of 87
Others % and in an increase in the AUC of SN-38 of
109 % in comparison to irinotecan given alone.
Since this medicinal product contains sorbitol,
patients with rare hereditary problems of Caution should be exercised in patients
fructose intolerance should not use this concurrently taking drugs known to inhibit (e.g.,
medicine. ketoconazole) or induce (e.g., rifampicin,
carbamazepine, phenobarbital, phenytoin) drug
Infrequent cases of renal insufficiency, metabolism by CYP3A4. Concurrent
hypotension or circulatory failure have been administration of irinotecan with an
observed in patients who experienced episodes inhibitor/inducer of this metabolic pathway may
of dehydration associated with diarrhoea and/or alter the metabolism of irinotecan and should be
vomiting, or sepsis. avoided (see section 4.4).
Contraceptive measures must be taken during In a small pharmacokinetic study (n = 5), in
and for at least 3 months after cessation of which irinotecan 350 mg/m² was co-
therapy (see section 4.6). administered with St. John's wort (Hypericum
Concomitant administration of irinotecan with a perforatum) 900 mg, a 42 % decrease in the
strong inhibitor (e.g., ketoconazole) or inducer active metabolite of irinotecan, SN-38, plasma
concentrations was observed. St. John's wort There is no evidence that the safety profile of
decreases SN-38 plasma levels. Therefore, St. irinotecan is influenced by cetuximab or vice
John's wort should not be administered together versa.
with irinotecan (see section 4.3).
In one study, irinotecan concentrations were
Co-administration of 5-fluorouracil/folinic acid similar in patients receiving irinotecan/5-FU/FA
in the combination regimen does not change the alone and in combination with bevacizumab.
pharmacokinetics of irinotecan. Concentrations of SN-38, the active metabolite
of irinotecan, were analysed in a subset of
Atazanavir sulphate. Co-administration of
patients (approximately 30 per treatment arm).
atazanavir sulphate, a CYP3A4 and UGT1A1
Concentrations of SN-38 were on average 33 %
inhibitor, has the potential to increase systemic higher in patients receiving irinotecan/5-FU/FA
exposure to SN-38, the active metabolite of in combination with bevacizumab compared
irinotecan. Physicians should take this into with irinotecan/5-FU/FA alone. Due to high
consideration when co-administering these
inter-patient variability and limited sampling, it
medicinal products.
is uncertain if the increase in SN-38 levels
Interactions common to all cytotoxics observed was due to bevacizumab. There was a
small increase in diarrhoea and leukocytopenia
The use of anticoagulants is common due to adverse events. More dose reductions of
increased risk of thrombotic events in tumoural irinotecan were reported for patients receiving
diseases. If vitamin K antagonist anticoagulants irinotecan/5-FU/FA in combination with
are indicated, an increased frequency in the bevacizumab.
monitoring of INR (International Normalised
Ratio) is required due to their narrow therapeutic Patients who develop severe diarrhoea,
index, the high intra-individual variability of leukocytopenia or neutropenia with the
blood thrombogenicity and the possibility of bevacizumab and irinotecan combination should
interaction between oral anticoagulants and have irinotecan dose modifications as specified
anticancer chemotherapy. in section 4.2.
Concomitant use contraindicated Results from a dedicated drug-drug interaction
trial demonstrated no significant effect of
− Yellow fever vaccine: risk of fatal generalised bevacizumab on the pharmacokinetics of
reaction to vaccines irinotecan and its active metabolite SN-38.
Concomitant use not recommended However, this does not preclude any increase of
toxicities due to their pharmacological
− Live attenuated vaccines (except yellow properties.
fever): risk of systemic, possible fatal disease
(e.g. infections). This risk is increased in 4.6 Fertility, pregnancy and lactation
subjects who are already immunosuppressed by Pregnancy
their underlying disease. Use an inactivated
vaccine where this exists (poliomyelitis). There is no information on the use of irinotecan
in pregnant women.
− Phenytoin: Risk of exacerbation of
convulsions resulting from the decrease of Irinotecan has been shown to be embryotoxic
phenytoin digestive absorption by cytotoxic and teratogenic in animals (see section 5.3).
substances. Therefore, based on results from animal studies
and the mechanism of action of irinotecan,
Concomitant use to take into consideration irinotecan should not be used during pregnancy
− Ciclosporine, tacrolimus: Excessive unless clearly necessary. The advantages of
immunosuppression with risk of treatment should be weighed against the possible
lymphoproliferation risk for the foetus in every individual case (see
sections 4.3 and 4.4).
Women of child-bearing potential irinotecan in addition to those seen with

capecitabine monotherapy or seen at a higher
Women of child-bearing potential and men have frequency grouping compared to capecitabine
to use effective contraception during and up to 1 monotherapy include: Very common, all grade
month and 3 months after treatment, adverse drug reactions:
respectively.
thrombosis/embolism; Common, all grade
Breast-feeding adverse drug reactions: hypersensitivity
reaction, cardiac ischemia/infarction; Common,
In lactating rats, 14C-irinotecan was detected in grade 3 and grade 4 adverse drug reactions:
milk. It is not known whether irinotecan is febrile neutropenia. For complete information on
excreted in human milk. Consequently, because adverse reactions of capecitabine, refer to the
of the potential for adverse reactions in nursing capecitabine summary product of characteristics.
infants, breast-feeding must be discontinued for
the duration of irinotecan therapy (see section Grade 3 and Grade 4 adverse drug reactions
4.3). reported in patients treated with capecitabine in
combination with irinotecan and bevacizumab in
Fertility addition to those seen with capecitabine
There are no human data on the effect of monotherapy or seen at a higher frequency
irinotecan on fertility. In animals adverse effects grouping compared to capecitabine monotherapy
of irinotecan on the fertility of offspring has include: Common, grade 3 and grade 4 adverse
been documented (see section 5.3). drug reactions: neutropenia,
thrombosis/embolism, hypertension, and cardiac
4.7 Effects on ability to drive and use ischemia/infarction. For complete information
machines on adverse reactions of capecitabine and
bevacizumab, refer to the respective
Patients should be warned about the potential for capecitabine and bevacizumab summary of
dizziness or visual disturbances which may product characteristics.
occur within 24 hours following the
The following adverse reactions considered to
administration of irinotecan, and advised not to
be possibly or probably related to the
drive or operate machinery if these symptoms
administration of irinotecan have been reported
occur.
from 765 patients at the recommended dose of
4.8 Undesirable Effects 350 mg/m² in monotherapy, and from 145
patients treated with irinotecan in combination
Undesirable effects detailed in this section refer therapy with 5-FU/FA in every-2-weeks
to irinotecan. There is no evidence that the schedule at the recommended dose of 180
safety profile of irinotecan is influenced by mg/m².
cetuximab or vice versa. In combination with The most common (≥ 1/10), dose-limiting
cetuximab, additional reported undesirable adverse reactions of irinotecan are delayed
effects were those expected with cetuximab diarrhoea (occurring more than 24 hours after
(such as acneform rash 88 %). For information administration) and blood disorders including
on adverse reactions on irinotecan in neutropenia, anaemia and thrombocytopenia.
combination with cetuximab, also refer to their
respective summary of product characteristics. Side effects have been summarised in the table
below with MedDRA frequencies. Within each
For information on adverse reactions in frequency grouping, undesirable effects are
combination with bevacizumab, refer to the presented in order of decreasing seriousness.
bevacizumab summary of product
characteristics.
Adverse drug reactions reported in patients
treated with capecitabine in combination with
Very common: ≥ 1/10 severe neutropenia resulting in death in

three cases
• Thrombocytopenia in case of
Common: ≥ 1/100 to < 1/10 monotherapy
Very rare • One case of peripheral thrombocytopenia
with antiplatelet antibodies has been
Uncommon: ≥ 1/1,000 to < 1/100 reported.
Skin and subcutaneous tissue disorders
Rare: ≥ 1/10,000 to < 1/1,000

Very common • Alopecia (reversible)
Very rare: < 1/10,000; not known (cannot be estimated

from the available data) Uncommon • Mild cutaneous reactions
Organ system
General disorders and administration site conditions
Frequency Side effects

Very common • Fever in the absence of infection and
without concomitant severe neutropenia in
Gastrointestinal disorders case of monotherapy
Common • Fever in the absence of infection and
without concomitant severe neutropenia in
Very common • Severe delayed diarrhoea case of combination therapy
• Severe nausea and vomiting in case of • Severe transient acute cholinergic
monotherapy syndrome (The main symptoms were
defined as early diarrhoea and various
Common • Severe nausea and vomiting in case of other symptoms such as abdominal pain,
combination therapy conjunctivitis, rhinitis, hypotension,
• Episodes of dehydration (associated with vasodilation, sweating, chills, malaise,
diarrhoea and/or vomiting) dizziness, visual disturbances, myosis,
• Constipation relative to irinotecan and/or lacrimation and increased salivation.)
loperamide • Asthenia
Uncommon • Pseudo-membranous colitis (one has Uncommon • Infusion site reactions
been documented
bacteriologically: Clostridium difficile)
• Renal insufficiency, hypotension or
cardio-circulatory failure as a consequence Investigations
of dehydration associated with diarrhoea
Very common • In combination therapy, transient serum
and/or vomiting
levels (grade 1 and 2) of serum
• Intestinal obstruction, ileus,
transaminases, alkaline phosphatase or
gastrointestinal haemorrhage
bilirubin were observed in the absence of
Rare • Colitis, including typhlitis, ischemic and progressive liver metastasis.
ulcerative colitis
Common • In monotherapy, transient and mild to
• Intestinal perforation
moderate increases in serum levels of
• Other mild effects include anorexia,
either transaminases, alkaline
abdominal pain and mucositis.
phosphatase or bilirubin were observed in
• Symptomatic or asymptomatic
the absence of progressive liver
pancreatitis
metastasis.
Blood and lymphatic system disorders • In combination therapy, transient grade 3
serum levels of bilirubin
• Transient and mild to moderate increases
of serum levels of creatinine
Very common • Neutropenia (reversible and not
cumulative) Rare • Hypokalemia and hyponatremia
• Anaemia
• Thrombocytopenia in case of Very rare • Increases of amylase and/or lipase
combination therapy
• Infectious episodes in case of Respiratory, thoracic and mediastinal disorders
monotherapy
Uncommon • Interstitial pulmonary disease presenting
Common • Febrile neutropenia as pulmonary infiltrates
• Infectious episodes in case of • Early effects such as dyspnoea
combination therapy
• Infectious episodes associated with Immune system disorders
Uncommon • Mild allergic reactions Nausea and vomiting

Rare • Anaphylactic/anaphylactoid reactions
In monotherapy:
Nausea and vomiting were severe in
Infections and infestations approximately 10 % of patients treated with
Uncommon • Renal insufficiency, hypotension or antiemetics.
cardio-circulatory failure have been
observed in patients who experienced In combination therapy:
sepsis.
Not known • Fungal infections (e.g. pneumocystis
A lower incidence of severe nausea and
jirovecii pneumonia, bronchopulmonary vomiting was observed (2.1 % and 2.8 % of
aspergillosis, systemic candida) patients respectively).
• Viral infections (e.g. herpes zoster,
influenza, hepatitis B reactivation, Dehydration
cytomegalovirus colitis)
Cardiac disorders Episodes of dehydration commonly associated
Rare • Hypertension during or following the with diarrhoea and/or vomiting have been
infusion reported.
Musculoskeletal and connective tissue disorders
Infrequent cases of renal insufficiency,
Rare • Early effects such as muscular
contraction or cramps and paraesthesia hypotension or cardio-circulatory failure have
Nervous system disorders
been observed in patients who experienced
episodes of dehydration associated with
Very rare • Transient speech disorders
diarrhoea and/or vomiting.
Metabolism and nutrition disorders
Other gastrointestinal disorders
Very rare • Tumour lysis syndrome
Constipation relative to irinotecan and/or
Gastrointestinal disorders loperamide has been observed, shared between:
Delayed diarrhoea − in monotherapy: in less than 10 % of patients
Diarrhoea (occurring more than 24 hours after − in combination therapy: 3.4 % of patients.
administration) is a dose-limiting toxicity of
irinotecan. Infrequent cases of intestinal obstruction, ileus,
or gastrointestinal haemorrhage and rare cases of
In monotherapy: colitis, including typhlitis, ischemic and
Severe diarrhoea was observed in 20 % of ulcerative colitis, were reported. Rare cases of
patients who follow recommendations for the intestinal perforation were reported. Other mild
management of diarrhoea. Of the evaluable effects include anorexia, abdominal pain and
cycles, 14 % have severe diarrhoea. The median mucositis.
time of onset of the first liquid stool was on day Rare cases of symptomatic or asymptomatic
5 after the infusion of irinotecan. pancreatitis have been associated with irinotecan
In combination therapy: therapy.
Severe diarrhoea was observed in 13.1 % of Blood disorders

patients who follow recommendations for the Neutropenia is a dose-limiting toxic effect.
management of diarrhoea. Of the evaluable Neutropenia was reversible and not cumulative;
cycles, 3.9 % have severe diarrhoea. the median day to nadir was 8 days whatever the
Uncommon cases of pseudo-membranous colitis use in monotherapy or in combination therapy.
have been reported, one of which has been In monotherapy:
documented bacteriologically (Clostridium
difficile). Neutropenia was observed in 78.7 % of patients
and was severe (neutrophil count < 500
cells/mm³) in 22.6 % of patients. Of the One case of peripheral thrombocytopenia with

evaluable cycles, 18 % had a neutrophil count < antiplatelet antibodies has been reported in the
1,000 cells/mm³ including 7.6 % with a post-marketing experience.
neutrophil count < 500 cells/mm³.
Infection and infestation
Total recovery was usually reached by day 22.
Infrequent cases of renal insufficiency,
Fever with severe neutropenia was reported in hypotension or cardio-circulatory failure have
6.2 % of patients and in 1.7 % of cycles. been observed in patients who experienced
sepsis.
Infectious episodes occurred in about 10.3 % of
patients (2.5 % of cycles) and were associated General disorders and infusion site reactions
with severe neutropenia in about 5.3 % of
Acute cholinergic syndrome
patients (1.1 % of cycles), and resulted in death
in two cases. Severe transient acute cholinergic syndrome was
Anaemia was reported in about 58.7 % of observed in 9 % of patients treated in
patients (8 % with haemoglobin < 8 g/dl and 0.9 monotherapy and in 1.4 % of patients treated in
% with haemoglobin < 6.5 g/dl). combination therapy. The main symptoms were
defined as early diarrhoea and various other
Thrombocytopenia (< 100,000 cells/mm³) was symptoms such as abdominal pain,
observed in 7.4 % of patients and 1.8 % of conjunctivitis, rhinitis, hypotension,
cycles with 0.9 % with platelets count ≤ 50,000 vasodilation, sweating, chills, malaise, dizziness,
cells/mm³ and 0.2 % of cycles. visual disturbances, myosis, lacrimation and
increased salivation occurring during or within
Nearly all the patients showed a recovery by day the first 24 hours after the infusion of irinotecan.
22. These symptoms disappear after atropine
In combination therapy: administration (see section 4.4).
Neutropenia was observed in 82.5 % of patients Asthenia was severe in less than 10 % of
and was severe (neutrophil count < 500 patients treated in monotherapy and in 6.2 % of
cells/mm³) in 9.8 % of patients. patients treated in combination therapy. The
causal relationship to irinotecan has not been
Of the evaluable cycles, 67.3 % had a neutrophil clearly established. Fever in the absence of
count < 1,000 cells/mm³ including 2.7 % with a infection and without concomitant severe
neutrophil count < 500 cells/mm³. neutropenia, occurred in 12 % of patients treated
Total recovery was usually reached within 7 – 8 in monotherapy and in 6.2 % of patients treated
days. in combination therapy.
Fever with severe neutropenia was reported in Mild infusion site reactions have been reported
3.4 % of patients and in 0.9 % of cycles. although uncommonly.
Infectious episodes occurred in about 2 % of Cardiac disorders

patients (0.5 % of cycles) and were associated Rare cases of hypertension during or following
with severe neutropenia in about 2.1 % of the infusion have been reported.
patients (0.5 % of cycles), and resulted in death
in one case. Respiratory disorders
Anaemia was reported in 97.2 % of patients (2.1 Interstitial pulmonary disease presenting as
% with haemoglobin < 8 g/dl). pulmonary infiltrates is uncommon during
irinotecan therapy. Early effects such as
Thrombocytopenia (< 100,000 cells/mm³) was dyspnoea have been reported (see section 4.4).
observed in 32.6 % of patients and 21.8 % of
cycles. No severe thrombocytopenia (< 50,000 Skin and subcutaneous tissue disorders
cells/mm³) has been observed.
Alopecia was very common and reversible. Mild important. It allows continued monitoring of the
cutaneous reactions have been reported although benefit/risk balance of the medicinal product.
uncommonly.
4.9 Overdose
Immune system disorders There have been reports of overdose at doses up
to approximately twice the recommended
Uncommon mild allergy reactions and rare cases
therapeutic dose, which may be fatal. The most
of anaphylactic/anaphylactoid reactions have
significant adverse reactions reported were
been reported.
severe neutropenia and severe diarrhoea. There
Musculoskeletal disorders is no known antidote for irinotecan. Maximum
supportive care should be instituted to prevent
Early effects such as muscular contraction or dehydration due to diarrhoea and to treat any
cramps and paresthesia have been reported. infectious complications.
Investigations
5. PHARMACOLOGICAL
Laboratory tests PROPERTIES
In monotherapy, transient and mild to moderate 5.1 Pharmacodynamic properties
increases in serum levels of either
transaminases, alkaline phosphatase or bilirubin Pharmacotherapeutic group: Other antineoplastic
were observed in 9.2 %, 8.1 % and 1.8 % of the agents
patients, respectively, in the absence of
progressive liver metastasis. Experimental data
Transient and mild to moderate increases of Irinotecan is a semi-synthetic derivative of

serum levels of creatinine have been observed in camptothecin. It is an antineoplastic agent which
7.3 % of the patients. acts as a specific inhibitor of DNA
topoisomerase I. It is metabolised by
In combination therapy transient serum levels carboxylesterase in most tissues to SN-38, which
(grades 1 and 2) of either SGPT, SGOT, alkaline was found to be more active than irinotecan in
phosphatase or bilirubin were observed in 15 %, purified topoisomerase I and more cytotoxic
11 %, 11 % and 10 % of the patients, than irinotecan against several murine and
respectively, in the absence of progressive liver human tumour cell lines. The inhibition of DNA
metastasis. Transient grade 3 was observed in 0 topoisomerase I by irinotecan or SN-38 induces
%, 0 %, 0 % and 1% of the patients, single-strand DNA lesions which block the
respectively. No grade 4 was observed. DNA replication fork and are responsible for the
Increases of amylase and/or lipase have been cytotoxicity. This cytotoxic activity was found
very rarely reported. to be time-dependent and was specific to the S
phase.
Rare cases of hypokalemia and hyponatremia
mostly related with diarrhoea and vomiting have In vitro, irinotecan and SN-38 were not found to
been reported. be significantly recognised by the P-
glycoprotein MDR, and display cytotoxic
Nervous system disorders activities against doxorubicin- and vinblastine-
resistant cell lines.
There have been very rare postmarketing reports
of transient speech disorders associated with Furthermore, irinotecan has a broad antitumour
irinotecan infusions. activity in vivo against murine tumour models
(P03 pancreatic ductal adenocarcinoma,
Reporting of suspected adverse reactions
MA16/C mammary adenocarcinoma, C38 and
Reporting suspected adverse reactions after C51 colon adenocarcinomas) and against human
authorisation of the medicinal product is xenografts (Co-4 colon adenocarcinoma, Mx-1
mammary adenocarcinoma, ST-15 and SC-16
gastric adenocarcinomas). Irinotecan is also Median 9.3 8.8 8.9 6.7 9.3 9.5
active against tumours expressing the P- response
duration
glycoprotein MDR (vincristine- and [months]
doxorubicin-resistant P388 leukaemias). p value NS 0.043 NS
Beside its antitumour activity, the most relevant Median 8.6 6.2 8.3 6.7 8.5 5.6
duration of
pharmacological effect of irinotecan is the response and
inhibition of acetylcholinesterase. stabilisation
[months]
Clinical data p value < 0.001 NS 0.003
In combination therapy for the first-line Median time to 5.3 3.8 5.4 5.0 5.1 3.0
treatment
treatment of metastatic colorectal carcinoma failure [months]
In combination therapy with 5-FU/FA p value 0.0014 NS < 0.001

Median survival 16.8 14.0 19.2 14.1 15.6 13.0
A phase III study was performed in 385 [months]
previously untreated metastatic colorectal cancer p value 0.028 NS 0.041
patients treated with either every-2-weeks * as per protocol population; 5-FU = 5-fluorouracil; FA = folinic
schedule (see section 4.2) or weekly schedule acid; NS = not significant
regimens. In the every-2-weeks schedule, on day In the weekly schedule, the incidence of severe
1, the administration of irinotecan at 180 mg/m² diarrhoea was 44.4 % in patients treated with
once every 2 weeks is followed by infusion with irinotecan in combination with 5-FU/FA and
folinic acid (200 mg/m² over a 2-hour 25.6 % in patients treated by 5-FU/FA alone.
intravenous infusion) and 5-fluorouracil (400 The incidence of severe neutropenia (neutrophil
mg/m² as an intravenous bolus, followed by 600 count < 500 cells/mm³) was 5.8 % in patients
mg/m² over a 22-hour intravenous infusion). On treated with irinotecan in combination with 5-
day 2, folinic acid and 5-fluorouracil are FU/FA and 2.4 % in patients treated by 5-
administered at the same doses and schedules. In FU/FA alone.
the weekly schedule, the administration of
irinotecan at 80 mg/m² is followed by infusion Additionally, median time to definitive
with folinic acid (500 mg/m² over a 2-hour performance status deterioration was
intravenous infusion) and then by 5-fluorouracil significantly longer in irinotecan combination
(2,300 mg/m² over a 24-hour intravenous group than in 5-FU/FA alone group (p = 0.046).
infusion) over 6 weeks. Quality of life was assessed in this phase III
In the combination therapy trial with the two study using the EORTC QLQ-C30
regimens described above, the efficacy of questionnaire. Time to definitive deterioration
irinotecan was evaluated in 198 treated patients. constantly occurred later in the irinotecan
groups. The evolution of the Global Health
Combined Weekly Every-2- Status/quality of life was slightly better in
regimens schedule weeks
(n = 198) (n = 50) schedule
irinotecan combination group although not
(n = 148) significant, showing that efficacy of irinotecan
Irinotec 5- Irinotec 5- Irinote 5- in combination could be reached without
an + 5- FU/FA an + 5- FU/FA can + FU/F affecting the quality of life.
FU/FA FU/FA 5- A
FU/FA In combination with bevacizumab
Response rate 40.8* 23.1* 51.2* 28.6* 37.5* 21.6*
[%] A phase III randomised, double-blind, active-
p value < 0.001 0.045 0.005 controlled clinical trial evaluated bevacizumab
Median time to 6.7 4.4 7.2 6.5 6.5 3.7 in combination with irinotecan/5-FU/FA as first-
progression line treatment for metastatic carcinoma of the
[months]
colon or rectum (study AVF2107g). The
p value < 0.001 NS 0.001
addition of bevacizumab to the combination of
irinotecan/5-FU/FA resulted in a statistically
significant increase in overall survival. The wild-type tumours from the patient population
clinical benefit, as measured by overall survival, evaluable for KRAS status comprised 64 %.
was seen in all pre-specified patient subgroups,
including those defined by age, sex, The efficacy data generated in this study are
summarised in the table below:
performance status, location of primary tumour,
number of organs involved and duration of Variable/statistic Overall population KRAS wild-type
metastatic disease. Refer also to the population
bevacizumab summary of product Cetuximab FOLFIRI Cetuximab FOLFIRI
characteristics. plus (N = 599) plus (N = 176)
FOLFIRI FOLFIRI
The efficacy results of study AVF2107g are (N = 599) (N = 172)
summarised in the table below. ORR
Arm 1 Arm 2 95% CI 46.9 (42.9, 38.7 59.3 (51.6, 43.2

Irinotecan/5- Irinotecan/5- 51.0) (34.8, 66.7) (35.8,
FU/FA/placebo FU/FA/bevacizumab 42.8) 50.9)
p value 0.0038 0.0025
Number of patients 411 402
Overall survival PFS
Median time 15.6 20.3 Hazard ratio (95% 0.85 (0.726, 0.998) 0.68 (0.501, 0.934)
[months] CI)
95% Confidence 14.29 – 16.99 18.46 – 24.18
p value 0.0479 0.0167
interval
b
Hazard ratio 0.660
CI = confidence interval, FOLFIRI = irinotecan plus infusional 5-
p value 0.00004 FU/FA, ORR = objective response rate (patients with complete
response or partial response), PFS = progression-free survival time
Progression-free
survival
Median time 6.2 10.6
In combination therapy with capecitabine
[months]
Data from a randomised, controlled phase III
Hazard ratio b 0.54
study (CAIRO) support the use of capecitabine
p value < 0.0001 at a starting dose of 1,000 mg/m² for 2 weeks
Overall response every 3 weeks in combination with irinotecan
rate for the first-line treatment of patients with
Rate [%] 34.8 44.8 metastatic colorectal cancer. 820 patients were
95% Confidence 30.2 – 39.6 39.9 – 49.8 randomised to receive either sequential
interval
treatment (n = 410) or combination treatment (n
p value 0.0036
= 410). Sequential treatment consisted of first-
Duration of line treatment with capecitabine (1,250 mg/m²
response
twice daily for 14 days), second-line irinotecan
Median time 7.1 10.4
[months]
(350 mg/m² on day 1), and third-line
25 – 75 Percentile 4.7 – 11.8 6.7 – 15.0
combination of capecitabine (1,000 mg/m² twice
[months] daily for 14 days) with oxaliplatin (130 mg/m²
a
5 mg/kg every 2 weeks; b Relative to control arm. on day 1). Combination treatment consisted of
In combination therapy with cetuximab first-line treatment of capecitabine (1,000 mg/m²
twice daily for 14 days) combined with
EMR 62 202-013: This randomised study in irinotecan (250 mg/m² on day 1) [XELIRI] and
patients with metastatic colorectal cancer who second-line capecitabine (1,000 mg/m² twice
had not received prior treatment for metastatic daily for 14 days) plus oxaliplatin (130 mg/m²
disease compared the combination of cetuximab on day 1). All treatment cycles were
and irinotecan plus infusional 5-FU/FA (599 administered at intervals of 3 weeks. In first-line
patients) to the same chemotherapy alone (599 treatment the median progression-free survival
patients). The proportion of patients with KRAS in the intent-to-treat population was 5.8 months
(95 % CI, 5.1 – 6.2 months) for capecitabine Number of 183 90 127 129
monotherapy and 7.8 months (95 % CI, 7.0 – 8.3 patients
months) for XELIRI (p = 0.0002). PFS at 6 NA NA 33.5 26.7 0.03

months [%]
Data from an interim analysis of a multicentre,
randomised, controlled phase II study (AIO
KRK 0604) support the use of capecitabine at a Survival at 36.2 13.8 0.0001 44.8 32.4 0.0351
12 months
starting dose of 800 mg/m² for 2 weeks every 3 [%]
weeks in combination with irinotecan and
bevacizumab for the first-line treatment of
Median 9.2 6.5 0.0001 10.8 8.5 0.0351
patients with metastatic colorectal cancer. survival
[months]
115 patients were randomised to treatment with
capecitabine combined with irinotecan
PFS = progression-free survival; NA = not applicable
(XELIRI) and bevacizumab: capecitabine (800
mg/m² twice daily for two weeks followed by a
7-day rest period), irinotecan (200 mg/m² as a 30 In phase II studies, performed on 455 patients in
minute infusion on day 1 every 3 weeks), and the every-3-week-dosage schedule, the
bevacizumab (7.5 mg/kg as a 30 to 90 minute progression-free survival at 6 months was 30 %
infusion on day 1 every 3 weeks); a total of 118 and the median survival was 9 months. The
patients were randomised to treatment with median time to progression was 18 weeks.
capecitabine combined with oxaliplatin plus Additionally, non-comparative phase II studies
bevacizumab: capecitabine (1,000 mg/m² twice were performed in 304 patients treated with a
daily for two weeks followed by a 7-day rest weekly schedule regimen, at a dose of 125
period), oxaliplatin (130 mg/m² as a 2 hour mg/m² administered as an intravenous infusion
infusion on day 1 every 3 weeks), and over 90 minutes for 4 consecutive weeks
bevacizumab (7.5 mg/kg as a 30 to 90 minute followed by 2 weeks rest. In these studies, the
infusion on day 1 every 3 weeks). median time to progression was 17 weeks and
Progression-free survival at 6 months in the median survival was 10 months. A similar safety
intent-to-treat population was 80 % (XELIRI profile has been observed in the weekly-dosage
plus bevacizumab) versus 74 % (XELOX plus schedule in 193 patients at the starting dose of
bevacizumab). Overall response rate (complete 125 mg/m², compared to the every-3-week-
response plus partial response) was 45 % dosage schedule. The median time of onset of
(XELOX plus bevacizumab) versus 47 % the first liquid stool was on day 11.
(XELIRI plus bevacizumab). In combination with cetuximab after failure of
In monotherapy for the second-line treatment irinotecan-including cytotoxic therapy
of metastatic colorectal carcinoma The efficacy of the combination of cetuximab
Clinical phase II/III studies were performed in with irinotecan was investigated in two clinical
more than 980 patients in the every-3-week- studies. A total of 356 patients with EGFR-
dosage schedule with metastatic colorectal expressing metastatic colorectal cancer who had
cancer who failed a previous 5-FU regimen. The recently failed irinotecan-including cytotoxic
efficacy of irinotecan was evaluated in 765 therapy and who had a minimum Karnofsky
patients with documented progression on 5-FU performance status of 60 %, but the majority of
at study entry. whom had a Karnofsky performance status of ≥
80 % received the combination treatment.
EMR 62 202-007: This randomised study
Phase III Irinotecan versus best Irinotecan versus 5- compared the combination of cetuximab and
trials supportive care (BSC) fluorouracil (5-FU)
irinotecan (218 patients) with cetuximab
Irinotecan BSC p value Irinotecan 5-FU p monotherapy (111 patients).
value
IMCL CP02-9923: This single arm open-label 38G). The UGT1A1 gene is highly polymorphic,
study investigated the combination therapy in resulting in variable metabolic capacities among
138 patients. individuals. One specific variation of the
UGT1A1 gene includes a polymorphism in the
The efficacy data from these studies are promoter region known as the UGT1A1*28
summarised in the table below.
variant. This variant and other congenital
Study n ORR DCR PFS OS deficiencies in UGT1A1 expression (such as
(months) (months) Crigler-Najjar and Gilbert's syndrome) are
n [%] 95% n [%] 95% Median 95% Median 95% associated with reduced activity of this enzyme.
CI CI CI CI Data from a meta-analysis indicate that
Cetuximab + irinotecan individuals with Crigler-Najjar syndrome (types
EMR 218 50 17.5, 121 48.6, 4.1 2.8, 8.6 7.6, 1 and 2) or those with UGT1A1*28 allele and/or
62 (22.9) 29.1 (55.5) 62.2 4.3 9.6 UGT1A1*6 variants (Gilbert's syndrome) are at
202-
007
increased risk of haematological toxicity (grades
3 and 4) following administration of irinotecan
IMCL 138 21 9.7, 84 52.2, 2.9 2.6, 8.4 7.2, at moderate or high doses (> 150 mg/m²). A
CP02- (15.2) 22.3 (60.9) 69.1 4.1 10.3
9923
relationship between UGT1A1 genotype and the
occurrence of irinotecan induced diarrhoea was
Cetuximab not established.
EMR 111 12 5.7, 36 23.9, 1.5 1.4, 6.9 5.6,
62 (10.8) 18.1 (32.4) 42.0 2.0 9.1 Patients known to be homozygous for
202- UGT1A1*28 and/or UGT1A1*6 should be
007
administered the normally indicated irinotecan
CI = confidence interval; DCR = disease control rate (patients
with complete response, partial response or stable disease for at
starting dose. However, these patients should be
least 6 weeks); ORR = objective response rate (patients with monitored for haematologic toxicities. A
complete response or partial response); OS = overall survival reduced irinotecan starting dose should be
time; PFS = progression-free survival
considered for patients who have experienced
The efficacy of the combination of cetuximab prior haematologic toxicity with previous
with irinotecan was superior to that of cetuximab treatment. The exact reduction in starting dose in
monotherapy, in terms of objective response rate this patient population has not been established
(ORR), disease control rate (DCR) and and any subsequent dose modifications should
progression-free survival (PFS). In the be based on a patient's tolerance of the treatment
randomised trial, no effects on overall survival (see sections 4.2 and 4.4).
were demonstrated (hazard ratio 0.91, p = 0.48).
There is at present insufficient data to conclude
Pharmacokinetic/Pharmacodynamic data on clinical utility of UGT1A1 genotyping.
The intensity of the major toxicities encountered
with irinotecan (e.g., neutropenia and diarrhoea)
is related to the exposure (AUC) to parent drug 5.2 Pharmacokinetic properties
and metabolite SN-38. Significant correlations In a phase I study in 60 patients with a dosage
were observed between haematological toxicity regimen of a 30-minute intravenous infusion of
(decrease in white blood cells and neutrophils at 100 – 750 mg/m² every 3 weeks, irinotecan
nadir) or diarrhoea intensity and both irinotecan showed a biphasic or triphasic elimination
and metabolite SN-38 AUC values in profile. The mean plasma clearance was 15
monotherapy. l/h/m² and the volume of distribution at steady
Patients with reduced UGT1A1 activity: state (Vss) was 157 l/m². The mean plasma half-
life of the first phase of the triphasic model was
Uridine diphosphate-glucuronosyl transferase 12 minutes, of the second phase 2.5 hours, and
1A1 (UGT1A1) is involved in the metabolic the terminal phase half-life was 14.2 hours. SN-
deactivation of SN-38, the active metabolite of 38 showed a biphasic elimination profile with a
irinotecan to inactive SN-38 glucuronide (SN- mean terminal elimination half-life of 13.8
hours. At the end of the infusion, at the Irinotecan clearance is decreased by about 40 %
recommended dose of 350 mg/m², the mean in patients with bilirubinaemia between 1.5 and
peak plasma concentrations of irinotecan and 3 times the ULN. In these patients a 200 mg/m²
SN-38 were 7.7 µg/ml and 56 ng/ml, irinotecan dose leads to plasma drug exposure
respectively, and the mean area under the curve comparable to that observed at 350 mg/m² in
(AUC) values were 34 µg·h/ml and 451 ng·h/ml, cancer patients with normal liver parameters.
respectively. A large interindividual variability
in pharmacokinetic parameters is generally 5.3 Preclinical safety data
observed for SN-38. Irinotecan and SN-38 have been shown to be
A population pharmacokinetic analysis of mutagenic in vitro in the chromosomal
irinotecan has been performed in 148 patients aberration test on CHO-cells as well as in the in
with metastatic colorectal cancer, treated with vivo micronucleus test in mice. However, they
various schedules and at different doses in phase have been shown to be devoid of any mutagenic
II trials. Pharmacokinetic parameters estimated potential in the Ames test.
with a three compartment model were similar to In rats treated once a week during 13 weeks at
those observed in phase I studies. All studies the maximum dose of 150 mg/m² (which is less
have shown that irinotecan and SN-38 exposure than half the human recommended dose), no
increase proportionally with irinotecan treatment-related tumours were reported 91
administered dose; their pharmacokinetics are weeks after the end of treatment.
independent of the number of previous cycles
and of the administration schedule. Single- and repeated-dose toxicity studies with
irinotecan have been carried out in mice, rats
In vitro, plasma protein binding for irinotecan and dogs. The main toxic effects were seen in
and SN-38 was approximately 65 % and 95 % the haematopoietic and lymphatic systems. In
respectively. dogs, delayed diarrhoea associated with atrophy
Mass balance and metabolism studies with 14C- and focal necrosis of the intestinal mucosa was
labelled drug have shown that more than 50 % reported. Alopecia was also observed in the dog.
of an intravenously administered dose of The severity of these effects was dose-related
irinotecan is excreted as unchanged drug, with and reversible.
33 % in the faeces mainly via the bile and 22 % Reproduction
in urine.
Irinotecan was teratogenic in rats and rabbits at
Two metabolic pathways account each for at doses below the human therapeutic dose. In rats,
least 12 % of the dose: pups born to treated animals with external
• Hydrolysis by carboxylesterase into active abnormalities showed a decrease in fertility.
metabolite SN-38. SN-38 is mainly eliminated This was not seen in morphologically normal
by glucuronidation, and further by biliary and pups. In pregnant rats there was a decrease in
renal excretion (less than 0.5 % of the irinotecan placental weight and in the offspring a decrease
dose). The SN-38 glucuronide is subsequently in foetal viability and increase in behavioural
probably hydrolysed in the intestine. abnormalities.
• Cytochrome P450 3A enzymes-dependent 6. PHARMACEUTICAL

oxidations resulting in opening of the outer PARTICULARS
piperidine ring with formation of APC
(aminopentanoic acid derivate) and NPC
(primary amine derivate) (see section 4.5).
6.1 List of excipients
Unchanged irinotecan is the major entity in
plasma, followed by APC, SN-38 glucuronide Sorbitol (E420)
and SN-38. Only SN-38 has significant Lactic acid
cytotoxic activity.
Sodium hydroxide (to adjust to pH 3.5) fluoropolymer on the inner side. Pack of one
vial.
Water for injections
Irinotecan Hydrochloride 300 mg:
6.2 Incompatibilities
15-ml brown glass vial, with a halobutyl rubber
This medicinal product must not be mixed with closure coated with a layer of an inert
other medicinal products except those mentioned fluoropolymer on the inner side. Pack of one
in section 6.6. vial.
6.3 Shelf life Irinotecan Hydrochloride 500 mg:
3 years. 25-ml brown glass vial, with a halobutyl rubber

closure coated with a layer of an inert
Diluted medicinal product (solution for infusion) fluoropolymer on the inner side. Pack of one
After dilution in 0.9 % sodium chloride solution vial.
or 5 % dextrose solution, chemical and physical Irinotecan Hydrochloride 1000 mg:
in-use stability has been demonstrated for up to
6 hours at room temperature (approximately 25 50-ml brown glass vial, with a halobutyl rubber
°C) and ambient lighting or 48 hours if stored at closure coated with a layer of an inert
refrigerated temperatures (approximately 2 °C – fluoropolymer on the inner side. Pack of one
8 °C). vial.
From a microbiological point of view, the Not all pack sizes may be marketed.
solution for infusion should be used
6.6 Special precautions for disposal and
immediately. If not used immediately, in-use
storage times and conditions prior to use are the other handling
responsibility of the user and would normally As with other antineoplastic agents, Irinotecan
not be longer than 6 hours at room temperature Hydrochloride must be prepared and handled
or 24 hours if stored at 2 °C – 8 °C unless with caution.
dilution has taken place in controlled and
validated aseptic conditions. The use of glasses, mask and gloves is required.
6.4 Special precautions for storage If Irinotecan Hydrochloride concentrate for

solution for infusion or the prepared solution for
Do not freeze. infusion should come into contact with the skin,
wash immediately and thoroughly with soap and
Keep the vial in the outer carton in order to water. If Irinotecan Hydrochloride concentrate
protect from light. for solution for infusion or the prepared solution
for infusion should come into contact with the
For storage conditions of the diluted medicinal
mucous membranes, wash immediately with
product, see section 6.3.
water.
6.5 Nature and contents of container Preparation of the intravenous solution
Irinotecan Hydrochloride 40 mg: As with any other injectable drugs, the
2-ml brown glass vial, with a halobutyl rubber Irinotecan Hydrochloride solution for infusion
closure coated with a layer of an inert must be prepared aseptically (see section 6.3).
fluoropolymer on the inner side. Pack of one If any precipitate is observed in the vials or after
vial. dilution, the product should be discarded
Irinotecan Hydrochloride 100 mg: according to standard procedures for cytotoxic
agents.
5-ml brown glass vial, with a halobutyl rubber
closure coated with a layer of an inert
Aseptically withdraw the required amount of

Irinotecan Hydrochloride 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 % dextrose
solution. The solution for 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.
For single use only.
7. MANUFACTURER:
Manufactured in India by:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Survey No.188/1 to 189/1,190/1 to 4,
Athiyawad, Dabhel,
Daman- 396210 (INDIA)

Irinotecan Hydrochloride 20 MGML, Concentrate For Solution For Infusion SMPC - Taj Pharmaceuticals

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IRINOTECAN 4.1 Therapeutic indications

Irinotecan Hydrochloride 20 mg/ml, concentrate Irinotecan Hydrochloride in combination with

4.3 Contraindications on day 5 after the infusion of irinotecan. Patients

• Diarrhoea associated with fever A prophylactic treatment with antiemetics is

Women of child-bearing potential irinotecan in addition to those seen with

Very common: ≥ 1/10 severe neutropenia resulting in death in

Rare: ≥ 1/10,000 to < 1/1,000

Very rare: < 1/10,000; not known (cannot be estimated

Frequency Side effects

Uncommon • Mild allergic reactions Nausea and vomiting

Severe diarrhoea was observed in 13.1 % of Blood disorders

cells/mm³) in 22.6 % of patients. Of the One case of peripheral thrombocytopenia with

Infectious episodes occurred in about 2 % of Cardiac disorders

Transient and mild to moderate increases of Irinotecan is a semi-synthetic derivative of

In combination therapy with 5-FU/FA p value 0.0014 NS < 0.001

summarised in the table below. ORR

Arm 1 Arm 2 95% CI 46.9 (42.9, 38.7 59.3 (51.6, 43.2

months) for XELIRI (p = 0.0002). PFS at 6 NA NA 33.5 26.7 0.03

• Cytochrome P450 3A enzymes-dependent 6. PHARMACEUTICAL

3 years. 25-ml brown glass vial, with a halobutyl rubber

6.4 Special precautions for storage If Irinotecan Hydrochloride concentrate for

Aseptically withdraw the required amount of

Manufactured in India by:

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