Irinotecan 40 Mg/2 Ml/100 Mg/5 Ml/300 Mg/15 Ml/500 Mg/25 Ml

IRINOTECAN FKSA is indicated for the treatment of patients with advanced colorectal cancer with a WHO performance status of 2 or lower:

• In combination with 5 - fluorouracil and folinic acid in patients without prior chemotherapy for advanced disease.
• As a single medicine in patients who have failed an established 5 - fluorouracil containing treatment regimen.

Posology

IRINOTECAN FKSA solution for infusion should be infused into a peripheral or central vein.

Recommended dosage in monotherapy (for previously treated patients): 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)

Recommended dosage in combination therapy (for previously untreated patients): Safety and efficacy of IRINOTECAN FKSA in combination with 5 - fluorouracil (5FU) and folinic acid (FA) have been assessed with either of the following schedules (see section 5.1)

IRINOTECAN FKSA plus 5FU/FA in weekly schedule: 80 mg/m2 administered as a weekly intravenous infusion over a 30 - to 90 - minute period followed by infusion with folinic acid and then by 5 - fluorouracil over 6 weeks. This treatment is followed by a week rest. The full dosage regimen is 80 mg/m2 as a 30 - to 90 - minute infusion on Day 1 and then weekly for 6 weeks. Folinic acid 500 mg/m2 IV as a 2 - hour infusion, followed by 5 - fluorouracil 2 000 mg/m2 IV as 24 - hour infusion, Day 1 and then weekly for 6 weeks. The treatment is to be repeated every 7 weeks.

IRINOTECAN FKSA plus 5FU/FA in every 2 weeks schedule: 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. The full dosage regimen is 180 mg/m2 IV as a 30 - to 90 - minute infusion on Day 1 only. Folinic acid 200 mg/m2 IV as a 2 - hour infusion, followed by 5 - fluorouracil 400 mg/m2 IV bolus, followed by 5 - fluorouracil 600 mg/m2 IV as a 22 - hour infusion. The folinic acid and 5 - fluorouracil are repeated for two consecutive days. Repeat the cycle every two weeks.

Dosage adjustments

Delayed dosing: IRINOTECAN FKSA should not be administered until the neutrophil count remains above 1 500 cells/mm3. In patients who experienced severe neutropenia or severe gastrointestinal adverse events such as diarrhoea, nausea and vomiting, dosing of IRINOTECAN FKSA should be delayed until there has been a full recovery of these effects, especially diarrhoea. IRINOTECAN FKSA 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. This must be strictly adhered to. At the start of a subsequent infusion of therapy, the dose of IRINOTECAN FKSA and 5FU when applicable, should be decreased according to the worst grade of adverse events observed in the prior infusion. Treatment should be delayed by 1 to 2 weeks to allow recovery from treatment - related adverse events.

With the following adverse events, a dose reduction of 15 to 20 % should be applied for IRINOTECAN FKSA 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).

Treatment duration: Treatment with IRINOTECAN FKSA should be continued until there is an objective progression of the disease or an unacceptable toxicity.

Special populations

Patients with impaired hepatic function:

• Patients with a bilirubin >1,5 times the ULN should not be treated with IRINOTECAN FKSA. In patients with a bilirubin u22641,5 times the upper limit of the normal range (ULN), a dose of 350 mg/m2 IRINOTECAN FKSA is recommended.
• In patients with bilirubin >1 and u22641,5 times the upper limit of the normal range (ULN), the risk of severe neutropenia is increased. Thus, frequent monitoring of complete blood counts should be conducted in this patient population.

Patients with impaired renal function: No specific pharmacokinetic studies have been performed in patients with renal impairment. (see sections 4.4 and 5.2).

Elderly: No specific pharmacokinetic studies have been performed in the elderly. However, the dose should be chosen carefully in this population due to their greater frequency of decreased hepatic, renal or cardiac function. This population should require more intense surveillance (see section 4.4).

Paediatric population: The safety and efficacy of IRINOTECAN FKSA in children below 18 years of age have not yet been established. No data is available.

Method of administration: Intravenous administration. Precautions to be taken before handling or administering the medicine. For instructions on dilution of the medicine before administration, see section 6.6.

• Patients with a history of severe hypersensitivity reactions to irinotecan hydrochloride trihydrate or to one of the excipients of IRINOTECAN FKSA. (see section 6.1)
• Chronic inflammatory bowel disease, and/or bowel obstruction or ileus. Patients should not be treated with IRINOTECAN FKSA until resolution of the ileus. (see section 4.4)
• Severe bone marrow failure, pre - existing or treatment - related.
• WHO performance status > 2.
• Pregnancy and breastfeeding (see section 4.4 and 4.6). Women of childbearing age receiving IRINOTECAN FKSA should be advised to avoid becoming pregnant and to inform the treating medical practitioner immediately should this occur (see section 4.6).
• Bilirubin >1,5 times the upper limit of the normal range.
• Children: The safety and efficacy of IRINOTECAN FKSA in children below 18 years of age have not been established.
• Concomitant use of the following: St Johnu2019s Wort, ketoconazole, yellow fever vaccine. (see section 4.5)
• Live attenuated vaccine (see section 4.5)

IRINOTECAN FKSA should be used in patients with a good performance status of less than 2. Given the nature and frequency of adverse events, the expected benefit must be balanced in case of risk factors, especially WHO performance status = 2 (or Karnofsky Index <50).

When IRINOTECAN FKSA is used in monotherapy, it is usually prescribed with the every - 3 - week dosage schedule. However, the weekly - dosage schedule (see section 5) may be considered in patients who may need a closer follow - up or who are at particular risk of severe neutropenia.

Delayed diarrhoea: Apart from the diarrhoea shortly after the infusion of IRINOTECAN FKSA, patients should be aware of the high risk of delayed diarrhoea occurring more than 24 hours after the administration of IRINOTECAN FKSA and at any time before the next cycle. In monotherapy, the median time of onset of the first liquid stool was on Day 5 after the infusion of IRINOTECAN FKSA. Patients should quickly inform their medical practitioner 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 hyperleukocytosis and those with performance status u2265 2. If not properly treated, the use of IRINOTECAN FKSA should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a qualified oncologist. It is strongly recommended that IRINOTECAN FKSA be administered only in healthcare institutions with adequately equipped facilities, including an intensive care unit.

Premedication with anti - emetic medicines are recommended in order to reduce nausea and vomiting associated with IRINOTECAN FKSA treatment. This treatment should be started at least 30 minutes before the infusion.

In all instances where the use of IRINOTECAN FKSA is considered for chemotherapy, it is especially important to ensure that the patient understands the need for sufficiently prolonged antidiarrhoeal treatment and abundant fluid intake. In rare cases where it is predictable that the patient would comply poorly with the guidances for the management of side effects, a strict follow - up of the patient by the treating medical practitioner or hospitalisation is recommended.

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 IRINOTECAN FKSA has been administered. After discharge from the hospital the patients should obtain the prescribed medicines so that they can treat the diarrhoea as soon as it occurs. In addition, they must inform their medical practitioner or the department administering IRINOTECAN FKSA that diarrhoea is occurring.

The currently recommended antidiarrhoeal treatment is 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 case 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:

• Diarrhoea associated with fever.
• Severe diarrhoea (requiring intravenous hydration).
• Diarrhoea persisting beyond 48 hours following the initiation of high - dose loperamide therapy.

Loperamide should not be given prophylactically, even in patients who experienced delayed diarrhoea at previous cycles. In patients who experienced severe diarrhoea, a reduction in dose is recommended for subsequent cycles (see section 4.2).

Haematology: 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 should be performed during IRINOTECAN FKSA treatment. Patients should be aware of the risk of infection and the significance of a fever. Febrile neutropenia (temperature u2265 38 u00b0C and neutrophil count u2264 1 000 cells/mm3) should be urgently treated in the hospital with broad spectrum intravenous antibiotics. IRINOTECAN FKSA administration should be delayed until the neutrophil count is u22651 500 cells/mm3. In patients who experienced severe asymptomatic neutropenia (< 500 cells/mm3), fever or infections associated with neutropenia, the dose of IRINOTECAN FKSA should be reduced. In patients who experienced severe haematologic 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. Significant correlations were observed between haematological toxicity (decrease in white blood cells and neutrophils at nadir) or diarrhoea intensity and both irinotecan and metabolite SN - 38 AUC values in monotherapy.

Liver impairment: Liver function tests should be performed at baseline and before each cycle. Patients with impaired liver function (bilirubin > 1,0 and u2264 1,5 times the upper limit of the normal range (ULN) and transaminases 5 times ULN) are at greater risk of developing severe neutropenia or febrile neutropenia and should be closely monitored, including complete blood counts. 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. IRINOTECAN FKSA should not be used in patients with a bilirubin > 1,5 times the ULN and the patients with bilirubin > ULN should be followed with caution. In patients with a bilirubin of < 1,5 times ULN a dose of 350 mg/m2 is recommended once every 3 weeks (see section 4.2).

Patients with reduced UGT1A1 activity: Patients that are UGT1A1 poor metabolisers, such as patients with Gilbertu2019s syndrome (e.g. homozygous for UGT1A1*28 or *6 variants) are at increased risk for severe neutropenia and diarrhoea following irinotecan treatment. This risk increases with the irinotecan dose level. Although a precise dose reduction in starting dose has not been established, a reduced irinotecan starting dose should be considered for patients that are UGT1A1 poor metabolisers, especially patients who are administered doses >180 mg/m2 or frail patients. Consideration should be given to applicable clinical guidelines for dose recommendations in this patient population. Subsequent doses may be increased based on individual patient tolerance to treatment. UGT1A1 genotyping can be used to identify patients at increased risk of severe neutropenia and diarrhoea, however the clinical utility of pre - treatment genotyping is uncertain, since UGT1A1 polymorphism does not account for all the toxicity seen from irinotecan therapy (see section 5.2).

Nausea and vomiting: Prophylactic treatment with an anti - emetic is recommended before each treatment with IRINOTECAN FKSA. 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 an acute cholinergic syndrome appears (defined as early diarrhoea and a group of symptoms such as sweating, abdominal cramping, lachrymation, miosis and salivation), atropine sulphate (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. These symptoms may disappear after atropine administration. Caution should be exercised in patients with asthma. In patients who experienced an acute and severe cholinergic syndrome, the use of prophylactic atropine sulphate is recommended with subsequent doses of IRINOTECAN FKSA.

Immunosuppressant effects/increased susceptibility to infections: Administration of live or live - attenuated vaccines in patients immunocompromised by IRINOTECAN FKSA, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving IRINOTECAN FKSA. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Respiratory disorders: 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 medicine, 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 hepatic, renal or cardiac function in an elderly patient, dose selection with IRINOTECAN FKSA should be cautious in this population.

Chronic inflammatory bowel disease and/or bowel obstruction: Patients must not be treated with IRINOTECAN FKSA until resolution of the bowel obstruction (see section 4.3).

Renal function: 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.

Irradiation therapy: 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).

Cardiac disorders: Myocardial ischaemic events have been observed following irinotecan therapy predominately in patients with underlying cardiac disease, other known risk factors for cardiac disease, or previous cytotoxic chemotherapy (see section 4.8). Consequently, patients with known risk factors should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

Vascular disorders: 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.

Others: 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. 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).

Concomitant use contraindicated (see section 4.3)

• Yellow fever vaccine: Risk of fatal generalised reaction to vaccines.
• Saint John's Wort: When St. John's Wort (Hypericum perforatum) is co - administered with Irinotecan there may be a decrease in the active metabolite of irinotecan, SN - 38, plasma levels. 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.

Concomitant use not recommended (see section 4.4)

Concurrent administration of irinotecan with a strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) may alter the metabolism of irinotecan of should be avoided (see section 4.4):

Strong CYP3A4 and/or UGT1A1 inducing medicines: IRINOTECAN FKSA is partly metabolised by cytochrome P450 CYP3A isoenzymes. Inducers of this system e.g. rifampicin, carbamazepine, phenobarbital or phenytoin, reduce exposure to irinotecan and its active metabolite SN - 38. 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 medicines leads to reduced exposure to irinotecan, SN - 38 and SN - 38 glucuronide and reduced pharmacodynamic effects. The effects of such anticonvulsant medicines 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. Consideration should be given to starting or substituting non - enzyme inducing anticonvulsants at least one week prior to initiation of IRITERO therapy in patients requiring anticonvulsant treatment.

Additionally, with phenytoin: Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic medicines.

Strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, protease inhibitors, clarithromycin, erythromycin, telithromycin): 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, idelalisib.

Caution for use

Vitamin K antagonists: The use of anticoagulants is common due to increased risk of haemorrhage and thrombotic events in tumoural diseases. If vitamin K antagonist anticoagulants are indicated, an increased frequency of monitoring International Nationalised Ratio (INR) 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 to take into consideration

Immunodepressant medicines: (e.g. ciclosporine, tacrolimus): Excessive immunosuppression with risk of lymphoproliferation.

Neuromuscular blocking medicines: Interaction between IRINOTECAN FKSA and neuromuscular blocking medicines cannot be ruled out. Medicines with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non - depolarising medicines may be antagonised. Excess acetylcholine may impair the muscle relaxant action of the non - depolarising medicines and may impair the return of normal muscle tone at the end of anaesthesia. Loperamide should not be given prophylactically.

Other combinations

5 - fluorouracil/folinic acid: Coadministration of 5 - fluorouracil/ folinic acid in the combination regimen does not change the pharmacokinetic parameters of IRINOTECAN FKSA. The pharmacokinetic parameters of IRINOTECAN FKSA are comparable to those observed in monotherapy.

Bevacizumab: In one study, irinotecan plasma concentrations were similar in patients receiving irinotecan alone and in combination with bevacizumab. Concentrations of SN - 38, the active metabolite of irinotecan, were analysed in a subset of patients. Concentrations of SN - 38 were on average 33 % higher in patients receiving irinotecan in combination with bevacizumab compared with irinotecan 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 leukopenia adverse events. More dose reductions of irinotecan were reported for patients receiving irinotecan in combination with bevacizumab.

Cetuximab: There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa.

Antineoplastic medicines: The adverse effects of IRINOTECAN FKSA, such as myelosuppression and diarrhoea, is expected to be exacerbated by other antineoplastic medicines having a similar adverse - effect profile.

Dexamethasone: Lymphocytopenia has been reported in patients receiving. IRINOTECAN FKSA, and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of lymphocytopenia. Hyperglycaemia has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of IRINOTECAN FKSA. It is probable that dexamethasone, given as antiemetic prophylaxis, contributed to hyperglycaemia in some patients.

Laxatives: Laxative use during therapy with IRINOTECAN FKSA is expected to worsen the incidence or severity of diarrhoea.

Diuretics: Dehydration secondary to vomiting and/or diarrhoea may be induced by IRINOTECAN FKSA. The medical practitioner may wish to withhold diuretics during dosing with IRINOTECAN FKSA and during periods of active vomiting or diarrhoea.

Azole antifungals: IRINOTECAN FKSA clearance is greatly reduced in patients receiving concomitant azole antifungals, leading to increased exposure to the active metabolite, SN - 38. Azole antifungals should be discontinued at least 1 week prior to starting IRINOTECAN FKSA therapy and should not be administered during IRINOTECAN FKSA therapy (see section 4.3).

Contraception

Due to the potential for genotoxicity, advise female patients of reproductive potential to use highly effective contraception during treatment and for 6 months after the last dose of irinotecan (see section 4.4). Due to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of irinotecan (see section 4.4).

Pregnancy

IRINOTECAN FKSA is contraindicated in pregnancy. There are limited data from the use of irinotecan in pregnant women. Irinotecan has been shown to be embryotoxic and teratogenic in animals (see section 5.3). Therefore, based on results from animal studies and the mechanism of action of irinotecan, IRINOTECAN FKSA should not be used during pregnancy. Women of childbearing potential should not be started on irinotecan until pregnancy is excluded. Pregnancy should be avoided if either partner is receiving irinotecan.

Breastfeeding

IRINOTECAN FKSA is contraindicated in lactation. The available data are limited but suggested that irinotecan and its metabolite are excreted in human milk. Consequently, because of the potential for adverse reactions in nursing infants, breast - feeding should be discontinued for the duration of IRINOTECAN FKSA therapy (see sections 4.3 and 4.4).

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). Prior to starting to take IRINOTECAN FKSA consider advising patients on the preservation of gametes.

Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of IRINOTECAN FKSA, and advised not to drive or operate machinery if these symptoms occur.

a. Summary of the safety profile

Dose - limiting adverse reactions of IRINOTECAN FKSA 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 is reversible and not cumulative. Severe transient acute cholinergic syndrome may be observed. The main symptoms are 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 IRINOTECAN FKSA. These symptoms disappear after atropine administration (see section 4.4).

b. Tabulated list of adverse reactions

MedDRA system organ class Frequency Adverse reactions Infections and infestations Frequent Neutropenic infection Frequency Pseudomembranous colitis, Sepsis, Fungal infections*, Viral unknown infectionsu2020 Blood and lymphatic system disorders Frequent Leukopenia, neutropenia, anaemia, thrombocytopenia. febrile neutropenia Frequency unknown Peripheral thrombocytopenia with antiplatelet antibodies Immune system disorders Less frequent Hypersensitivity Frequency unknown Anaphylactic, anaphylactoid reactions. Endocrine disorders Less frequent Diaphoresis, increased salvation Metabolism and nutrition disorders Frequent Decreased appetite Less frequent Hypokalaemia, hypomagnesaemia Frequency unknown Dehydration (due to diarrhoea and vomiting), Hypovolaemia Nervous system disorders Frequent Cholinergic syndrome Less frequent Paraesthesia, abnormal gait, confusion, headache, dizziness. Frequency unknown Transient speech disorders, Muscular contractions involuntary Eye disorders Less frequent Increased lacrimation, myosis Frequency unknown Conjunctivitis, visual disturbance Cardiac Disorders Less frequent Myocardial ischaemia, syncope, bradycardia Frequency unknown Hypertension (during or after infusion), Cardio circulatory failure Vascular disorders Frequent Hypotension or cardiac - circulatory failure Venous and arterial thromboembolic events which includes (angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep vein thrombophlebitis, heart arrest, myocardial infarct, myocardial ischaemia, peripheral vascular disorder, pulmonary embolus, sudden death thrombophlebitis, thrombosis, vascular disorder) Less frequent Hypertension (during or after infusion), flushing Frequency unknown Vasodilation Respiratory, thoracic and mediastinal disorder Frequent Dyspnoea (see section 4.4) Less frequent Interstitial lung disease with pulmonary infiltrates, Rhinitis, Upper respiratory tract infection, interstitial pneumonia (see section 4.4) Frequency unknown Hiccups Gastrointestinal disorders Frequent Diarrhoea, nausea, vomiting, dehydration, (associated with diarrhoea and /or vomiting) constipation, abdominal pain and mucositis, anorexia, stomatitis. Less frequent Rectal disorder, gi monilia, intestinal obstruction, ileus or gastrointestinal haemorrhage, intestinal perforation, transient increase in amylase and lipase, anorexia, mucositis, abdominal enlargement, bloated feeling or gas, Clostridium difficile induced pseudo - membranous colitis, indigestion Frequency unknown Intestinal perforation, intestinal obstruction, gastrointestinal haemorrhage, toxic megacolon, asymptomatic pancreatitis, Ileus, Colitis, Typhlitis, Colitis ischaemic, Colitis ulcerative Hepatobiliary disorders Frequent Hyperbilirubinemia Frequency unknown Steatohepatitis, Hepatic steatosis Skin and subcutaneous tissue disorders Frequent Alopecia (reversible), cutaneous reactions such as dry skin, pruritus, skin discolouration Less frequent Rash Frequency Skin reaction, sweating Musculoskeletal and connective tissue disorders Frequent Muscular contraction, or cramps Renal and urinary disorders Less frequent Urinary tract infection Frequency unknown Renal insufficiency, Renal impairment and acute renal failure Reproductive system and breast disorders Less frequent Breast pain General disorders and administration site conditions Frequent Reaction at infusion site, fever, acute cholinergic syndrome (symptoms include early diarrhoea, abdominal pain, conjunctivitis, rhinitis, hypotension, vasodilation, sweating, chills, malaise, dizziness, visual disturbances, miosis, lacrimation and increased salivation), mucosal inflammation, asthenia, pyrexia, extravasation, tumour lysis syndrome Frequency unknown Infusion site reaction, transient speech disorders Investigations Frequent Transient increases in serum levels of transaminases (ALT/AST), alkaline phosphatase, bilirubin, creatinine Frequency unknown Increases in amylase and lipase; hypokalaemia, hyponatraemia (associated with diarrhoea and vomiting) and transaminases, increased GGTP (gamma - glutamyl transpeptidase) *e.g. Pneumocystis jirovecii pneumonia, bronchopulmonary aspergillosis, systemic candida. u2020e.g. Herpes zoster, influenza, hepatitis B reactivation, cytomegalovirus colitis.

Symptoms of overdose

Overdosage may occur at dosages twice the recommended dosage, and can be fatal. The most significant adverse reactions reported were severe neutropenia and diarrhoea.

Treatment of overdose

There is no antidote for IRINOTECAN FKSA and the only possible treatment is maximum supportive treatment to prevent dehydration due to diarrhoea and to treat infectious complications.