1. Name Of The Medicinal Product
CAMPTO 20 mg/ml, concentrate for solution for infusion.
2. Qualitative And Quantitative Composition
The concentrate contains 20 mg/ml irinotecan hydrochloride, trihydrate (equivalent to 17.33 mg/ml irinotecan). Vials of CAMPTO contain 40 mg, 100 mg or 300 mg of irinotecan hydrochloride, trihydrate. For excipients, see « List of excipients ».
3. Pharmaceutical Form
Concentrate for solution for infusion.
4. Clinical Particulars
4.1 Therapeutic Indications
CAMPTO is indicated for the treatment of patients with advanced colorectal cancer:
• in combination with 5-fluorouracil and folinic acid in patients without prior chemotherapy for advanced disease,
• as a single agent in patients who have failed an established 5-fluorouracil containing treatment regimen.
CAMPTO 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 (please see 5.1).
CAMPTO in combination with 5-fluorouracil, folinic acid and bevacizumab is indicated for first-line treatment of patients with metastatic carcinoma of the colon or rectum.
Campto in combination with capecitabine with or without bevacizumab is indicated for first-line treatment of patients with metastatic colorectal carcinoma.
4.2 Posology And Method Of Administration
For adults only. CAMPTO solution for infusion should be infused into a peripheral or central vein.
Recommended dosage:
In monotherapy (for previously treated patient):
The recommended dosage of CAMPTO is 350 mg/m² administered as an intravenous infusion over a 30- to 90- minute period every three weeks (see «Instructions for Use/Handling» and «Special Warnings and Special Precautions for Use» sections ).
In combination therapy (for previously untreated patient):
Safety and efficacy of CAMPTO in combination with 5-fluorouracil (5FU) and folinic acid (FA) have been assessed with the following schedule (see « Pharmacodynamic properties »):
• CAMPTO plus 5FU/FA in every 2 weeks schedule
The recommended dose of CAMPTO is 180 mg/m² administered once every 2 weeks as an intravenous infusion over a 30- to 90-minute period, followed by infusion with folinic acid and 5-fluorouracil.
For the posology and method of administration of concomitant cetuximab, refer to the product information for this medicinal product.
Normally, the same dose of irinotecan is used as administered in the last cycles of the prior irinotecan-containing regimen. Irinotecan must not be administered earlier than 1 hour after the end of the cetuximab infusion
For the posology and method of administration of bevacizumab, refer to the bevacizumab summary product of characteristics.
For the posology and method of administration of capecitabine combination, please see section 5.1 and refer to the appropriate sections in the capecitabine summary of product characteristics.
Dosage adjustments:
CAMPTO should be administered after appropriate recovery of all adverse events to grade 0 or 1 NCI-CTC grading (National Cancer Institute Common Toxicity Criteria) and when treatment-related diarrhoea is fully resolved.
At the start of a subsequent infusion of therapy, the dose of CAMPTO, and 5FU when applicable, should be decreased according to the worst grade of adverse events observed in the prior infusion. Treatment should be delayed by 1 to 2 weeks to allow recovery from treatment-related adverse events.
With the following adverse events a dose reduction of 15 to 20 % should be applied for CAMPTO and/or 5FU when applicable:
• haematological toxicity (neutropenia grade 4, febrile neutropenia (neutropenia grade 3-4 and fever grade 2-4), thrombocytopenia and leukopenia (grade 4)),
• non haematological toxicity (grade 3-4).
Recommendations for dose modifications of cetuximab when administered in combination with irinotecan must be followed according to the product information for this medicinal product.
Refer to the bevacizumab summary product of characteristics for dose modifications of bevacizumab when administered in combination with CAMPTO/5FU/FA.
In combination with capecitabine for patients 65 years of age or more, a reduction of the starting dose of capecitabine to 800 mg/m2 twice daily is recommended according to the summary of product characteristics for capecitabine. Refer also to the recommendations for dose modifications in combination regimen given in the summary of product characteristics for capecitabine.
Treatment Duration:
Treatment with CAMPTO should be continued until there is an objective progression of the disease or an unacceptable toxicity.
Special populations:
Patients with Impaired Hepatic Function: In monotherapy: Blood bilirubin levels (up to 3 times the upper limit of the normal range (UNL)) in patients with performance status
• In patients with bilirubin up to 1.5 times the upper limit of the normal range (ULN), the recommended dosage of CAMPTO is 350 mg/m²,
• In patients with bilirubin ranging from 1.5 to 3 times the ULN, the recommended dosage of CAMPTO is 200 mg/m²,
• Patients with bilirubin beyond to 3 times the ULN should not be treated with CAMPTO (see « Contraindications » and « Special Warnings and Special Precautions for Use » sections).
No data are available in patients with hepatic impairment treated by CAMPTO in combination.
Patients with Impaired Renal Function: CAMPTO is not recommended for use in patients with impaired renal function, as studies in this population have not been conducted. (See « Special Warnings and Special Precautions for Use » and « Pharmacokinetic Properties »).
Elderly: No specific pharmacokinetic studies have been performed in elderly. However, the dose should be chosen carefully in this population due to their greater frequency of decreased biological functions. This population should require more intense surveillance (see « Special Warnings and Special Precautions for Use »).
4.3 Contraindications
• Chronic inflammatory bowel disease and/or bowel obstruction (see « Special Warnings and Special Precautions for Use »).
• History of severe hypersensitivity reactions to irinotecan hydrochloride trihydrate or to one of the excipients of CAMPTO.
• Lactation (see « Pregnancy and Lactation » and « Special Warnings and Special Precautions for Use » sections).
• Bilirubin > 3 times the upper limit of the normal range (see « Special warnings and Special Precautions for Use » section).
• 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.
4.4 Special Warnings And Precautions For Use
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Given the nature and incidence of adverse events, CAMPTO will only be prescribed in the following cases after the expected benefits have been weighted against the possible therapeutic risks:
• in patients presenting a risk factor, particularly those with a WHO performance status = 2.
• in the few rare instances where patients are deemed unlikely to observe recommendations regarding management of adverse events (need for immediate and prolonged antidiarrhoeal treatment combined with high fluid intake at onset of delayed diarrhoea). Strict hospital supervision is recommended for such patients.
When CAMPTO is used in monotherapy, it is usually prescribed with the every-3-week-dosage schedule. However, the weekly-dosage schedule (see « Pharmacological properties ») may be considered in patients who may need a closer follow-up or who are at particular risk of severe neutropenia.
Delayed diarrhoea
Patients should be made aware of the risk of delayed diarrhoea occurring more than 24 hours after the administration of CAMPTO and at any time before the next cycle. In monotherapy, the median time of onset of the first liquid stool was on day 5 after the infusion of CAMPTO®. Patients should quickly inform their physician of its occurrence and start appropriate therapy immediately.
Patients with an increased risk of diarrhoea are those who had a previous abdominal/pelvic radiotherapy, those with baseline hyperleucocytosis, those with performance status
As soon as the first liquid stool occurs, the patient should start drinking large volumes of beverages containing electrolytes and an appropriate antidiarrhoeal therapy must be initiated immediately. This antidiarrhoeal treatment will be prescribed by the department where CAMPTO has been administered. After discharge from the hospital, the patients should obtain the prescribed drugs so that they can treat the diarrhoea as soon as it occurs. In addition, they must inform their physician or the department administering CAMPTO when/if diarrhoea is occurring.
The currently recommended antidiarrhoeal treatment consists of high doses of loperamide (4 mg for the first intake and then 2 mg every 2 hours). This therapy should continue for 12 hours after the last liquid stool and should not be modified. In no instance should loperamide be administered for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus, nor for less than 12 hours.
In addition to the anti-diarrhoeal treatment, a prophylactic broad spectrum antibiotic should be given, when diarrhoea is associated with severe neutropenia (neutrophil count < 500 cells/mm³).
In addition to the antibiotic treatment, hospitalisation is recommended for management of the diarrhoea, in the following cases:
- Diarrhoea associated with fever,
- Severe diarrhoea (requiring intravenous hydration),
- Diarrhoea persisting beyond 48 hours following the initiation of high-dose loperamide therapy.
Loperamide should not be given prophylactically, even in patients who experienced delayed diarrhoea at previous cycles.
In patients who experienced severe diarrhoea, a reduction in dose is recommended for subsequent cycles (see « Posology and Method of Administration » section).
Haematology
Weekly monitoring of complete blood cell counts is recommended during CAMPTO treatment. Patients should be aware of the risk of neutropenia and the significance of fever. Febrile neutropenia (temperature > 38°C and neutrophil count
In patients who experienced severe haematological events, a dose reduction is recommended for subsequent administration (see « Posology and Method of Administration » section).
There is an increased risk of infections and haematological toxicity in patients with severe diarrhoea. In patients with severe diarrhoea, complete blood cell counts should be performed.
Liver impairment
Liver function tests should be performed at baseline and before each cycle.
Weekly monitoring of complete blood counts should be conducted in patients with bilirubin ranging from 1.5 to 3 times ULN, due to decrease of the clearance of irinotecan (see “Pharmacokinetic properties“ section) and thus increasing the risk of hematotoxicity in this population. For patients with a bilirubin > 3 times ULN (see « Contraindications » section).
NAUSEA AND VOMITING
A prophylactic treatment with antiemetics is recommended before each treatment with CAMPTO. Nausea and vomiting have been frequently reported. Patients with vomiting associated with delayed diarrhoea should be hospitalised as soon as possible for treatment.
Acute cholinergic syndrome
If acute cholinergic syndrome appears (defined as early diarrhoea and various other signs and symptoms such as sweating abdominal cramping, myosis and salivation) atropine sulphate (0.25 mg subcutaneously) should be administered unless clinically contraindicated (see « Undesirable Effects » section).
Caution should be exercised in patients with asthma. In patients who experienced an acute and severe cholinergic syndrome, the use of prophylactic atropine sulphate is recommended with subsequent doses of CAMPTO.
RESPIRATORY DISORDERS
Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Interstitial pulmonary disease can be fatal. Risk factors possibly associated with the development of interstitial pulmonary disease include the use of pneumotoxic drugs, radiation therapy and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during irinotecan therapy.
Extravasation
While irinotecan is not a known vesicant, care should be taken to avoid extravasation and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site and application of ice is recommended.
ELDERLY
Due to the greater frequency of decreased biological functions, in particular hepatic function, in elderly patients, dose selection with CAMPTO should be cautious in this population (see « Posology and Method of Administration » section).
Chronic inflammatory bowel disease and/or bowel obstruction
Patients must not be treated with CAMPTO until resolution of the bowel obstruction (see « Contraindications »).
Patients with Impaired Renal Function
Studies in this population have not been conducted. (see « Posology and Method of Administration » and « Pharmacokinetic Properties »).
Cardiac Disorders
Myocardial ischaemic events have been observed following irinotecan therapy predominately in patients with underlying cardiac disease, other known risk factors for cardiac disease, or previous cytotoxic chemotherapy (see « Undesirable Effects » section).
Consequently, patients with known risk factors should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia)
Immunosuppressant Effects/Increased Susceptibility to Infections
Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including irinotecan, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving irinotecan. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Others
Since this medicinal contains sorbitol, it is unsuitable in hereditary fructose intolerance. Infrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting, or sepsis.
Contraceptive measures must be taken during and for at least three months after cessation of therapy.
Concomitant administration of irinotecan with a strong inhibitor (e.g. ketoconazole) or inducer (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, St John's Wort) of CYP3A4 may alter the metabolism of irinotecan and should be avoided (see section 4.5).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out. Since CAMPTO has anticholinesterase activity, drugs with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarising drugs may be antagonised.
Several studies have shown that concomitant administration of CYP3A-inducing anticonvulsant drugs (e.g., carbamazepine, phenobarbital or phenytoin) leads to reduced exposure to irinotecan, SN-38 and SN-38 glucuronide and reduced pharmacodynamic effects. The effects of such anticonvulsant drugs was reflected by a decrease in AUC of SN-38 and SN-38G by 50% or more. In addition to induction of cytochrome P450 3A enzymes, enhanced glucuronidation and enhanced biliary excretion may play a role in reducing exposure to irinotecan and its metabolites.
A study has shown that the co-administration of ketoconazole resulted in a decrease in the AUC of APC of 87% and in an increase in the AUC of SN-38 of 109% in comparison to irinotecan given alone.
Caution should be exercised in patients concurrently taking drugs known to inhibit (e.g., ketoconazole) or induce (e.g., rifampicin, carbamazepine, phenobarbital or phenytoin) drug metabolism by cytochrome P450 3A4. Concurrent administration of irinotecan with an inhibitor/inducer of this metabolic pathway may alter the metabolism of irinotecan and should be avoided (see section 4.4).
In a small pharmacokinetic study (n=5), in which irinotecan 350 mg/m2 was co-administered with St. John's Wort (Hypericum perforatum) 900 mg, a 42% decrease in the active metabolite of irinotecan, SN-38, plasma concentrations was observed.
St. John's Wort decreases SN-38 plasma levels. As a result, St. John's Wort should not be administered with irinotecan (see section 4.3).
Coadministration of 5-fluorouracil/folinic acid in the combination regimen does not change the pharmacokinetics of irinotecan.
Atazanavir sulphate. Coadministration of atazanavir sulfate, a CYP3A4 and UGT1A1 inhibitor, has the potential to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should take this into consideration when co-administering these drugs.
Interactions common to all cytotoxics :
The use of anticoagulants is common due to increased risk of thrombotic events in tumoral diseases. If vitamin K antagonist anticoagulants are indicated, an increased frequency in the monitoring of INR (International Normalised Ratio) is required due to their narrow therapeutic index , the high intra-individual variability of blood thrombogenicity and the possibility of interaction between oral anticoagulants and anticancer chemotherapy.
Concomitant use contraindicated
- Yellow fever vaccine: risk of fatal generalised reaction to vaccines
Concomitant use not recommended
- Live attenuated vaccines (except yellow fever): risk of systemic, possible fatal disease (eg-infections). This risk is increased in subjects who are already immunosuppressed by their underlying disease
Use an inactivated vaccine where this exists (poliomyelitis)
- Phenytoin: Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic drug or risk of toxicity enhancement due to increased hepatic metabolism by phenytoin
Concomitant use to take into consideration
- Ciclosporine, Tacrolimus: Excessive immunosuppression with risk of lymphoproliferation
There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa.
In one study (AVF2107g), irinotecan concentrations were similar in patients receiving bolus CAMPTO/5FU/FA (125 mg/m2 of irinotecan, 500 mg/m2 of 5-FU, and 20 mg/m2 of leucovorin, given in repeated 6-week cycles, comprising weekly treatment for 4 weeks, followed by a 2-week rest) alone and in combination with bevacizumab. Plasma concentrations of SN-38, the active metabolite of irinotecan, were analyzed in a subset of patients (approximately 30 per treatment arm). Concentrations of SN-38 were on average 33% higher in patients receiving bolus CAMPTO/5FU/FA in combination with bevacizumab compared with bolus CAMPTO/5FU/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 grades 3/4 diarrhoea and leukopenia adverse events in the arm receiving bevacizumab. More dose reductions of irinotecan were reported for patients receiving CAMPTO/5FU/FA in combination with bevacizumab.
Patients who develop severe diarrhoea, leukopenia, or neutropenia with the bevacizumab and irinotecan combination should have irinotecan dose modifications as specified in section 4.2 Posology and method of administration.
4.6 Pregnancy And Lactation
Pregnancy
There is no data from the use of irinotecan in pregnant women. Irinotecan has been shown to be embryotoxic and teratogenic in animals. Therefore, based on results from animal studies and the mechanism of action of irinotecan, CAMPTO should not be used during pregnancy unless clearly necessary.
Women of child-bearing potential
Women of childbearing potential and men have to use effective contraception during and up to 1 month and 3 months after treatment respectively.
Fertility
There are no human data on the effect of irinotecan on fertility. In animals adverse effects of irinotecan on the fertility of offspring has been documented (see section 5.3).
Lactation
In lactating rats, 14C-irinotecan was detected in milk. It is not known whether irinotecan is excreted in human milk. Consequently, because of the potential for adverse reactions in nursing infants, breast-feeding must should be discontinued for the duration of CAMPTO therapy (see « Contraindications »)
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 CAMPTO, and advised not to drive or operate machinery if these symptoms occur.
4.8 Undesirable Effects
Undesirable effects detailed in this section refer to irinotecan. There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa. In combination with cetuximab, additional reported undesirable effects were those expected with cetuximab (such as acneform rash 88%). For information on adverse reactions on irinotecan in combination with cetuximab, also refer to their respective summaries of product characteristics.
For information on adverse reactions in combination with bevacizumab, refer to the bevacizumab summary of product characteristics.
Adverse drug reactions reported in patients treated with capecitabine in combination with irinotecan in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy include: Very common, all grade adverse drug reactions: thrombosis/embolism; Common, all grade adverse drug reactions: hypersensitivity reaction, cardiac ischemia/infarction; Common, grade 3 and grade 4 adverse drug reactions: febrile neutropenia. For complete information on adverse reactions of capecitabine, refer to the capecitabine summary product of characteristics.
Grade 3 and Grade 4 adverse drug reactions reported in patients treated with capecitabine in combination with irinotecan and bevacizumab in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy include: Common, grade 3 and grade 4 adverse drug reactions: neutropenia, thrombosis/embolism, hypertension, and cardiac ischemia/infarction. For complete information on adverse reactions of capecitabine and bevacizumab, refer to the respective capecitabine and bevacizumab summary of product characteristics.
The following adverse reactions considered to be possibly or probably related to the administration of CAMPTO have been reported from 765 patients at the recommended dose of 350 mg/m² in monotherapy, and from 145 patients treated by CAMPTO in combination therapy with 5FU/FA in every 2 weeks schedule at the recommended dose of 180 mg/m².
Gastrointestinal disorders
Delayed diarrhoea
Diarrhoea (occurring more than 24 hours after administration) is a dose-limiting toxicity of CAMPTO.
In monotherapy :
Severe diarrhoea was observed in 20 % of patients who follow recommendations for the management of diarrhoea. Of the evaluable cycles, 14 % have a severe diarrhoea. The median time of onset of the first liquid stool was on day 5 after the infusion of CAMPTO.
In combination therapy :
Severe diarrhoea was observed in 13.1 % of patients who follow recommendations for the management of diarrhoea. Of the evaluable cycles, 3.9 % have a severe diarrhoea.
Uncommon cases of pseudo-membranous colitis have been reported, one of which has been documented bacteriologically (Clostridium difficile).
Nausea and vomiting
In monotherapy :
Nausea and vomiting were severe in approximately 10 % of patients treated with antiemetics.
In combination therapy :
A lower incidence of severe nausea and vomiting was observed (2.1 % and 2.8 % of patients respectively).
Dehydration
Episodes of dehydration commonly associated with diarrhoea and/or vomiting have been reported.
Infrequent cases of renal insufficiency, hypotension or cardio-circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting.
Other gastrointestinal disorders
Constipation relative to CAMPTO and/or loperamide has been observed, shared between :
• in monotherapy : in less than 10 % of patients
• in combination therapy : 3.4 % of patients.
Infrequent cases of intestinal obstruction, ileus, or gastrointestinal haemorrhage and rare cases of colitis, including typhlitis, ischemic and ulcerative colitis, were reported. Rare cases of intestinal perforation were reported. Other mild effects include anorexia, abdominal pain and mucositis.
Rare cases of symptomatic or asymptomatic pancreatitis have been associated with irinotecan therapy.
BLOOD DISORDERS
Neutropenia is a dose-limiting toxic effect. Neutropenia was reversible and not cumulative; the median day to nadir was 8 days whatever the use in monotherapy or in combination therapy.
In monotherapy :
Neutropenia was observed in 78.7 % of patients and was severe (neutrophil count < 500 cells/mm3) in 22.6 % of patients. Of the evaluable cycles, 18 % had a neutrophil count below 1,000 cells/mm³ including 7.6 % with a neutrophil count < 500 cells/mm³.
Total recovery was usually reached by day 22.
Fever with severe neutropenia was reported in 6.2 % of patients and in 1.7 % of cycles.
Infectious episodes occurred in about 10.3 % of patients (2.5 % of cycles) and were associated with severe neutropenia in about 5.3 % of patients (1.1 % of cycles), and resulted in death in 2 cases.
Anaemia was reported in about 58.7 % of patients (8 % with haemoglobin < 8 g/dl and 0.9 % with haemoglobin < 6.5 g/dl).
Thrombocytopenia (< 100,000 cells/mm³) was observed in 7.4 % of patients and 1.8 % of cycles with 0.9 % with platelets count
Nearly all the patients showed a recovery by day 22.
In combination therapy :
Neutropenia was observed in 82.5 % of patients and was severe (neutrophil count < 500 cells/mm3) in 9.8 % of patients.
Of the evaluable cycles, 67.3 % had a neutrophil count below 1,000 cells/mm³ including 2.7 % with a neutrophil count < 500 cells/mm³.
Total recovery was usually reached within 7-8 days.
Fever with severe neutropenia was reported in 3.4 % of patients and in 0.9 % of cycles.
Infectious episodes occurred in about 2 % of patients (0.5 % of cycles) and were associated with severe neutropenia in about 2.1 % of patients (0.5 % of cycles), and resulted in death in 1 case.
Anaemia was reported in 97.2 % of patients (2.1 % with haemoglobin < 8 g/dl).
Thrombocytopenia (< 100,000 cells/mm³) was observed in 32.6 % of patients and 21.8 % of cycles. No severe thrombocytopenia (< 50,000 cells/mm³) has been observed.
One case of peripheral thrombocytopenia with antiplatelet antibodies has been reported in the post-marketing experience.
INFECTION AND INFESTATION
Infrequent cases of renal insufficiency, hypotension or cardio-circulatory failure have been observed in patients who experienced sepsis.
GENERAL DISORDERS AND INFUSION SITE REACTIONS
Acute cholinergic syndrome
Severe transient acute cholinergic syndrome was observed in 9 % of patients treated in monotherapy and in 1.4 % of patients treated in combination therapy. The main symptoms were defined as early diarrhoea and various other symptoms such as abdominal pain, conjunctivitis, rhinitis, hypotension, vasodilatation, sweating, chills, malaise, dizziness, visual disturbances, myosis, lachrimation and increased salivation occurring during or within the first 24 hours after the infusion of CAMPTO. These symptoms disappear after atropine administration (see « Special Warning and Special Precautions for Use »).
Asthenia was severe in less than 10 % of patients treated in monotherapy and in 6.2 % of patients treated in combination therapy. The causal relationship to CAMPTO has not been clearly established. Fever in the absence of infection and without concomitant severe neutropenia, occurred in 12 % of patients treated in monotherapy and in 6.2 % of patients treated in combination therapy.
Mild infusion site reactions have been reported although uncommonly.
CARDIAC DISORDER
Rare cases of hypertension during or following the infusion have been reported.
RESPIRATORY DISORDERS
Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Early effects such as dyspnoea have been reported (see section 4.4).
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Alopecia was very common and reversible. Mild cutaneous reactions have been reported although uncommonly.
IMMUNE SYSTEM DISORDERS
Uncommon mild allergy reactions and rare cases of anaphylactic/anaphylactoid reactions have been reported.
Musculoskeletal disorders
Early effects such as muscular contraction or cramps and paresthesia have been reported.
Laboratory tests
In monotherapy, transient and mild to moderate increases in serum levels of either transaminases, alkaline phosphatase or bilirubin were observed in 9.2 %, 8.1 % and 1.8 % of the patients, respectively, in the absence of progressive liver metastasis.
Transient and mild to moderate increases of serum levels of creatinine have been observed in 7.3 % of the patients.
In combination therapy transient serum levels (grades 1 and 2) of either SGPT, SGOT, alkaline phosphatase or bilirubin were observed in 15 %, 11 %, 11 % and 10 % of the patients, respectively, in the absence of progressive liver metastasis. Transient grade 3 were observed in 0 %, 0%, 0 % and 1 % of the patients, respectively. No grade 4 was observed.
Increases of amylase and/or lipase have been very rarely reported.
Rare cases of hypokalemia and hyponatremia mostly related with diarrhea and vomiting have been reported.
NERVOUS SYSTEM DISORDERS
There have been very rare postmarketing reports of transient speech disorders associated with CAMPTO infusions.
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 CAMPTO. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Cytostatic topoisomerase I inhibitor. ATC Code : L01XX19
Experimental data
Irinotecan is a semi-synthetic derivative of camptothecin. It is an antineoplastic agent which acts as a specific inhibitor of DNA topoisomerase I. It is metabolised by carboxylesterase in most tissues to SN-38, which was found to be more active than irinotecan in purified topoisomerase I and more cytotoxic than irinotecan against several murine and human tumour cell lines. The inhibition of DNA topoisomerase I by irinotecan or SN-38 induces single-strand DNA lesions which blocks the DNA replication fork and are responsible for the cytotoxicity. This cytotoxic activity was found time-dependent and was specific to the S phase.
In vitro, irinotecan and SN-38 were not found to be significantly recognised by the P -glycoprotein MDR, and displays cytotoxic activities against doxorubicin and vinblastine resistant cell lines.
Furthermore, irinotecan has a broad antitumor activity in vivo against murine tumour models (P03 pancreatic ductal adenocarcinoma, MA16/C mammary adenocarcinoma, C38 and C51 colon adenocarcinomas) and against human xenografts (Co-4 colon adenocarcinoma, Mx-1 mammary adenocarcinoma, ST-15 and SC-16 gastric adenocarcinomas). Irinotecan is also active against tumors expressing the P-glycoprotein MDR (vincristine- and doxorubicin-resistant P388 leukaemia's).
Beside the antitumor activity of CAMPTO, the most relevant pharmacological effect of irinotecan is the inhibition of acetylcholinesterase.
Clinical data
In combination therapy for the first-line treatment of metastatic colorectal carcinoma
In combination therapy with Folinic Acid and 5-Fluorouracil
A phase III study was performed in 385 previously untreated metastatic colorectal cancer patients treated with either every 2 weeks schedule (see « Posology and method of administration ») or weekly schedule regimens. In the every 2 weeks schedule, on day 1, the administration of CAMPTO at 180 mg/m² once every 2 weeks is followed by infusion with folinic acid (200 mg/m² over a 2-hour intravenous infusion) and 5-fluorouracil (400 mg/m² as an intravenous bolus, followed by 600 mg/m² over a 22-hour intravenous infusion). On day 2, folinic acid and 5-fluorouracil are administered at the same doses and schedules. In the weekly schedule, the administration of CAMPTO at 80 mg/m² is followed by infusion with folinic acid (500 mg/m² over a 2-hour intravenous infusion) and then by 5-fluorouracil (2300 mg/m² over a 24-hour intravenous infusion) over 6 weeks.
In the combination therapy trial with the 2 regimens described above, the efficacy of CAMPTO was evaluated in 198 treated patients:
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5FU : 5-fluorouracil
FA : folinic acid
NS : Non Significant
*: As per protocol population analysis
In the weekly schedule, the incidence of severe diarrhoea was 44.4% in patients treated by CAMPTO in combination with 5FU/FA and 25.6% in patients treated by 5FU/FA alone. The incidence of severe neutropenia (neutrophil count < 500 cells/mm3) was 5.8% in patients treated by CAMPTO in combination with 5FU/FA and in 2.4% in patients treated by 5FU/FA alone.
Additionally, median time to definitive performance status deterioration was significantly longer in CAMPTO combination group than in 5FU/FA alone group (p=0.046).
Quality of life was assessed in this phase III study using the EORTC QLQ-C30 questionnaire. Time to definitive deterioration constantly occurred later in the CAMPTO groups. The evolution of the Global Health Status/Quality of life was slightly better in CAMPTO combination group although not significant, showing that efficacy of CAMPTO in combination could be reached without affecting the quality of life.
In combination therapy with bevazicumab
A phase III randomised, double-blind, active-controlled clinical trial evaluated bevacizumab in combination with CAMPTO/5FU/FA as first-line treatment for metastatic carcinoma of the colon or rectum (Study AVF2107g). The addition of bevacizumab to the combination of CAMPTO/5FU/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 summarized in the table below.
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