|
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 20 mg irinotecan hydrochloride trihydrate, equivalent to 17.33 mg irinotecan.
Each vial with 2 ml contains 40 mg irinotecan hydrochloride trihydrate
Each vial with 5 ml contains 100 mg irinotecan hydrochloride trihydrate
Each vial with 25 ml contains 500 mg irinotecan hydrochloride trihydrate
Excipients:
Includes sorbitol, (E420) 45.0 mg/ml
For a full list of excipients, see section 6.1
Deleted ‘vial’ after ml and ‘Also’ before includes sorbitol and inserted “vial with”.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Irinotecan is indicated for the treatment of patients with advanced colorectal cancer.
· In combination with 5-fluorouracil (5-FU) and folinic acid (FA) in patients without prior chemotherapy for advanced cancer
· As a single agent in patients who have failed an established 5-FU containing treatment regimen
Inserted “patients with” advanced colorectal…and “(5-FU)” and “(FA)” in first bullet, replacing ‘5-fluorouracil’ in full in second bullet.
Irinotecan in combination with cetuximab is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type metastatic colorectal cancer, who had not received prior treatment for metastatic disease or after failure of irinotecan-including cytotoxic therapy (see section 5.1).
Irinotecan in combination with 5-FU, FA and bevacizumab is indicated for first-line treatment of patients with metastatic carcinoma of the colon or rectum.
Irinotecan in combination with capecitabine with or without bevacizumab is indicated for first-line treatment of patients with metastatic colorectal carcinoma.
Inserted new text above.
4.2 Posology and method of administration
Recommended dosage
Dosages of irinotecan mentioned in this summary of product characteristics refer to mg of irinotecan hydrochloride trihydrate.
Inserted new text above under ‘recommended dosage’.
In monotherapy (for previously treated patients)
The recommended dose of irinotecan is 350 mg/m2 administered as an intravenous infusion over a 30 to 90 minute period every three weeks (see sections 4.4 and 6.6 ).
Deleted ‘hydrochloride’ after irinotecan and shortened to numbers of sections in bracket.
In combination therapy (for previously untreated patients)
The safety and efficacy of irinotecan in combination with 5-fluorouracil (5-FU) and folinic acid (FA) have been assessed in the following schedule (see section 5.1)
Irinotecan plus 5-FU/FA every 2 weeks schedule
The recommended dose of irinotecan is 180 mg/m2 administered once every 2 weeks as an intravenous infusion over a 30 to 90 minute period, followed by an infusion of FA and 5-FU.
Deleted ‘hydrochloride’ after every irinotecan and ‘dosing’ before schedule. Shortened to number of section in bracket and replaced ‘folinic acid’ and ‘5-fluorouracil’ with FA and 5-FU.
For the posology and method of administration of concomitant cetuximab, refer to the product information for this medicinal product. Normally, the same dose of irinotecan is used as administered in the last cycles of the prior irinotecan-containing regimen. Irinotecan must not be administered earlier than 1 hour after the end of the cetuximab infusion.
For the posology and method of administration of bevacizumab, refer to the bevacizumab summary of product characteristics.
For the posology and method of administration of capecitabine combination, please see section 5.1 and refer to the appropriate sections in the capecitabine summary of product characteristics.
Inserted new text above.
Dosage adjustments
Irinotecan should be administered after appropriate recovery of all adverse events to grade 0 or 1 of NCI-CTC (National Cancer Institute Common Toxicity Criteria) grading and when treatment-related diarrhoea is fully resolved.
At the start of a subsequent infusion treatment, the dose of irinotecan, and 5-FU when applicable, should be decreased according to the worst grade of adverse events observed in the prior infusion. Treatment should be delayed by 1 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 5-FU when applicable:
· haematological toxicity (neutropenia grade 4, febrile neutropenia [neutropenia grade 3-4 and fever grade 2-4], thrombocytopenia and leucopenia [grade 4]),
· non-haematological toxicity (grade 3-4).
Deleted ‘hydrochloride’ after every irinotecan and in bullet 1 replaced some “( )” with “[ ]”.
Recommendations for dose modifications of cetuximab when administered in combination with irinotecan must be followed according to the product information for this medicinal product.
Refer to the bevacizumab summary of product characteristics for dose modifications of bevacizumab when administered in combination with irinotecan/5-FU/FA.
In combination with capecitabine for patients 65 years of age or more, a reduction of the starting dose of capecitabine to 800 mg/m2 twice daily is recommended according to the summary of product characteristics for capecitabine. Refer also to the recommendations for dose modifications in combination regimen given in the summary of product characteristics for capecitabine.
Inserted new text above.
Treatment duration
Treatment with irinotecan should be continued until there is an objective progression of the disease or an unacceptable toxicity.
Deleted ‘hydrochloride’ after irinotecan.
Special populations
Patients with impaired hepatic function
Inserted “Patients with”.
Monotherapy:
Blood bilirubin levels (up to 3 times the upper limit of the normal range [ULN]), in patients with WHO performance status £ 2, should determine the initial dose of irinotecan. In these patients with hyperbilirubinaemia and prothrombin time greater than 50%, the clearance of irinotecan is reduced (see section 5.2), and therefore the risk of haematotoxicity is increased. Thus, weekly monitoring of complete blood counts should be conducted in this patient population.
· In patients with bilirubin levels up to 1.5 times the ULN, the recommended dose of irinotecan is 350 mg/ m2
· In patients with bilirubin levels between 1.5 to 3 times the ULN, the recommended dose of irinotecan is 200 mg/ m2
· Patients with bilirubin levels above 3 times the ULN, should not be treated with irinotecan (see sections 4.3 and 4.4).
No data are available for patients with impaired hepatic function treated with irinotecan in combination therapy.
Inserted “[ULN]” and replaced all ‘upper limit of normal range’ in bullets. Deleted ‘hydrochloride’ after every irinotecan and shortened to numbers of sections in brackets. Hematotoxicity to haematotoxicity.
Patients with impaired renal function
Irinotecan is not recommended for use in patients with impaired renal function, as the product has not been studied in this patient group (see sections 4.4 and 5.2).
Inserted “Patients with” and shortened to numbers of sections in bracket.
Elderly
No specific pharmacokinetic studies have been carried out in the elderly. However, the dose should be chosen carefully in this patient group due to their greater frequency of decreased biological functions. This population should require more intense surveillance (see section 4.4).
Replaced ‘functioning of vital organs particularly liver with “biological functions”. Simplified from ‘patient group required more intensive monitoring’ to above last sentence. Deleted ‘Paediatric section’.
4.3 Contraindications
Chronic inflammatory bowel disease and/or bowel obstruction (see section 4.4).
History of severe hypersensitivity reactions to irinotecan hydrochloride trihydrate or to any of the excipients.
Pregnancy and lactation (see sections 4.4 and 4.6).
Bilirubin > 3 times the ULN (see section 4.4).
Severe bone marrow failure.
WHO performance status > 2.
Concomitant use with St John's wort (see section 4.5).
For additional contraindications of cetuximab or bevacizumab or capecitabine, refer to the product information for these medicinal products.
Added “trihydrate” in second bullet, shortened to numbers of sections in brackets and used abbreviated “ULN”. Inserted new above text on cetuximab, bevacizumab or capecitabine and deleted ‘other forms of interaction’.
4.4 Special warnings and precautions for use
When irinotecan is used in monotherapy, it is usually prescribed using the three week dosage schedule. However, a weekly-dosage schedule (see section 5) may be considered in patients who need a closer follow-up or who are at particular risk of severe neutropenia.
Delayed diarrhoea
Patients should be made aware of the risk of delayed diarrhoea, i.e. diarrhoea may occur more than 24 hours after the administration of irinotecan at any stage before the next administration. In monotherapy the median time of onset of the first liquid stool was five days after the infusion of irinotecan. Patients should quickly inform their physician of the occurrence of diarrhoea and start appropriate therapy immediately.
Patients with an increased risk of diarrhoea are those who have had previous abdominal/pelvic radiotherapy, those with baseline hyperleukocytosis and those with performance status ≥ 2 and women. If not appropriately treated, the diarrhoea can be life threatening, especially if the patient is concomitantly neutropenic.
As soon as the first liquid stool occurs, the patient should start drinking large volumes of liquid containing electrolytes, and an adequate antidiarrhoeal therapy must be initiated immediately. Specific arrangements must be made to ensure that the clinic which administers irinotecan will also prescribe the antidiarrhoeal treatment. After discharge from the hospital, the patients should obtain the prescribed drugs so that the diarrhoea can be treated as soon as it occurs. In addition, they must inform their physician, or the clinic where irinotecan was administered, when/if diarrhoea is occurring.
If the patient has had severe diarrhoea, a reduction in the dose is recommended for subsequent cycles (see section 4.2).
Deleted ‘hydrochloride’ after every irinotecan and ‘hyperleucocytosis’ to “hyperleukocytosis”
Shortened to numbers of sections in bracket.
Haematology
During irinotecan treatment, weekly monitoring of complete blood cell counts is recommended. 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 hospital with broad-spectrum intravenous antibiotics.
A dose reduction for subsequent administration is recommended for patients who have experienced severe haematological events (see section 4.2).
There is an increased risk of infections and haematological toxicity in patients with severe diarrhoea. In patients with severe diarrhoea, a complete blood cell count should be taken.
Deleted ‘hydrochloride’ after irinotecan and shortened to numbers of sections in bracket.
Patients with reduced uridine diphosphate glucuronosyltransferase (UGT1A1) activity
SN-38 is detoxified by UGT1A1 to SN-38 glucuronide. Individuals with a congenital deficiency of UGT1A1 (Crigler-Najjar syndrome type 1 and type 2 or individuals who are homozygous for the UGT1A1*28 allele [Gilbert’s syndrome]) are at increased risk of toxicity from irinotecan. A reduced initial dose should be considered for these patients.
Inserted new text above, under ‘Haematology’.
Impaired hepatic function
Weekly monitoring of complete blood counts should be conducted in patients with bilirubin ranging from 1.5 to 3 times the ULN due to decrease of the clearance of irinotecan (see section 5.2) and thus increasing the risk of haematotoxicity in this population. For patients with a bilirubin > 3 times ULN see section 4.3.
Deleted ‘Patients with hyperbilirubinaemia’ and used abbreviated ULN; shortened to numbers of sections in bracket.
Nausea and vomiting
Acute cholinergic syndrome
If acute cholinergic syndrome appears (defined as early diarrhoea and certain other symptoms such as sweating, abdominal cramps, lacrimation, miosis and salivation), atropine sulphate (0.25 mg subcutaneously) should be administered unless clinically contraindicated (see section 4.8).
Caution should be exercised in the treatment of patients with asthma. If the patient experiences an acute and severe cholinergic syndrome, the use of prophylactic atropine sulphate is recommended with subsequent administration of irinotecan.
Elderly
Due to the greater frequency of decreased biological functions, for example hepatic function, in elderly patients, dose selection with irinotecan treatment should be used with caution in this population (see section 4.2).
Deleted ‘hydrochloride’ after irinotecan and shortened to numbers of sections in bracket in above paragraphs.
Patients with bowel obstruction
Patients must not be treated with irinotecan until the bowel obstruction is resolved (see section 4.3).
Patients with impaired renal function
Studies have not been carried out in this patient group (see sections 4.2 and 5.2).
Inserted “Patients with” in both headings. Deleted ‘hydrochloride’ after irinotecan and shortened to numbers of sections in bracket
Others
Since the medicine contains sorbitol, it is not suitable for patients with hereditary fructose intolerance. Infrequent cases of renal insufficiency, hypotension or circulatory failure have been observed where the patients have been dehydrated in association with diarrhoea and/or vomiting, or had sepsis.
Women of childbearing potential and men must use effective contraceptive measures during and for at least three months after the cessation of therapy (see section 4.6).
Concomitant administration of irinotecan with a strong inhibitor (e.g. ketoconazole) or inducer (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, St John's wort) of cytochrome P450 3A4 (CYP3A4) may alter the metabolism of irinotecan and should be avoided (see section 4.5).
Replaced ‘contraceptive must be taken’ with second paragraph. Inserted cytochrome P450 3A4 then bracket for abbreviated. Shortened to numbers of sections in bracket.
4.5 Interaction with other medicinal products and other forms of interaction
Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out. Irinotecan is an anticholinesterase, and medicines which have anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and antagonise the neuromuscular blockade of non-depolarising agents.
Several studies have shown that concomitant administration of cytochrome P450 3A (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 were reflected by a decrease in AUC of SN-38 and SN-38G by 50% or more. In addition to induction of CYP3A 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 the principal oxidative metabolite APC of 87% and in an increase in the AUC of SN-38 of 109% in comparison to irinotecan given alone. Caution should be exercised in patients concurrently taking drugs known to inhibit (e.g. ketoconazole) or induce (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin) drug metabolism by CYP3A4. 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. Consequently St John’s wort should not be administered with irinotecan (see section 4.3).
Coadministration of 5-FU/FA in the combination regimen does not change the pharmacokinetics of irinotecan.
Inserted cytochrome P450 3A4 in second paragraph and then used abbreviated “(CYP3A)” throughout. In 3rd paragraph inserted “the principal oxidative metabolite”. Replaced with 5-FU/FA instead of in full and shortened to numbers of sections in brackets.
There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa.
In one study, irinotecan concentrations were similar in patients receiving irinotecan/5-FU/FA alone and in combination with bevacizumab. Concentrations of SN-38, the active metabolite of irinotecan, were analysed in a subset of patients (approximately 30 per treatment arm). Concentrations of SN-38 were on average 33 % higher in patients receiving irinotecan/5-FU/FA in combination with bevacizumab compared with irinotecan/5-FU/FA alone. Due to high inter-patient variability and limited sampling, it is uncertain if the increase in SN-38 levels observed was due to bevacizumab. There was a small increase in diarrhoea and leukocytopenia adverse events. More dose reductions of irinotecan were reported for patients receiving irinotecan/5-FU/FA in combination with bevacizumab.
Patients who develop severe diarrhoea, leukocytopenia or neutropenia with the bevacizumab and irinotecan combination should have irinotecan dose modifications as specified in section 4.2.
Inserted this new text above, under 4.5
4.6 Pregnancy and lactation
Pregnancy
There is no information on the use of irinotecan in pregnant women. Irinotecan has been shown to be embryotoxic, foetotoxic and teratogenic in rabbits and rats. Therefore, irinotecan should not be used during pregnancy (see sections 4.3 and 4.4).
Women of child-bearing potential:
Women of childbearing age receiving irinotecan should inform the treating physician immediately should pregnancy occur (see sections 4.3 and 4.4). Contraceptive measures must be taken by women of childbearing potential and also by male patients during and for at least three months after treatment.
Lactation
In lactating rats, 14C-irinotecan has been detected in milk. It is not known whether irinotecan is excreted in human milk. Breast-feeding must be discontinued for the duration of irinotecan treatment due to the potential of adverse effects in nursing infants (see section 4.3).
Under ‘Pregnancy’ inserted “pregnant women” instead of human pregnancy. Inserted new “Contraceptive…” statement under ‘Women of child-bearing potential’. Changed to “Breast-feeding must be discontinued…” from ‘should’. Shortened to numbers of sections in brackets.
4.7 Effects on ability to drive and use machines
Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of irinotecan, and advised not to drive or operate machinery if these symptoms occur.
Deleted ‘hydrochloride’ after irinotecan
4.8 Undesirable effects
Undesirable effects detailed in this section refer to irinotecan. There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa. In combination with cetuximab, additional reported undesirable effects were those expected with cetuximab (such as acne form rash 88 %). Therefore also refer to the product information for cetuximab.
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 5-FU/FA every two weeks at the recommended dose of 180 mg/m2.
Side effects have been summarised in the table below with MedDRA frequencies. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Very common: ≥ 1/10
Common: ≥ 1/100 to < 1/10
Uncommon: ≥ 1/1000 to < 1/100
Rare: ≥ 1/10,000 to < 1/1,000
Very rare < 1/10,000; not known (cannot be estimated from the available data)
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Body System
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Frequency
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Adverse Reaction
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Infections and Infestations
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Uncommon
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In patients who experienced sepsis, renal insufficiency, hypotension or cardio-circulatory failure have been observed
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Blood and Lymphatic System Disorders
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Very common
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Neutropenia (reversible and not cumulative)
Anaemia
Thrombocytopenia in case of combination therapy
Infectious episodes with monotherapy.
|
|
Common
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Febrile neutropenia
Infectious episodes with combination therapy.
Infectious episodes associated with severe neutropenia resulting in death in 3 cases.
Thrombocytopenia with monotherapy.
|
|
Very rare
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One case of peripheral thrombocytopenia with antiplatelet antibodies has been reported
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|
Immune System Disorders
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Uncommon
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Mild allergy reactions
|
|
Rare
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Anaphylactic/ Anaphylactoid reactions
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|
Metabolism and Nutrition Disorders
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Very rare
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Tumour lysis syndrome
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|
Nervous System Disorders
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Very rare
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Transient speech disorder
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|
Cardiac Disorders
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Rare
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Hypertension during or following the infusion
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|
Respiratory, Thoracic and Mediastinal Disorders
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Uncommon
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Interstitial pulmonary disease presenting as pulmonary infiltrates
Early effects such as dyspnoea
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|
Gastrointestinal Disorders
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Very common
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Severe delayed diarrhoea.
Severe nausea and vomiting with monotherapy
|
|
Common
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Severe nausea and vomiting in case of combination therapy
Episodes of dehydration (associated with diarrhoea and/or vomiting).
Constipation related to irinotecan and/or loperamide.
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|
Uncommon
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Pseudomembranous colitis (one case has been documented bacteriologically: Clostridium difficile)
Renal insufficiency, hypotension or cardio-circulatory failure as a consequence of dehydration associated with diarrhoea and/or vomiting
Intestinal obstruction, ileus, or gastrointestinal haemorrhage
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|
Rare
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Colitis, including typhlitis, ischaemic and ulcerative colitis
Intestinal perforation
Other mild effects include anorexia, abdominal pain and mucositis
Symptomatic or asymptomatic pancreatitis
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|
Skin and Subcutaneous Tissue Disorders
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Very common
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Alopecia (reversible)
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|
Uncommon
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Mild cutaneous reaction
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|
Musculoskeletal and Connective Tissue Disorders
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Rare
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Early effects such as muscular contraction or cramps and paraesthesia
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|
General Disorders and Administration Site Reactions
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Very common
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Fever in the absence of infection and without concomitant severe neutropenia with monotherapy
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|
Common
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Severe transient acute cholinergic syndrome (the main symptoms were early diarrhoea and various other symptoms such as abdominal pain, conjunctivitis, rhinitis, hypotension, vasodilatation, sweating, chills, malaise, dizziness, visual disturbances, miosis, lacrimation and increased salivation)
Asthenia
Fever in the absence of infection and without concomitant severe neutropenia with combination therapy.
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|
Uncommon
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Infusion site reactions
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|
Investigations
|
Very common
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In combination therapy transient serum levels (grade 1 and 2) of either ALT, AST, alkaline phosphatase or bilirubin were observed in the absence of progressive liver metastasis
|
|
Common
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In monotherapy, transient and mild to moderate increases in serum levels of either ALT, AST, alkaline phosphatase or bilirubin were observed in the absence of progressive liver metastasis.
Transient and mild to moderate increases of serum levels of creatinine.
In combination therapy, transient grade 3 serum levels of bilirubin.
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|
Rare
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Hypokalemia
Hyponatremia
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Very rare
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Increases of amylase and/or lipase
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The most common (≥ 1/10), dose-limiting adverse reactions of irinotecan are delayed diarrhoea (occurring more than 24 hours after administration) and blood disorders including neutropenia, anaemia and thrombocytopenia.
Commonly severe transient acute cholinergic syndrome was observed. The main symptoms were defined as early diarrhoea and various other symptoms such as abdominal pain, conjunctivitis, rhinitis, hypotension, vasodilation, sweating, chills, malaise, dizziness, visual disturbances, miosis, lacrimation 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).
Delayed diarrhoea
In monotherapy: Severe diarrhoea was observed in 20% of the patients who followed the recommendations for the management of diarrhoea. Of the evaluable cycles, 14% have severe diarrhoea. The median time of onset of the first liquid stool was on day 5 after the infusion of irinotecan.
In combination therapy: Severe diarrhoea was observed in 13.1% of the patients who followed recommendations for the management of diarrhoea. Of the evaluable treatment cycles, 3.9% have severe diarrhoea.
Blood Disorders
Neutropenia
Neutropenia was reversible and not cumulative; the median day to nadir was 8 days whatever the use in monotherapy or in combination therapy.
In monotherapy: Neutropenia was observed in 78.7% of patients and was severe (neutrophil count < 500 cells/mm3) in 22.6% of patients. Of the evaluable cycles, 18% had a neutrophil count < 1,000 cells/mm³ including 7.6% with a neutrophil count < 500 cells/mm³. Total recovery was usually reached by day 22. Fever with severe neutropenia was reported in 6.2% of patients and in 1.7% of cycles. Infectious episodes occurred in about 10.3% of patients (2.5% of cycles) and were associated with severe neutropenia in about 5.3% of patients (1.1% of cycles), and resulted in death in 2 cases.
In combination therapy: Neutropenia was observed in 82.5% of patients and was severe (neutrophil count < 500 cells/mm3) in 9.8 % of patients. Of the evaluable cycles, 67.3 % had a neutrophil count <1,000 cells/mm³ including 2.7% with a neutrophil count < 500 cells/mm³. Total recovery was usually reached within 7-8 days. Fever with severe neutropenia was reported in 3.4% of patients and in 0.9% of cycles.
Infectious episodes occurred in about 2% of patients (0.5% of cycles) and were associated with severe neutropenia in about 2.1% of patients (0.5% of cycles), and resulted in death in 1 case.
Anaemia
In monotherapy: Anaemia was reported in about 58.7% of patients (8% with haemoglobin < 8 g/dl and 0.9% with haemoglobin < 6.5 g/dl).
In combination therapy: Anaemia was reported in 97.2% of patients (2.1% with haemoglobin < 8 g/dl).
Thrombocytopenia
In monotherapy: Thrombocytopenia (< 100,000 cells/mm³) was observed in 7.4% of patients and 1.8% of cycles with 0.9% of patients 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: 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.
Updated whole of section 4.8 with new text and table into Medra format
4.9 Overdose
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 treatment should be initiated to prevent dehydration due to diarrhoea and to treat any infectious complications.
Deleted ‘hydrochloride’ after irinotecan
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: other antineoplastic agents
Inserted new text above under 5.1.
Experimental data
In addition to the antitumour effect of irinotecan, the most relevant pharmacological effect of irinotecan is the inhibition of acetylcholinesterase.
Deleted ‘hydrochloride’ after irinotecan
Clinical data
In monotherapy for the second-line treatment of metastatic colorectal carcinoma:
More than 980 patients with metastatic colorectal cancer, who had failed a previous 5-FU treatment, were enrolled in clinical phase II/III studies, in the every 3 week dosage schedule. The efficacy of irinotecan was evaluated in 765 patients with disease progression during 5-FU treatment at study entry.
|
Progression Free Survival at 6 months (%)
Survival at 12 months (%)
Median Survival (months)
|
Phase III
|
|
Irinotecan versus best supportive care (BSC)
|
Irinotecan versus 5-FU
|
|
Irinotecan
|
Supportive care
|
p values
|
Irinotecan
|
5-FU
|
p values
|
|
n = 183
|
n = 90
|
n = 127
|
n = 129
|
|
NA
36.2
9.2
|
NA
13.8
6.5
|
p=0.0001
p=0.0001
|
33.5
44.8
10.8
|
26.7
32.4
8.5
|
p=0.03
p=0.0351
p=0.0351
|
NA: Not Applicable
Inserted “for the second-line treatment of metastatic colorectal carcinoma” under clinical data. Deleted ‘hydrochloride’ after every irinotecan and ‘*: Statistically significant difference’. Inserted “best” and “(BSC)” in table.
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 carried out on 385 patients with metastatic colorectal cancer receiving first line treatment, either by administering the treatment every 2 weeks (see section 4.2) or every week. In the 2 weekly schedule, on the first day, the administration of irinotecan at 180 mg/m2 once every 2 weeks was followed by infusion of FA (200 mg/m2 as a 2-hour intravenous infusion) and 5-FU (400 mg/m2 as an intravenous bolus, followed by 600 mg/m2 as a 22-hour intravenous infusion). On day 2, FA and 5-FU were administered using the same doses and schedules. In the weekly schedule, the administration of irinotecan at 80 mg/m2 was followed by infusion with FA (500 mg/m2 as a 2-hour intravenous infusion) and then by 5-FU (2,300 mg/m2 as a 24-hour intravenous infusion) over 6 weeks.
In the combination treatment trial with the 2 regimens described above, the efficacy of irinotecan was evaluated in 198 patients:
|
|
Combined regimens
(n=198)
|
Weekly schedule
(n=50)
|
Every 2 weeks schedule (n=148)
|
|
Irin. +5-FU/FA
|
5-FU/FA
|
Irin. +5-FU/FA
|
5-FU/FA
|
Irin. +5-FU/FA
|
5-FU/FA
|
|
Response rate (%) p value
|
40.8 *
|
23.1 *
|
51.2 *
|
28.6 *
|
37.5 *
|
21.6 *
|
|
p < 0.001
|
p = 0.045
|
p = 0.005
|
|
Median time to progression (months) p value
|
6.7
|
4.4
|
7.2
|
6.5
|
6.5
|
3.7
|
|
p < 0.001
|
NS
|
p = 0.001
|
|
Median duration of response (months) p value
|
9.3
|
8.8
|
8.9
|
6.7
|
9.3
|
9.5
|
|
NS
|
p = 0.043
|
NS
|
|
Median duration of response and stabilisation (months)
p value
|
8.6
|
6.2
|
8.3
|
6.7
|
8.5
|
5.6
|
|
p < 0.001
|
NS
|
p = 0.003
|
|
Median time to treatment failure (months)
p value
|
5.3
|
3.8
|
5.4
|
5.0
|
5.1
|
3.0
|
|
p = 0.0014
|
NS
|
p < 0.001
|
|
Median survival (months)
p value
|
16.8
|
14.0
|
19.2
|
14.1
|
15.6
|
13.0
|
|
p = 0.028
|
NS
|
p = 0.041
|
Irin: irinotecan
5-FU: 5-fluorouracil,
FA: folinic acid,
NS: nonsignificant,
*: as per protocol population analysis
In the weekly schedule, the incidence of severe diarrhoea was 44.4% in the patients treated with irinotecan in combination with 5-FU/FA and 25.6% in the patients treated with 5-FU/FA alone. The incidence of severe neutropenia (neutrophil count < 500 cells/mm3) was 5.8% in the patients treated with irinotecan in combination with 5-FU/FA and 2.4% in the patients treated with 5-FU/FA alone.
Additionally, the median time to definitive performance status deterioration was significantly longer in the group that received irinotecan in combination with 5-FU/FA than in the 5-FU/FA alone group (p = 0.046).
Quality of life was assessed in this phase III study by using the EORTC QLQ-C30 questionnaire. Time to definitive deterioration constantly occurred later in the irinotecan groups. The global health status/quality of life was slightly better in the irinotecan combination group although not significantly, showing that efficacy of irinotecan in combination treatment could be reached without affecting the quality of life.
Inserted “for the first-line treatment of metastatic colorectal carcinoma” and “In combination therapy with Folinic Acid and 5-Fluorouracil”. Deleted ‘hydrochloride’ after every irinotecan in above paragraphs and used abbreviated “5-FU” and “FA”. Deleted ‘HCL’ in table and updated “= or <” symbols. Inserted “Irin: irinotecan” and “NS: nonsignificant” under table.
In combination therapy with cetuximab
EMR 62 202-013: This randomised study in patients with metastatic colorectal cancer who had not received prior treatment for metastatic disease compared the combination of cetuximab and irinotecan plus infusional 5-fluorouracil/folinic acid (5-FU/FA) (599 patients) to the same chemotherapy alone (599 patients). The proportion of patients with KRAS wild-type tumours from the patient population evaluable for KRAS status comprised 64%.
The efficacy data generated in this study are summarised in the table below:
|
|
Overall population
|
KRAS wild-type population
|
|
Variable/statistic
|
Cetuximab plus FOLFIRI (N=599)
|
FOLFIRI
(N=599)
|
Cetuximab plus FOLFIRI (N=172)
|
FOLFIRI
(N=176)
|
|
ORR
|
|
|
|
|
|
% (95%CI)
|
46.9 (42.9, 51.0)
|
38.7 (34.8, 42.8)
|
59.3 (51.6, 66.7)
|
43.2 (35.8, 50.9)
|
|
p-value
|
0.0038
|
0.0025
|
|
PFS
|
|
|
|
|
|
Hazard Ratio (95% CI)
|
0.85 (0.726, 0.998)
|
0.68 (0.501, 0.934)
|
|
p-value
|
0.0479
|
0.0167
|
CI = confidence interval, FOLFIRI = irinotecan plus infusional 5-FU/FA, ORR = objective response rate (patients with complete response or partial response), PFS = progression-free survival time
In combination with cetuximab after failure of irinotecan-including cytotoxic therapy
The efficacy of the combination of cetuximab with irinotecan was investigated in two clinical studies. A total of 356 patients with EGFR-expressing metastatic colorectal cancer who had recently failed irinotecan-including cytotoxic therapy and who had a minimum Karnofsky performance status of 60%, but the majority of whom had a Karnofsky performance status of ≥ 80 % received the combination treatment.
EMR 62 202-007: This randomised study compared the combination of cetuximab and irinotecan (218 patients) with cetuximab monotherapy (111 patients).
IMCL CP02-9923: This single arm open-label study investigated the combination therapy in 138 patients.
The efficacy data from these studies are summarised in the table below.
|
Study
|
n
|
ORR
|
DCR
|
PFS (months)
|
OS (months)
|
|
|
|
n[%]
|
95% CI
|
n[%]
|
95% CI
|
Median
|
95% CI
|
Median
|
95% CI
|
|
Cetuximab + irinotecan
|
|
EMR 62
202-007
|
218
|
50 (22.9)
|
17.5, 29.1
|
121 (55.5)
|
48.6, 62.2
|
4.1
|
2.8, 4.3
|
8.6
|
7.6, 9.6
|
|
IMCL
CP02-9923
|
138
|
21 (15.2)
|
9.7, 22.3
|
84 (60.9)
|
52.2, 69.1
|
2.9
|
2.6, 4.1
|
8.4
|
7.2, 10.3
|
|
Cetuximab
|
|
EMR 62
202-007
|
111
|
12 (10.8)
|
5.7, 18.1
|
36 (32.4)
|
23.9, 42.0
|
1.5
|
1.4, 2.0
|
6.9
|
5.6, 9.1
|
|
CI = confidence interval; DCR = disease control rate (patients with complete response, partial response or stable disease for at least 6 weeks); ORR = objective response rate (patients with complete response or partial response); OS = overall survival time; PFS = progression-free survival
|
The efficacy of the combination of cetuximab with irinotecan was superior to that of cetuximab monotherapy, in terms of objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). In the randomised trial, no effects on overall survival were demonstrated (hazard ratio 0.91, p = 0.48).
In combination therapy with bevacizumab
A phase III randomised, double-blind, active-controlled clinical trial evaluated bevacizumab in combination with irinotecan/5-FU/FA as first-line treatment for metastatic carcinoma of the colon or rectum (study AVF2107g). The addition of bevacizumab to the combination of irinotecan/5-FU/FA resulted in a statistically significant increase in overall survival. The clinical benefit, as measured by overall survival, was seen in all pre-specified patient subgroups, including those defined by age, sex, performance status, location of primary tumour, number of organs involved and duration of metastatic disease. Refer also to the bevacizumab summary of product characteristics. The efficacy results of study AVF2107g are summarised in the table below.
|
|
Arm 1
Irinotecan/5-FU/FA/placebo
|
Arm 2
Irinotecan/5-FU/FA/bevacizumab a
|
|
Number of patients
|
411
|
402
|
|
Overall survival
|
|
|
|
Median time [months]
|
15.6
|
20.3
|
|
95% Confidence interval
|
14.29 – 16.99
|
18.46 – 24.18
|
|
Hazard ratio b
|
|
0.660
|
|
p value
|
|
0.00004
|
|
Progression-free survival
|
|
|
|
Median time [months]
|
6.2
|
10.6
|
|
Hazard ratio b
|
|
0.54
|
|
p value
|
|
< 0.0001
|
|
Overall response rate
|
|
|
|
Rate [%]
|
34.8
|
44.8
|
|
95% Confidence interval
|
30.2 – 39.6
|
39.9 – 49.8
|
|
p value
|
|
0.0036
|
|
Duration of response
|
|
|
|
Median time [months]
|
7.1
|
10.4
|
|
25 – 75 Percentile [months]
|
4.7 – 11.8
|
6.7 – 15.0
|
|
a 5 mg/kg every 2 weeks; b Relative to control arm.
|
In combination therapy with capecitabine
Data from a randomised, controlled phase III study (CAIRO) support the use of capecitabine at a starting dose of 1000 mg/m2 for 2 weeks every 3 weeks in combination with irinotecan for the first-line treatment of patients with metastatic colorectal cancer. 820 Patients were randomized to receive either sequential treatment (n=410) or combination treatment (n=410). Sequential treatment consisted of first-line treatment with capecitabine (1250 mg/m2 twice daily for 14 days), second-line irinotecan (350 mg/m2 on day 1), and third-line combination of capecitabine (1000 mg/m2 twice daily for 14 days) with oxaliplatin (130 mg/m2 on day 1). Combination treatment consisted of first-line treatment of capecitabine (1000 mg/m2 twice daily for 14 days) combined with irinotecan (250 mg /m2 on day 1) (XELIRI) and second-line capecitabine (1000 mg/m2 twice daily for 14 days) plus oxaliplatin (130 mg/m2 on day 1). All treatment cycles were administered at intervals of 3 weeks. In first-line treatment the median progression-free survival in the intent-to-treat population was 5.8 months (95%CI, 5.1 -6.2 months) for capecitabine monotherapy and 7.8 months (95%CI, 7.0-8.3 months) for XELIRI (p=0.0002).
Data from an interim analysis of a multicentre, randomised, controlled phase II study (AIO KRK 0604) support the use of capecitabine at a starting dose of 800 mg/m2 for 2 weeks every 3 weeks in combination with irinotecan and bevacizumab for the first-line treatment of patients with metastatic colorectal cancer. 115 patients were randomised to treatment with capecitabine combined with irinotecan (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 minute infusion on day 1 every 3 weeks), and bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks); a total of 118 patients were randomised to treatment with capecitabine combined with oxaliplatin plus bevacizumab: capecitabine (1000 mg/m2 twice daily for two weeks followed by a 7-day rest period), oxaliplatin (130 mg/m2 as a 2 hour infusion on day 1 every 3 weeks), and bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks). Progression-free survival at 6 months in the intent-to-treat population was 80% (XELIRI plus bevacizumab) versus 74 % (XELOX plus bevacizumab). Overall response rate (complete response plus partial response) was 45 % (XELOX plus bevacizumab) versus 47 % (XELIRI plus bevacizumab).
Pharmacokinetic/Pharmacodynamic data
Inserted all of above new text for new indications, under 5.1
5.2 Pharmacokinetic properties
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 or previous cycles and of the administration schedule.
Corrected “metastatic” spelling.
Two metabolic pathways account each for at least 12 % of the dose:
- Oxidation promoted by CYP3A enzymes resulting in opening of the outer piperidine ring with formation of aminopentanoic acid derivative (APC) and primary amine derivative (NPC) (see section 4.5).
Used abbreviated “CYP3A” and shortened to numbers of section in bracket.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sorbitol (E420)
Lactic acid (E270)
Sodium hydroxide and/or hydrochloric acid (for pH adjustment)
Water for Injections
Inserted “(E420)” and “(E270)”.
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Inserted new text above.
6.3 Shelf life
Chemical and physical in-use stability has been demonstrated in glucose 50 mg/ml (5%) and sodium chloride 9 mg/ml (0.9%) for 72 hours at 2-8 °C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Changed to “50 mg/ml (5%)” and “9 mg/ml (0.9%).
6.4 Special precautions for storage
For storage conditions of the diluted medicinal product, see section 6.3.
Inserted new text above in this section.
6.5 Nature and contents of container
· 40 mg/2 ml: One 5 ml Onco-Tain® Type 1 brown glass vial, with a fluorobutyl rubber closure coated with teflon on the inner side.
· 100 mg/5 ml: One 5 ml Onco-Tain® Type 1 brown glass vial, with a fluorobutyl rubber closure coated with teflon on the inner side.
· 500 mg/25 ml: One 30 ml Onco-Tain® Type 1 brown glass vial, with a fluorobutyl rubber closure coated with teflon on the inner side.
Each pack contains 1 vial. Not all pack sizes may be marketed.
Onco-Tain® is the vial external protection system, propriety of Hospira.
In 1st bullet changed to “5 ml Onco-Tain®” and inserted “Onco-Tain®” in each bullet. Also replaced ‘halobutyl’ with “fluorobutyl” in each bullet above. Inserted new sentence on Onco-Tain®
6.6 Special precautions for disposal
Must be diluted before use. For single use only. Any remaining solution should be discarded.
As with other antineoplastic agents, irinotecan infusions must be prepared and handled with caution. The use of goggles, mask and gloves is required. Pregnant women should not handle cytotoxics.
If irinotecan concentrate or infusion solutions should come into contact with the skin, it must be washed off immediately and thoroughly with soap and water. If irinotecan concentrate or infusion solutions should come into contact with the mucous membranes, it must be washed off immediately with water.
Preparation of the intravenous infusion: As with any other infusion, irinotecan infusion must be prepared using aseptic technique (see section 6.3).
If any precipitate is observed in the vials or in the infusion solution, the product must be discarded according to local standard procedures for discarding cytotoxic agents.
Aseptically withdraw the required amount of irinotecan concentrate from the vial with a calibrated syringe and inject into a 250 ml infusion bag or bottle containing either 9 mg/ml (0.9%) sodium chloride solution or 50 mg/ml (5%) glucose solution only. The infusion should then be thoroughly mixed by manual rotation.
Disposal: All materials used for dilution and administration should be disposed of according to local procedures applicable to the discarding of cytotoxic agents.
In 2nd paragraph inserted “infusions” and last sentence on Pregnant women. In 4th paragraph replaced ‘solution’ with just “infusion”. In 5th and 7th paragraph inserted “local” procedures. In 6th paragraph changed to “50 mg/ml (5%)” and “9 mg/ml (0.9%).
10 DATE OF REVISION OF THE TEXT
20/10/2009
Updated date above.
|
