Irinox

Each ml contains: Irinotecan Hydrochloride Trihydrate equivalent to Irinotecan 20 mg.
Irinotecan Hydrochloride concentrate for solution for injection an antineoplastic agent of the topoisomerase I inhibitor class.
Irinotecan hydrochloride is a pale yellow to yellow crystalline powder. Irinotecan Hydrochloride concentrate for solution for injection is available in 40 mg (2 ml) and 100 mg (5 ml) multi dose vials. Each ml contains irinotecan hydrochloride trihydrate, 20 mg; sorbitol, 45 mg; lactic acid, 0.9 mg; water for injection, q.s.
Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata or is chemically synthesized.
The chemical name is (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1H-pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4'bipiperidine]-1'-carboxylate, monohydrochloride, trihydrate. Its empirical formula is C₃₃H₃₈N₄O₆•HCl•3H₂O and molecular weight is 677.19. It is slightly soluble in water and organic solvents.

Pharmacotherapeutic group: Cytostatic topoisomerase I inhibitor. ATC Code: l01XX19.
Pharmacology: Pharmacodynamics: 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 Irinotecan Hydrochloride concentrate for solution for injection, the most relevant pharmacological effect of irinotecan is the inhibition of acetylcholinesterase.
Pharmacokinetics: In a phase I study in 60 patients with a dosage regimen of a 30-minute intravenous infusion of 100 to 750 mg/m² every three weeks, irinotecan showed a biphasic or triphasic elimination profile. The mean plasma clearance was 15 l/h/m² and the volume of distribution at steady state (Vs): 157 l/m². The mean plasma half-life of the first phase of the triphasic model was 12 minutes, of the second phase 2.5 hours, and the terminal phase half-life was 14.2 hours. SN-38 showed a biphasic elimination profile with a mean terminal elimination half-life of 13.8 hours. At the end of the infusion, at the recommended dose of 350 mg/m², the mean peak plasma concentrations of irinotecan and SN-38 were 7.7 µg/ml and 56 ng/ml, respectively, and the mean area under the curve (AUC) values were 34 µg.h/ml and 451 ng.h/ml, respectively. A large inter-individual variability in pharmacokinetic parameters is generally observed for SN-38.
A population pharmacokinetic analysis of irinotecan has been performed in 148 patients with metastatic colorectal cancer, treated with various schedules and at different doses in phase II trials. Pharmacokinetic parameters estimated with a three compartment model were similar to those observed in phase I studies. All studies have shown that irinotecan (CPT-11) and SN-38 exposure increase proportionally with CPT-11 administered dose; their pharmacokinetics are independent of the number of previous cycles and of the administration schedule.
In vitro, plasma protein binding for irinotecan and SN-38 was approximately 65% and 95% respectively.
Mass balance and metabolism studies with 14 C-labelled drug have shown that more than 50% of an intravenously administered dose of irinotecan is excreted as unchanged drug, with 33% in the faeces mainly via the bile and 22% in urine.
Two metabolic pathways account each for at least 12% of the dose: Hydrolysis by carboxylesterase into active metabolite SN-38, SN-38 is mainly eliminated by glucuronidation, and further by biliary and renal excretion (less than 0.5% of the irinotecan dose) The SN-38 glucuronite is subsequently probably hydrolysed in the intestine.
Cytochrome P450 3A enzymes-dependent oxidations resulting in opening of the outer piperidine ring with formation of APC (aminopentanoic acid derivate) and NPC (primary amine derivate).
Unchanged irinotecan is the major entity in plasma, followed by APC, SN-38 glucuronide and SN-38. Only SN-38 has significant cytotoxic activity.
Irinotecan clearance is decreased by about 40% in patients with bilirubinemia between 1.5 and 3 times the upper normal limit. In these patients a 200 mg/m² irinotecan dose leads to plasma drug exposure comparable to that observed at 350 mg/m² in cancer patients with normal liver parameters.

Irinotecan Hydrochloride concentrate for solution for injection 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.

For adults only. Irinotecan Hydrochloride concentrate for solution for injection should be infused into a peripheral or central vein.
Recommended dosage: For adults only:
In monotherapy (for previously treated patient): The recommended dosage of Irinotecan Hydrochloride concentrate for solution for injection is 350 mg/m² administered as an intravenous infusion over a 30- to 90-minute period every three weeks.
In combination therapy (for previously untreated patient): Safety and efficacy of Irinotecan Hydrochloride concentrate for solution for injection in combination with 5-fluorouracil (5-FU) and folinic acid (FA) have been assessed with the following schedule: Irinotecan Hydrochloride concentrate for solution for injection plus 5-FU/FA in every 2 weeks schedule. The recommended dose of Irinotecan Hydrochloride concentrate for solution for injection is 180 mg/m2 administered once every 2 weeks as an intravenous infusion over 30- to 90-minute period, followed by infusion with FA and 5-FU.
Dosage adjustments: Irinotecan Hydrochloride concentrate for solution for injection 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 Irinotecan Hydrochloride concentrate for solution for injection, 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 Hydrochloride Injection 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 Hydrochloride concentrate for solution for injection 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 2, should determine the starting dose of Irinotecan Hydrochloride concentrate for solution for injection. In these patients with hyperbilirubinemia and prothrombin time greater than 50%, the clearance of irinotecan is decreased and therefore the risk of hematotoxicity is increased. Thus, weekly monitoring of complete blood counts should be conducted in this patient population.
In patients with bilirubin up to 1.5 times the upper limit of the normal range (ULN), the recommended dosage of Irinotecan Hydrochloride concentrate for solution for injection is 350 mg/m²; In patients with bilirubin ranging from 1.5 to 3 times the ULN, the recommended dosage of Irinotecan Hydrochloride concentrate for solution for injection is 200 mg/m²; Patients with bilirubin beyond to 3 times the ULN should not be treated with Irinotecan Hydrochloride concentrate for solution for injection.
No data are available in patients with hepatic impairment treated by Irinotecan Hydrochloride concentrate for solution for injection in combination.
Patients with impaired renal function: Irinotecan Hydrochloride Concentrate for Solution for Injection is not recommended for use in patients with impaired renal function, as studies in this population have not been conducted.
Elderly: This population should require more intensive surveillance.
Preparation And handling: As with other antineoplastic agents, Irinotecan Hydrochloride Concentrate for Solution for Injection must be prepared and handled with caution. The use of glasses, mask and gloves is required. If Irinotecan Hydrochloride concentrate for solution for injection should come into contact with skin, wash immediately and thoroughly with soap and water. If Irinotecan Hydrochloride concentrate for solution for injection solution or infusion solution comes into contact with the mucous membranes, wash immediately with water.
Preparation for Intravenous infusion administration: As with any other injectable drugs, the Irinotecan Hydrochloride concentrate for solution for injection solution must be prepared aseptically. If any precipitate is observed in the vials or after reconstitution, the product should be discarded according to standard procedures for cytotoxic agents. Aseptically withdraw the required amount of Irinotecan Hydrochloride concentrate for solution for injection solution from the vial with a calibrated syringe and inject into a 250 ml infusion bag or bottle containing either 0.9% sodium chloride solution or 5% dextrose solution. The infusion should then be thoroughly mixed by manual rotation.
Administration: Irinotecan Hydrochloride concentrate for solution for injection solution for infusion should be infused into a peripheral or central vein. Irinotecan Hydrochloride concentrate for solution for injection should not be delivered as an intravenous bolus or an intravenous infusion shorter than 30 minutes or longer than 90 minutes.

There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhoea. There is no known antidote for Irinotecan Hydrochloride concentrate for solution for injection. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.

Chronic inflammatory bowel disease and/or bowel obstruction (see Precautions).
History of severe hypersensitivity reactions to irinotecan hydrochloride trihydrate or to one of the excipients of Irinotecan Hydrochloride concentrate for solution for injection.
Lactation (see Use in Pregnancy & Lactation and Precautions).
Bilirubin > 3 times the upper limit of the normal range (see Precautions).
Severe bone marrow failure.
WHO performance status > 2.
In pregnant women.

The use of Irinotecan Hydrochloride concentrate for solution for injection should be confined to units specialized 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, Irinotecan Hydrochloride concentrate for solution for injection 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 Irinotecan Hydrochloride concentrate for solution for injection is used in monotherapy, it is usually prescribed with the every-3-week-dosage schedule. However, the weekly-dosage schedule (see Pharmacology: Pharmacodynamics under Actions) 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 Irinotecan Hydrochloride concentrate for solution for injection 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 Hydrochloride concentrate for solution for injection. 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 c≥ 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 Irinotecan Hydrochloride concentrate for solution for injection 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 Irinotecan Hydrochloride concentrate for solution for injection 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. ln 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 Dosage & Administration).
Haematology: Weekly monitoring of complete blood cell counts is recommended during Irinotecan Hydrochloride concentrate for solution for injection 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 Dosage & Administration).
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 Pharmacology: Pharmacokinetics under Actions) and thus increasing the risk of hematotoxicity in this population. For patients with a bilirubin > 3 times ULN (see Contraindications).
Nausea and vomiting: A prophylactic treatment with antiemetics is recommended before each treatment with Irinotecan Hydrochloride concentrate for solution for injection. 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 Adverse Reactions).
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 Hydrochloride concentrate for solution for injection.
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.
Chronic inflammatory bowel disease and/or bowel obstruction: Patients must not be treated with lrinotecan Hydrochloride concentrate for solution for injection until resolution of the bowel obstruction (see Contraindications).
Patients with impaired renal function: Studies in this population have not been conducted (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
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.
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.
Patients with reduced UGT1A1 activity: The active metabolite irinotecan, SN-38, metabolized predominantly by UDP-glucuronosyl transferase (UGT). lt has been reported that patients who are homoyzygous (UGT1A1*6/*6 or UGT1A1*28/*28) or heterozygous (UGT1A1*6/*28) in allele UGT1A1*6, UGT1A1*28 of UGT may be at increased risk for serious adverse reactions (especially neutropenia) caused by reduced glucuronidation of SN-38. Added caution should be exercised when administering in such patients.
Other: Since this medicine contains sorbitol, it is unsuitable in hereditary fructose intolerance. lnfrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhea 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.
Effects on ability to drive and use machines: Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of Irinotecan Hydrochloride concentrate for solution for injection, and advised not to drive or operate machinery if these symptoms occur.
Use in Elderly: Due to the greater frequency of decreased biological functions, in particular hepatic function, in elderly patients, dose selection with Irinotecan Hydrochloride concentrate for solution for injection should be cautious in this population (see Dosage & Administration).

Pregnancy: Irinotecan is teratogenic in rats and rabbits. Irinotecan may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of irinotecan in pregnant women. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with irinotecan.
Lactation: In rats, radioactivity appeared in the milk within 5 minutes of intravenous administration of radio labelled irinotecan and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving therapy with irinotecan.

The following adverse reactions considered to be possibly or probably related to the administration of Irinotecan Hydrochloride concentrate for solution for injection have been reported from 765 patients at the recommended dose of 350 mg/m² in monotherapy, and from 145 patients treated by Irinotecan Hydrochloride concentrate for solution for injection 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 Irinotecan Hydrochloride concentrate for solution for injection.
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 Irinotecan Hydrochloride concentrate for solution for injection.
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 Irinotecan Hydrochloride concentrate for solution for injection 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 50,000 cells/mm³ and 0.2% of cycles.
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 Irinotecan Hydrochloride concentrate for solution for injection. These symptoms disappear after atropine administration (see Precautions).
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 Irinotecan Hydrochloride concentrate for solution for injection 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.
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 was 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 Irinotecan Hydrochloride concentrate for solution for injection infusions.
Post-marketing surveillance: Cardiac disorders: Myocardial ischemic events have been observed following irinotecan therapy predominantly in patients with underlying cardiac disease, other known risk factors for cardiac disease or previous cytotoxic chemotherapy.
Gastrointestinal disorders: Infrequent cases of intestinal obstruction, ileus, megacolon, or gastrointestinal hemorrhage, and rare cases of colitis, including typhlitis, ischemic and ulcerative colitis were reported. In some cases, colitis was complicated by ulceration, bleeding, ileus, or infection. Cases of ileus without preceding colitis have also been reported. Rare cases of intestinal perforation were reported.
Rare cases of symptomatic pancreatitis or asymptomatic elevated pancreatic enzymes have been observed.
Hypovolemia: There have been rare cases of renal impairment and acute renal failure, generally in patients who became infected and/or volume depleted from severe gastrointestinal toxicities. Infrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhea and/or vomiting, or sepsis.
Immune system disorders: Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been reported.
Musculoskeletal and connective tissue disorders: Early effects such as muscular contraction or cramps and paresthesia have been reported.
Nervous system disorders: Speech disorders, generally transient in nature, have been reported in patients treated with irinotecan; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan.
Respiratory, thoracic and mediastinal disorders: Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Early effects such as dyspnea have been reported . Hiccups have also been reported.
Investigations: Rare cases of hyponatremia mostly related with diarrhea and vomiting have been reported. Increases in serum levels of transaminases (i.e., AST and AlT) in the absence of progressive liver metastasis have been very rarely reported.

CYP3A4 and/or UGT1A1 inhibitors: Irinotecan and active metabolite SN-38 are metabolized via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) (see Pharmacology: Pharmacokinetics under Actions). Co-administration of irinotecan with inhibitors of CYP3A4 and/or UGT1A1 may result in increased systemic exposure to irinotecan and the active metabolite SN-38. Physicians should take this into consideration when administering irinotecan with these drugs.
Ketoconazole: Irinotecan clearance is greatly reduced in patients receiving concomitant ketoconazole, leading to increased exposure to SN-38. Ketoconazole should be discontinued at least 1 week prior to starting irinotecan therapy and should not be administered during irinotecan therapy.
Atazanavir sulfate: Co-administration 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.
CYP3A4 inducers: Anticonvulsants: Concomitant administration of CYP3A-inducing anticonvulsant drugs (e.g., carbamazepine, phenobarbital or phenytoin) leads to reduced exposure to the active metabolite SN-38. Consideration should be given to starting or substituting non-enzyme-inducing anticonvulsants at least one week prior to initiation of irinotecan therapy in patients requiring anticonvulsant treatment.
St. John's Wort (Hypericum perforatum): Exposure to the active metabolite SN-38 is reduced in patients taking concomitant St. John's Wort. St. John's Wort should be discontinued at least 1 week prior to the first cycle of irinotecan, and should not be administered during irinotecan therapy.
Other interactions: Neuromuscular blocking agents: Interactions between irinotecan hydrochloride and neuromuscular blocking agents cannot be ruled out since IRINOTECAN HYDROCHLORIDE 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 antagonized.
Antineoplastic agents: The adverse effects of irinotecan, such as myelosuppression and diarrhea, would be expected to be exacerbated by other antineoplastic agents having a similar adverse-effect profile.
Dexamethasone: Lymphocytopenia has been reported in patients receiving irinotecan, and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of lymphocytopenia. However, serious opportunistic infections have not been observed and no complications have specifically been attributed to lymphocytopenia.
Hyperglycemia has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of irinotecan. lt is probable that dexamethasone, given as antiemetic prophylaxis, contributed to hyperglycemia in some patients.
Laxatives: laxative use during therapy with irinotecan is expected to worsen the incidence or severity of diarrhea.
Diuretics: Dehydration secondary to vomiting and/or diarrhea may be induced by irinotecan. The physician may wish to withhold diuretics during dosing with irinotecan and during periods of active vomiting or diarrhea.
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.

Store below 30°C and protect from light and freezing.

Cytotoxic Chemotherapy

L01CE02 - irinotecan ; Belongs to the class of Topoisomerase 1 (TOP1) inhibitors. Used in the treatment of cancer.

POM