Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
For additional contraindications of cetuximab or bevacizumab or capecitabine, refer to the product information for these medicinal products.
The use of CAMPTO should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a physician qualified in the use of anticancer chemotherapy.
Given the nature and incidence of adverse events, CAMPTO will only be prescribed in the following cases after the expected benefits have been weighted against the possible therapeutic risks:
When CAMPTO is used in monotherapy, it is usually prescribed with the every-3-week-dosage schedule. However, the weekly-dosage schedule (see section 5) may be considered in patients who may need a closer follow-up or who are at particular risk of severe neutropenia.
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 ≥ 2 and women. If not properly treated, diarrhoea can be life-threatening, especially if the patient is concomitantly neutropenic.
As soon as the first liquid stool occurs, the patient should start drinking large volumes of beverages containing electrolytes and an appropriate antidiarrhoeal therapy must be initiated immediately. This antidiarrhoeal treatment will be prescribed by the department where CAMPTO has been administered. After discharge from the hospital, the patients should obtain the prescribed medicinal products so that they can treat the diarrhoea as soon as it occurs. In addition, they must inform their physician or the department administering 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 antidiarrhoeal treatment, a prophylactic broad-spectrum antibiotic should be given, when diarrhoea is associated with severe neutropenia (neutrophil count <500 cells/mm³).
In addition to the antibiotic treatment, hospitalisation is recommended for management of the diarrhoea, in the following cases:
Loperamide should not be given prophylactically, even in patients who experienced delayed diarrhoea at previous cycles.
In patients who experienced severe diarrhoea, a reduction in dose is recommended for subsequent cycles (see section 4.2).
In clinical studies, the frequency of NCI CTC Grade 3 and 4 neutropenia has been significantly higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation. Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more have also had a significantly greater likelihood of experiencing first-cycle Grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL.
Weekly monitoring of complete blood cell counts is recommended during CAMPTO treatment. Patients should be aware of the risk of neutropenia and the significance of fever. Febrile neutropenia (temperature >38°C and neutrophil count ≤1,000 cells/mm³) should be urgently treated in the hospital with broad-spectrum intravenous antibiotics.
In patients who experienced severe haematological events, a dose reduction is recommended for subsequent administration (see section 4.2).
There is an increased risk of infections and haematological toxicity in patients with severe diarrhoea. In patients with severe diarrhoea, complete blood cell counts should be performed.
Liver function tests should be performed at baseline and before each cycle.
Weekly monitoring of complete blood counts should be conducted in patients with bilirubin ranging from 1.5 to 3 times the ULN, due to decrease of the clearance of irinotecan (see section 5.2) and thus increasing the risk of hematotoxicity in this population. For patients with a bilirubin > 3 times the ULN (see section 4.3).
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.
If acute cholinergic syndrome appears (defined as early diarrhoea and various other signs and symptoms such as sweating, abdominal cramping, myosis and salivation), atropine sulfate (0.25 mg subcutaneously) should be administered unless clinically contraindicated (see section 4.8).
These symptoms may be observed during or shortly after infusion of irinotecan, are thought to be related to the anticholinesterase activity of the irinotecan parent compound, and are expected to occur more frequently with higher irinotecan doses.
Caution should be exercised in patients with asthma. In patients who experienced an acute and severe cholinergic syndrome, the use of prophylactic atropine sulfate is recommended with subsequent doses of CAMPTO.
Interstitial lung disease presenting as lung infiltration is uncommon during irinotecan therapy. Interstitial lung disease can be fatal. Risk factors possibly associated with the development of interstitial lung disease include the use of pneumotoxic medicinal products, radiation therapy and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during irinotecan therapy.
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.
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 section 4.2).
Patients must not be treated with CAMPTO until resolution of the bowel obstruction (see section 4.3).
Increases in serum creatinine or blood urea nitrogen have been observed. There have been cases of acute renal failure. These events have generally been attributed to complications of infection or to dehydration related to nausea, vomiting, or diarrhoea. Rare instances of renal dysfunction due to tumour lysis syndrome have also been reported.
Patients who have previously received pelvic/abdominal irradiation are at increased risk of myelosuppression following the administration of irinotecan. Physicians should use caution in treating patients with extensive prior irradiation (e.g. > 25% of bone marrow irradiated and within 6 weeks prior to start of treatment with irinotecan). Dosing adjustment may apply to this population (see section 4.2).
Myocardial ischaemic events have been observed following irinotecan therapy predominately in patients with underlying cardiac disease, other known risk factors for cardiac disease, or previous cytotoxic chemotherapy (see section 4.8).
Consequently, patients with known risk factors should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
Irinotecan has been rarely associated with thromboembolic events (pulmonary embolism, venous thrombosis, and arterial thromboembolism) in patients presenting with multiple risk factors in addition to the underlying neoplasm.
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.
Women of childbearing potential and men have to use effective contraception during and up to 1 month and 3 months after treatment respectively.
Concomitant administration of irinotecan with a strong inhibitor (e.g. ketoconazole) or inducer (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin) of CYP3A4 may alter the metabolism of irinotecan and should be avoided (see section 4.5).
Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Yellow fever vaccine: Risk of fatal generalised reaction to vaccines
Saint John’s Wort: Decrease in the active metabolite of irinotecan, SN-38, plasma levels. 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. As a result, St. John’s Wort should not be administered with irinotecan.
Live attenuated vaccines: Risk of generalised reaction to vaccines, possibly fatal. Concomitant use is contraindicated during treatment with irinotecan and for 6 months following discontinuation of chemotherapy. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Concurrent administration of irinotecan with a strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) may alter the metabolism of irinotecan and should be avoided (see section 4.4):
Strong CYP3A4 and/or UGT1A1 inducing medicinal products: (e.g. rifampicin, carbamazepine, phenobarbital or phenytoin):
Risk of reduced exposure to irinotecan, SN-38 and SN-38 glucuronide and reduced pharmacodynamic effects. Several studies have shown that concomitant administration of CYP3A4-inducing anticonvulsant medicinal products leads to reduced exposure to irinotecan, SN-38 and SN-38 glucuronide and reduced pharmacodynamic effects. The effects of such anticonvulsant medicinal products were reflected by a decrease in AUC of SN-38 and SN-38G by 50% or more. In addition to induction of CYP3A4 enzymes, enhanced glucuronidation and enhanced biliary excretion may play a role in reducing exposure to irinotecan and its metabolites. Additionally with phenytoin: Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic medicinal products.
Strong CYP3A4 inhibitors: (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, protease inhibitors, clarithromycine, erythromycine, telithromycine):
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.
UGT1A1 inhibitors: (e.g. atazanavir, ketoconazole, regorafenib)
Risk to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should take this into consideration if the combination is unavoidable.
Other CYP3A4 inhibitors: (e.g. crizotinib, idelalisib)
Risk of increase in irinotecan toxicity, due to a decrease in irinotecan metabolism by crizotinib or idelalisib.
Vitamin K antagonists: Increased risk of haemorrhage and thrombotic events in tumoral diseases. If vitamin K antagonists are indicated, an increased frequency in the monitoring of INR (International Normalised Ratio) is required.
Immunodepressant agents (e.g. ciclosporine, tacrolimus): Excessive immunosuppression with risk of lymphoproliferation.
Neuromuscular blocking agents: Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out. Since CAMPTO has anticholinesterase activity, medicinal products with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarising medicinal products may be antagonised.
5-fluorouracil/folinic acid: Coadministration of 5-fluorouracil/folinic acid in the combination regimen does not change the pharmacokinetics of irinotecan.
Bevacizumab: Results from a dedicated drug-drug interaction trial demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38. However, this does not preclude any increase of toxicities due to their pharmacological properties.
Cetuximab: There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa
Women of childbearing potential and men have to use effective contraception during and up to 1 month and 3 months after treatment respectively.
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.
In lactating rats, 14C-irinotecan was detected in milk. It is unknown whether irinotecan is excreted in human milk. Consequently, because of the potential for adverse reactions in nursing infants, breast-feeding should be discontinued for the duration of CAMPTO therapy (see section 4.3).
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).
CAMPTO has moderate influence on the 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.
Adverse reaction data have been extensively collected from studies in metastatic colorectal cancer; the frequencies are presented below. The adverse reactions for other indications are expected to be similar to those for colorectal cancer.
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.
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.
Very commonly severe transient acute cholinergic syndrome was observed.
The main symptoms were defined as early diarrhoea and various other symptoms such as abdominal pain, sweating, myosis and increased salivation occurring during or within the first 24 hours after the infusion of CAMPTO. These symptoms disappear after atropine administration (see section 4.4).
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. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), and very rare (<1/10,000).
Adverse Reactions Reported with CAMPTO in Monotherapy (350 mg/m² every 3 weeks schedule):
Common: Infection
Very common: Neutropenia, Anaemia
Common: Thrombocytopenia, Febrile neutropenia
Very common: Decreased appetite
Very common: Cholinergic syndrome
Very common: Diarrhoea, Vomiting, Nausea, Abdominal pain
Common: Constipation
Very common: Alopecia (reversible)
Very common: Mucosal inflammation, Pyrexia, Asthenia
Common: Blood creatinine increased, Transaminases (ALT and AST) increased, Blood bilirubin increased, Blood alkaline phosphatase increased
Severe diarrhoea was observed in 20% of patients who follow recommendations for the management of diarrhoea. Of the evaluable cycles, 14% have severe diarrhoea. The median time of onset of the first liquid stool was on day 5 after the infusion of CAMPTO.
Nausea and vomiting were severe in approximately 10% of patients treated with antiemetics.
Constipation has been observed in less than 10% of patients.
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.
Febrile neutropenia was reported in 6.2% of patients and in 1.7% of cycles.
Infections occurred in about 10.3% of patients (2.5% of cycles) and were associated with severe neutropenia in about 5.3% of patients (1.1% of cycles), and resulted in death in 2 cases.
Anaemia was reported in about 58.7% of patients (8% with haemoglobin <8 g/dl and 0.9% with haemoglobin <6.5 g/dl).
Thrombocytopenia (<100,000 cells/mm³) was observed in 7.4% of patients and 1.8% of cycles with 0.9% with platelets count ≤ 50,000 cells/mm³ and 0.2% of cycles.
Nearly all the patients showed a recovery by day 22.
Acute cholinergic syndrome severe transient acute cholinergic syndrome was observed in 9% of patients treated in monotherapy.
Asthenia was severe in less than 10% of patients treated in monotherapy. The causal relationship to CAMPTO has not been clearly established.
Pyrexia in the absence of infection and without concomitant severe neutropenia, occurred in 12% of patients treated in monotherapy.
Laboratory tests: 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.
Adverse reactions 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 adverse reactions were those expected with cetuximab (such as dermatitis acneiform 88%). For information on adverse reactions on irinotecan in combination with cetuximab, also refer to their respective 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, myocardial ischaemia/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 myocardial ischaemia/infarction. For complete information on adverse reactions of capecitabine and bevacizumab, refer to the respective capecitabine and bevacizumab summary of product characteristics.
Grade 3 hypertension was the principal significant risk involved with the addition of bevacizumab to bolus CAMPTO/5-FU/FA. In addition, there was a small increase in the Grade ¾ chemotherapy adverse events of diarrhoea and leukopenia with this regimen compared to patients receiving bolus CAMPTO/5-FU/FA alone. For other information on adverse reactions in combination with bevacizumab, refer to the bevacizumab summary of product characteristics.
CAMPTO has been studied in combination with 5-FU and FA for metastatic colorectal cancer.
Safety data of adverse reactions from clinical studies demonstrate very commonly observed NCI Grade 3 or 4 possibly or probably-related adverse events in the blood and the lymphatic system disorders, gastrointestinal disorders, and skin and subcutaneous tissue disorders MedDRA System Organ Classes.
The following adverse reactions considered to be possibly or probably related to the administration of CAMPTO have been reported 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.
Adverse Reactions Reported with CAMPTO in Combination Therapy (180 mg/m² every 2 weeks schedule):
Common: Infection
Very common: Thrombocytopenia, Neutropenia, Anaemia
Common: Febrile neutropenia
Very common: Decreased appetite
Very common: Cholinergic syndrome
Very common: Diarrhoea, Vomiting, Nausea
Common: Abdominal pain, Constipation
Very common: Alopecia (reversible)
Very common: Mucosal inflammation, Asthenia
Common: Pyrexia
Very common: Transaminases (ALT and AST) increased, Blood bilirubin increased, Blood alkaline phosphatase increased
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.
A lower incidence of severe nausea and vomiting was observed (2.1% and 2.8% of patients respectively).
Constipation relative to CAMPTO and/or loperamide has been observed in 3.4% of patients.
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.
Febrile neutropenia was reported in 3.4% of patients and in 0.9% of cycles.
Infections 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.
Acute cholinergic syndrome severe transient acute cholinergic syndrome was observed in 1.4% of patients treated in combination therapy.
Asthenia was severe in 6.2% of patients treated in combination therapy. The causal relationship to CAMPTO has not been clearly established.
Pyrexia in the absence of infection and without concomitant severe neutropenia, occurred in 6.2% of patients treated in combination therapy.
Laboratory tests: 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 hypokalaemia and hyponatraemia mostly related with diarrhoea and vomiting have been reported.
The following additional drug-related events have been reported in clinical studies with irinotecan: pain, sepsis, anorectal disorder, GI candida infection, hypomagnesaemia, rash, skin signs, gait disturbance, confusion, headache, syncope, flushing, bradycardia, urinary tract infection, breast pain, gamma-glutamyltransferase increased, extravasation, and tumour lysis syndrome, cardiovascular disorders (angina pectoris, cardiac arrest, myocardial infarction, myocardial ischaemia, peripheral vascular disorder, vascular disorder), and thromboembolic events (arterial thrombosis, cerebral infarction, cerebrovascular accident, deep vein thrombosis, peripheral embolism, pulmonary embolism, thrombophlebitis, thrombosis, and sudden death) (see section 4.4).
Frequencies from post-marketing surveillance are not known (cannot be estimated from available data).
Infections and infestations: Pseudomembranous colitis one of which has been documented bacteriologically (Clostridium difficile), Sepsis, Fungal infections*, Viral infections†
lood and lymphatic system disorders: Thrombocytopenia with antiplatelet antibodies
mmune system disorders: Hypersensitivity, Anaphylactic reaction
etabolism and nutrition disorders: Dehydration (due to diarrhoea and vomiting), Hypovolaemia
Nervous system disorders: Speech disorder generally transient in nature, in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan, Paraesthesia, Muscular contractions involuntary
Cardiac disorders: Hypertension (during or after infusion), Cardio circulatory failure‡
Vascular disorders: Hypotension‡
Respiratory, thoracic and mediastinal disorders: Interstitial lung disease presenting as lung infiltration is uncommon during irinotecan therapy; early effects such as dyspnoea have been reported (see section 4.4), Dyspnoea (see section 4.4), Hiccups
Gastrointestinal disorders: Intestinal obstruction, Ileus: cases of ileus without preceding colitis have also been reported, Megacolon, Gastrointestinal haemorrhage, Colitis; in some cases, colitis was complicated by ulceration, bleeding, ileus, or infection, Typhlitis, Colitis ischaemic, Colitis ulcerative, Symptomatic or asymptomatic pancreatic enzymes increased, Intestinal perforation
Hepatobiliary disorders: Steatohepatitis, Hepatic steatosis
Skin and subcutaneous tissue disorders: Skin reaction
Musculoskeletal and connective tissue disorders: Cramps
Renal and urinary disorders: Renal impairment and acute renal failure generally in patients who become infected and/or volume depleted from severe gastrointestinal toxicities‡, Renal insufficiency‡
General disorders and administration site conditions: Infusion site reaction
Investigations: Amylase increased, Lipase increased, Hypokalaemia, Hyponatraemia mostly related with diarrhoea and vomiting, Transaminases increased (i.e. AST and ALT) in the absence of progressive liver metastasis have been very rarely reported.
* e.g. Pneumocystis jirovecii pneumonia, bronchopulmonary aspergillosis, systemic candida.
† e.g. Herpes zoster, influenza, hepatitis B reactivation, cytomegalovirus colitis.
‡ 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, or sepsis.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
By reporting side effects you can help provide more information on the safety of this medicine.
None known.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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