Irinotecan accord

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IRINOTECAN ACCORD

Composition:

Active substance: irinotecan hydrochloride trihydrate;

1 ml of concentrate contains irinotecan hydrochloride trihydrate 20 mg;

Excipients: sorbitol (E 420), lactic acid, hydrochloric acid diluted, sodium hydroxide, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: pale yellow clear solution. When examined under appropriate visual inspection conditions, the solution should be free from visible mechanical particles.

Pharmacotherapeutic group. Antineoplastic agents. ATC code L01CB02.

Pharmacological properties.

Pharmacodynamics.

Irinotecan is a semisynthetic derivative of camptothecin. It is an antineoplastic agent that acts as a specific inhibitor of DNA topoisomerase I. Under the action of carboxylesterase in most tissues, the drug is metabolized to SN-38, a compound that is more active against purified topoisomerase I and more cytotoxic than irinotecan against several human and murine tumor cell lines. Inhibition of DNA topoisomerase I by irinotecan or SN-38 leads to single-strand DNA damage, which blocks the replication fork and results in cytotoxic effects. This cytotoxic activity has been shown to be time-dependent and specific to the S-phase of the cell cycle.

It has been demonstrated in vitro that irinotecan and SN-38 are not significantly recognized by the multidrug-resistant P-glycoprotein and exert cytotoxic effects on cell lines resistant to doxorubicin and vinblastine.

In addition, irinotecan demonstrates a broad spectrum of antitumor activity in vivo against tumor models in mice (pancreatic ductal adenocarcinoma P03, mammary adenocarcinoma MA16/C, colorectal adenocarcinomas C38 and C51) and human tumor xenografts (colorectal adenocarcinoma Co-4, mammary adenocarcinoma Mx-1, gastric adenocarcinomas ST-15 and ST-16). Irinotecan is also effective against tumors expressing the multidrug-resistant P-glycoprotein (resistant to vincristine and doxorubicin in P388 leukemia).

In addition to its antitumor activity, the most significant pharmacological effect of irinotecan is the inhibition of acetylcholinesterase activity.

Clinical study data

First-line combination therapy for metastatic colorectal carcinoma

• In combination with folinic acid (FA) and 5-fluorouracil (5-FU).

A phase III study was conducted involving 385 patients who had not previously received treatment for colorectal cancer. The drug was administered either every two weeks (see section "Administration and dosage") or once weekly. In the every-two-weeks regimen, on day 1, after administration of irinotecan at a dose of 180 mg/m² body surface area, folinic acid (200 mg/m² body surface area over two hours) and 5-fluorouracil (400 mg/m² body surface area as intravenous bolus followed by a 22-hour intravenous infusion) were infused. On day 2, folinic acid and 5-fluorouracil were administered at the same dose and in the same manner. In the once-weekly regimen for 6 weeks, after infusion of irinotecan at a dose of 80 mg/m² body surface area, folinic acid (500 mg/m² body surface area over two hours) and 5-fluorouracil (2300 mg/m² body surface area over 24 hours) were administered intravenously.

In the study evaluating the outcomes of combination therapy using the two regimens described above, the efficacy of irinotecan was assessed in 198 patients.

Table 1

	Combination therapy regimens (n = 198)		Once-weekly administration (n = 50)		Once-every-two-weeks administration (n = 148)
	Irinotecan + 5-FU/FA	5-FU/FA	Irinotecan + 5-FU/FA	5-FU/FA	Irinotecan + 5-FU/FA	5-FU/FA
Response rate (%)	40.8*	23.1*	51.2*	28.6*	37.5*	21.6*
p-value	p < 0.001		p = 0.045		p = 0.005
Median time to progression (months)	6.7	4.4	7.2	6.5	6.5	3.7
p-value	p < 0.001		NS		p = 0.001
Median duration of response (months)	9.3	8.8	8.9	6.7	9.3	9.5
p-value	NS		p = 0.043		NS
Median duration of response and disease stabilization (months)	8.6	6.2	8.3	6.7	8.5	5.6
p-value	p < 0.001		NS		p = 0.003
Median treatment failure-free survival (months)	5.3	3.8	5.4	5.0	5.1	3.0
p-value	p = 0.0014		NS		p < 0.001
Median survival (months)	16.8	14.0	19.2	14.1	15.6	13.0
p-value	p = 0.028		NS		p = 0.041

NS — not significant;

* — according to the population analysis protocol.

With once-weekly administration, the incidence of severe diarrhea was 44.4% in patients receiving irinotecan with 5-FU/FA and 25.6% in patients receiving 5-FU/FA alone. The incidence of severe neutropenia (neutrophil count < 500 cells/mm³) was 5.8% in patients receiving irinotecan with 5-FU/FA and 2.4% in those receiving 5-FU/FA alone. In addition, the median time to significant deterioration in health status was significantly longer in the combination regimen group with irinotecan than in the group receiving 5-FU/FA alone (p = 0.046).

Quality of life in this Phase III study was assessed using the EORTC QLQ-C30 questionnaire. Significant deterioration in patients' health status occurred consistently later in the irinotecan treatment group. Gradual changes in the Global Health Status/Quality of Life score were slightly better in the combination therapy group with irinotecan (although not statistically significant), suggesting that effective treatment with irinotecan as part of combination therapy does not compromise quality of life.

• In combination with bevacizumab.

The evaluation of bevacizumab in combination with irinotecan/5-FU/FA as first-line therapy for metastatic carcinoma of the colon or rectum was conducted in a randomized, double-blind, active-controlled Phase III clinical trial (study AVF2107g). The addition of bevacizumab to the irinotecan/5-FU/FA combination resulted in a statistically significant improvement in overall survival. The clinical benefit, assessed by overall survival, was evident across all predefined patient subgroups, including those defined by age, sex, performance status, primary tumor location, number of affected organs, and duration of metastatic disease. Efficacy results from study AVF2107g are presented in Table 2.

Table 2

	Group 1 Irinotecan/5-FU/FA + placebo	Group 2 Irinotecan/5-FU/FA + bevacizumab
Number of patients	411	402
Overall survival
Median duration (months)	15.6	20.3
95% CI	14.29–16.99	18.46–24.18
Hazard ratio b		0.660
p-value		0.00004
Progression-free survival
Median duration (months)	6.2	10.6
Hazard ratio b		0.54
p-value		< 0.0001
Overall response rate
Rate (%)	34.8	44.8
95% CI	30.2–39.6	39.9–49.8
p-value		0.0036
Duration of response
Median duration (months)	7.1	10.4
25–75 percentile (months)	4.7–11.8	6.7–15.0

a — 5 mg/kg every two weeks;

b — compared to the control group;

CI — confidence interval.

• In combination therapy with cetuximab.

The randomized EMR 62202-013 study involving 599 patients with metastatic colorectal cancer who had not received prior treatment was conducted to compare the combination of cetuximab with irinotecan with or without the addition of 5-FU/FA infusions (599 patients). In the patient group assessed for KRAS gene status, patients with tumors characterized by wild-type KRAS accounted for 64%. Efficacy results obtained in this study are presented in Table 3.

Table 3

Variables / statistics	Total number of patients		Patients with wild-type KRAS gene
	Cetuximab + irinotecan + 5-FU/FA (n = 599)	Irinotecan + 5-FU/FA (n = 559)	Cetuximab + irinotecan + 5-FU/FA (n = 172)	Irinotecan + 5-FU/FA (n = 176)
Objective response rate (patients with complete or partial response)
% (95 % CI)	46.9 (42.9; 51.0)	38.7 (34.8; 42.8)	59.3 (51.6; 66.7)	43.2 (35.8; 50.9)
p-value	0.0038		0.0025
Progression-free survival
Hazard ratio (95 % CI)	0.85 (0.726; 0.998)		0.68 (0.501; 0.934)
p-value	0.0479		0.0167

• In combination therapy with capecitabine.

Results of a randomized, controlled phase III study (CAIRO) confirm the rationale for using capecitabine at an initial dose of 1000 mg/m² body surface area (for 2 out of every 3 weeks) in combination with irinotecan as first-line therapy for the treatment of patients with metastatic colorectal cancer. A total of 820 patients were randomized into either a sequential treatment group (n = 410) or a combination therapy group (n = 410). Sequential treatment consisted of first-line therapy (capecitabine 1250 mg/m² body surface area twice daily for 14 days), second-line therapy (irinotecan 350 mg/m² body surface area on day 1), and third-line combination therapy (capecitabine 1000 mg/m² body surface area twice daily for 14 days and oxaliplatin 130 mg/m² body surface area on day 1). Combination therapy consisted of first-line therapy (capecitabine 1000 mg/m² body surface area twice daily for 14 days) in combination with irinotecan (250 mg/m² body surface area on day 1) (XELIRI) and second-line therapy (capecitabine 1000 mg/m² body surface area twice daily for 14 days and oxaliplatin 130 mg/m² body surface area on day 1). All treatment cycles were administered every three weeks. During first-line therapy, the median progression-free survival in the intent-to-treat population was 5.8 months (95% CI: 5.1–6.2 months) with capecitabine monotherapy and 7.8 months (95% CI: 7.0–8.3 months) with XELIRI (p = 0.0002).

Interim results from a multicenter, randomized, controlled phase II study (AIO KRK 0604) support the use of capecitabine at an initial dose of 800 mg/m² body surface area (for 2 out of every 3 weeks) in combination with irinotecan and bevacizumab as first-line therapy for patients with metastatic colorectal cancer. A total of 115 patients were randomized to receive the combination of capecitabine and irinotecan (XELIRI) plus bevacizumab: capecitabine (800 mg/m² body surface area twice daily for two weeks followed by a 7-day break), irinotecan (200 mg/m² body surface area as a 30-minute infusion on day 1 of each three-week cycle), and bevacizumab (7.5 mg/kg as a 30–90 minute infusion on day 1 of each three-week cycle). Overall, 118 patients were randomized to the capecitabine plus oxaliplatin and bevacizumab group: capecitabine (1000 mg/m² body surface area twice daily for two weeks followed by a 7-day break), oxaliplatin (130 mg/m² body surface area as a 2-hour infusion on day 1 of each three-week cycle), and bevacizumab (7.5 mg/kg as a 30–90 minute infusion on day 1 of each three-week cycle). The progression-free survival rate at 6 months in the intent-to-treat population was 80% in the XELIRI plus bevacizumab group and 74% in the XELOX plus bevacizumab group. The overall response rate (complete and partial response) was 45% in the XELOX plus bevacizumab group and 47% in the XELIRI plus bevacizumab group.

• Monotherapy as second-line treatment of metastatic colorectal carcinoma.

Phase II/III clinical studies involving over 980 patients with metastatic colorectal cancer were conducted using a dosing schedule of once every three weeks, in whom prior treatment with 5-FU had failed. The efficacy of irinotecan was evaluated in 765 patients who had documented disease progression on 5-FU at study entry.

Table 4

	Phase III
	Irinitecan compared with supportive care			Irinitecan compared with 5-FU
	Irinitecan (n = 183)	Supportive care (n = 90)	p-value	Irinitecan (n = 127)	5-FU (n = 129)	p-value
Progression-free survival at 6 months (%)	NR	NR		33.5*	26.7	p = 0.03
Survival at 12 months (%)	36.2*	13.8	p = 0.0001	44.8*	32.4	p = 0.0351
Median survival (months)	9.2*	6.5	p = 0.0001	10.8*	8.5	p = 0.0351

NA – not applicable;

* – statistically significant difference.

In phase II studies involving 455 patients using a dosing regimen of once every three weeks, progression-free survival at 6 months was 30%, and median survival was 9 months. Median time to disease progression was 18 weeks.

Additional non-comparative phase II studies were conducted involving 304 patients who received irinotecan at a dose of 125 mg/m² body surface area as 90-minute intravenous infusions weekly for 4 weeks, followed by a 2-week rest period. In these studies, median time to disease progression was 17 weeks, and median survival was 10 months. The safety profile observed in 193 patients treated with the weekly regimen at an initial dose of 125 mg/m² body surface area was similar to that observed in studies using the every-three-weeks irinotecan administration schedule. The median time to the first episode of diarrhea was 11 days.

• In combination with cetuximab after failure of cytotoxic therapy containing irinotecan.

The efficacy of the combination of cetuximab and irinotecan was evaluated in two clinical studies. Overall, 356 patients with metastatic colorectal cancer expressing epidermal growth factor receptors received combination therapy: patients in whom cytotoxic therapy containing irinotecan had failed. The minimum Karnofsky performance status score was 60, but in most patients it was ≥ 80.

In the randomized study EMR 62 202-007, combination therapy with cetuximab and irinotecan (218 patients) was compared to cetuximab monotherapy (111 patients).

In the open-label, single-arm study IMCL CP02-9923, combination therapy was evaluated in 138 patients.

Efficacy results from these studies are presented in Table 5.

Table 5

Study	N	Objective response rate		Disease control rate		Progression-free survival, months		Overall survival duration, months
		n (%)	95 % CI	n (%)	95 % CI	Median	95 % CI	Median	95 % CI
Cetuximab + irinotecan
EMR 62 202-007	218	50 (22.9)	17.5; 29.1	121 (55.5)	48.6; 62.2	4.1	2.8; 4.3	8.6	7.6; 9.6
IMCLCP02-9923	138	21 (15.2)	9.7; 22.3	84 (60.9)	52.2; 69.1	2.9	2.6; 4.1	8.4	7.2; 10.3
Cetuximab
EMR 62 202-007	111	12 (10.8)	5.7; 18.1	36 (32.4)	23.9; 42.0	1.5	1.4; 2.0	6.9	5.6; 9.1

1 – disease control rate (patients with complete response, partial response, or stable disease for at least 6 months);

2 – objective response rate (patients with complete or partial response).

In terms of objective response rate, disease control rate, and progression-free survival, the combination of cetuximab and irinotecan is more effective than cetuximab monotherapy. In the randomized trial, no impact on overall survival was demonstrated (hazard ratio 0.91; p = 0.48).

• Patients with reduced UGT1A1 activity.

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is involved in the metabolic inactivation of SN-38, the active metabolite of irinotecan, forming the inactive SN-38 glucuronide (SN-38G). The UGT1A1 gene is highly polymorphic, resulting in various metabolic activity levels within a population. The first identified variant of the UGT1A1 gene contains a polymorphic region in the promoter area and is designated UGT1A1*28. This variant, as well as other inherited UGT1A1 expression disorders (Gilbert’s syndrome or Crigler-Najjar syndrome), are associated with reduced enzyme activity. Meta-analysis data indicate that patients with Crigler-Najjar syndrome (types 1 and 2) or homozygous for the UGT1A1*28 allele (Gilbert’s syndrome) are at increased risk of developing hematological toxicity (grades III–IV) following administration of moderate or high doses of irinotecan (> 150 mg/m²). No association has been established between the UGT1A1 genotype and the occurrence of irinotecan-induced diarrhea.

Patients known to be homozygous for the UGT1A1*28 allele should receive the standard initial dose of irinotecan. However, they should be closely monitored for signs of hematological toxicity. For patients who have previously experienced hematological toxicity during prior treatment cycles, consideration should be given to reducing the initial dose of irinotecan. The exact extent of dose reduction in this patient group has not been established. Any further dosage adjustments should be based on the patient’s tolerance to treatment (see sections "Special precautions" and "Dosage and administration").

Currently, there are insufficient clinical data to conclude on the utility of UGT1A1 genotyping in patients.

Pharmacokinetics.

Absorption

At the end of infusion with 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 values of the area under the plasma concentration-time curve (AUC) were 34 µg*h/mL and 351 µg*h/mL, respectively. SN-38 typically exhibits substantial inter-individual variability in pharmacokinetic parameters.

Distribution

In a phase I study involving 60 patients who received irinotecan at doses ranging from 100 to 750 mg/m² body surface area as a 30-minute intravenous infusion every three weeks, the steady-state volume of distribution (Vss) was 157 L/m² body surface area.

Plasma protein binding in vitro was approximately 65% for irinotecan and approximately 95% for SN-38.

Metabolism

Mass balance and metabolism studies using 14C-labeled irinotecan demonstrated that more than 50% of the intravenously administered dose is excreted unchanged, with 33% of the dose eliminated in feces (primarily via bile) and 22% in urine.

Each of the following two metabolic pathways accounts for the transformation of at least 12% of the dose:

• Hydrolysis by carboxylesterases to form the active metabolite SN-38, which is primarily eliminated via glucuronidation, followed by excretion of the glucuronide conjugate by the liver and kidneys (less than 0.5% of the irinotecan dose). SN-38 glucuronide is believed to undergo further hydrolysis in the intestine;
• Oxidation by cytochrome P450 3A enzymes, leading to cleavage of the outer piperidine ring and formation of an aminopentanoic acid derivative and a primary amine derivative (see section "Interaction with other medicinal products and other forms of interaction").

Unchanged irinotecan is the predominant fraction of the drug in plasma, followed in descending order by the aminopentanoic acid derivative, SN-38 glucuronide, and SN-38. Only SN-38 exhibits significant cytotoxic activity.

Elimination

In a phase I study involving 60 patients who received irinotecan at doses from 100 to 750 mg/m² body surface area as a 30-minute intravenous infusion every three weeks, irinotecan exhibited a biphasic or triphasic elimination profile. The mean plasma clearance of irinotecan was 15 L/h/m². The mean elimination half-life in phase I of the triphasic model was 12 minutes, in phase II – 2.5 hours, and the terminal half-life – 14.2 hours. SN-38 showed a biphasic elimination profile with a mean elimination half-life of 13.8 hours.

In patients with bilirubin levels 1.5 to 3 times above the upper limit of normal, irinotecan clearance is reduced by 40%. In patients in this group, administration of 200 mg/m² body surface area of irinotecan results in the same plasma drug exposure as administration of 350 mg/m² body surface area of irinotecan in patients with normal liver function.

Linearity/Non-linearity

Population pharmacokinetic analysis of irinotecan was performed in a cohort of 148 patients with metastatic colorectal cancer who received irinotecan at various doses and dosing schedules in phase II studies. Pharmacokinetic parameters derived using a three-compartment model were similar to those obtained in phase I studies. Results from all studies indicate that exposure to irinotecan (CPT-11) and SN-38 increases proportionally with the CPT-11 dose. The pharmacokinetics of these compounds do not depend on the number of prior treatment cycles or the dosing regimen.

Pharmacokinetic/Pharmacodynamic Relationships

The severity of the most prominent toxic effects of irinotecan (e.g., leukopenia and diarrhea) is related to the exposure (AUC) of the parent drug and its metabolite SN-38. A significant correlation has been observed between hematological toxicity (nadir counts of leukocytes and neutrophils) or the severity of diarrhea and the AUC values of irinotecan and its metabolite SN-38 during monotherapy.

Preclinical Safety Data

Irinotecan and SN-38 have been shown to exhibit mutagenic activity in vitro in CHO cells in the chromosomal aberration test, as well as in vivo in mice in the micronucleus test.

However, in the Ames test, they were shown to lack any mutagenic potential.

In rats administered the maximum dose of 150 mg/m² once weekly for 13 weeks (less than half the recommended human dose), no treatment-related tumors were reported 91 weeks after the end of treatment.

Toxicity studies following single and repeated doses of irinotecan were conducted in mice, rats, and dogs. The main toxic effects involved the hematopoietic and lymphatic systems. In dogs, delayed diarrhea associated with atrophy and focal necrosis of the intestinal mucosa was reported. Alopecia was also observed. The severity of these effects was dose-dependent and reversible.

Reproductive Function

Irinotecan showed teratogenic effects in rats and rabbits at doses lower than the human therapeutic dose. Rats with external abnormalities born from irinotecan-treated rats showed reduced fertility. This was not observed in offspring born without morphological defects. In pregnant female rats treated with irinotecan, reduced placental weight was observed, and in their offspring, reduced fetal viability and increased incidence of behavioral abnormalities were noted.

Clinical Characteristics

Indications

Treatment of patients with advanced colorectal cancer:

• in combination with 5-fluorouracil and folinic acid in the treatment of patients who have not received prior chemotherapy for advanced colorectal cancer;
• as monotherapy in patients for whom a treatment regimen containing 5-fluorouracil has proven ineffective.

In combination therapy with irinotecan hydrochloride and cetuximab for the treatment of patients with metastatic colorectal cancer with wild-type KRAS gene expressing epidermal growth factor receptors (EGFR), who have not previously received treatment for metastatic disease or for whom cytotoxic therapy with irinotecan hydrochloride has proven ineffective (see section "Pharmacodynamics").

In combination therapy with irinotecan hydrochloride, 5-fluorouracil, folinic acid, and bevacizumab as first-line therapy for the treatment of patients with metastatic carcinoma of the colon or rectum.

In combination therapy with irinotecan hydrochloride and capecitabine with or without bevacizumab for the treatment of patients with metastatic colorectal cancer.

Contraindications

• Chronic inflammatory bowel diseases and/or intestinal obstruction (see section "Special precautions").
• Hypersensitivity reactions to the active substance(s) or to any of the excipients of the medicinal product.
• Breastfeeding period (see section "Use during pregnancy or breastfeeding").
• Serum bilirubin levels exceeding the upper normal limit by more than 3 times (see section "Special precautions").
• Severe bone marrow insufficiency.
• General health status > 2 (according to WHO classification).
• Concomitant use of St. John's wort preparations (see section "Interaction with other medicinal products and other types of interactions").
• Immunization with live attenuated vaccines (see section "Interaction with other medicinal products and other types of interactions").

Information on additional contraindications when used in combination with cetuximab, bevacizumab, or capecitabine is provided in the instructions for medical use of these medicinal products.

Special safety measures

As with other antineoplastic agents, the medicinal product should be handled and prepared with care. Protective goggles, mask, and gloves should be used.

If the medicinal product solution or infusion solution comes into contact with the skin, it should be immediately rinsed with water and washed thoroughly with soap and water. If the medicinal product solution or infusion solution comes into contact with mucous membranes, they should be immediately rinsed with water.

Preparation for intravenous infusion

As with any injectable medicinal product, the solution should be prepared under aseptic conditions (see section "Shelf life").

If precipitate is observed in the vial or after dilution, the product should be discarded following standard procedures for disposal of cytotoxic agents.

Under aseptic conditions, withdraw the required amount of the medicinal product from the vial using a calibrated syringe and transfer it into a 250 ml infusion bag or bottle containing 0.9% sodium chloride solution or 5% glucose solution. The resulting solution should be thoroughly mixed by gently inverting the infusion bag or bottle.

Disposal

For single use only. All materials used for dilution, unused medicinal product, or waste should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other types of interactions

Concomitant use of medicinal products that is contraindicated (see section "Contraindications")

St. John's Wort

Decreased plasma levels of the active metabolite of irinotecan, SN-38. In a pharmacokinetic study with a small number of participants (n = 5), where irinotecan was administered at a dose of 350 mg/m² body surface area in combination with St. John's wort (Hypericum perforatum) at a dose of 900 mg, a 42% reduction in plasma concentration of SN-38, the active metabolite of irinotecan, was observed. Therefore, St. John's wort should not be used concomitantly with irinotecan.

Live attenuated vaccines (e.g., yellow fever vaccine)

Risk of developing systemic diseases with potentially fatal outcomes. Concomitant administration of live attenuated vaccines is contraindicated during treatment with irinotecan and for 6 months after completion of chemotherapy. Inactivated vaccines may be used, but the immune response to such vaccines may be reduced.

Not recommended concomitant use of medicinal products (see section "Special precautions")

Concomitant administration of irinotecan with strong inducers/inhibitors of cytochrome P450 3A4 (CYP3A4) isoenzymes may alter the metabolism of irinotecan, and such combinations should therefore be avoided (see section "Special precautions").

Strong CYP3A4 and/or UGT1A1 inducers (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, or apalutamide):

Risk of reduced efficacy of irinotecan, SN-38, SN-38 glucuronide, and reduced pharmacodynamic effect. Several studies have demonstrated that concomitant use of anticonvulsant drugs that are CYP3A4 inducers reduces the efficacy of irinotecan, SN-38, and SN-38 glucuronide, and diminishes the pharmacodynamic effect. The effect of anticonvulsant drugs results in a reduction of AUC for SN-38 and SN-38 glucuronide by 50% or more. In addition to CYP3A4 enzyme induction, reduced efficacy of irinotecan and its metabolites may also be due to enhanced glucuronidation and increased biliary excretion. Also, when used with phenytoin, there is a risk of seizure exacerbation due to reduced absorption of phenytoin in the gastrointestinal tract under the influence of cytotoxic medicinal products.

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

A study demonstrated that concomitant administration with ketoconazole resulted in an 87% reduction in AUC of the APC metabolite and a 109% increase in AUC of the SN-38 metabolite compared to irinotecan monotherapy.

UGT1A1 inhibitors (e.g., atazanavir, ketoconazole, regorafenib)

Risk of increased systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should consider this if concomitant use cannot be avoided.

Other CYP3A4 inhibitors (e.g., crizotinib, idelalisib)

Risk of increased irinotecan toxicity due to reduced metabolism when used concomitantly with crizotinib or idelalisib.

Use with caution

Vitamin K antagonists: increased risk of bleeding and thrombotic events in cancer patients. If vitamin K antagonists are indicated, more frequent monitoring of the international normalized ratio (INR) is required.

Concomitant use requiring attention

Immunosuppressants (e.g., cyclosporine, tacrolimus): excessive immunosuppression with risk of lymphocyte proliferation.

Neuromuscular blocking agents: interaction between irinotecan and neuromuscular blockers cannot be excluded. Since irinotecan has anticholinesterase activity, other medicinal products with anticholinesterase activity may prolong the neuromuscular blockade caused by succinylcholine and reverse the blockade caused by non-depolarizing agents.

Other combinations

5-Fluorouracil/Folinic acid: concomitant administration of 5-FU/FA as part of combination therapy does not alter the pharmacokinetics of irinotecan.

Bevacizumab: results from a dedicated interaction study did not demonstrate a significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38. However, this does not exclude any potential increase in toxicity due to their pharmacological properties.

Cetuximab: information on the effect of cetuximab on the safety profile of irinotecan or vice versa is lacking.

Antineoplastic agents (including flucytosine as a prodrug of 5-fluorouracil): adverse reactions of irinotecan, such as bone marrow suppression, may be enhanced by other antineoplastic medicinal products with a similar adverse reaction profile.

Special precautions for use.

This medicinal product should be used exclusively in a department specialized in cytotoxic chemotherapy. The drug should be administered under the supervision of a physician experienced in anticancer chemotherapy.

Considering the nature and frequency of adverse reactions, the medicinal product should be used only after assessing the benefit-risk ratio of treatment in the following cases:

• for treatment of patients with risk factors, including patients with a WHO performance status score > 2;
• in rare individual cases when patients are unlikely to comply with recommendations for managing adverse reactions (the need for immediate and prolonged treatment of diarrhea in combination with high fluid intake at the onset of delayed diarrhea). Such patients should be closely monitored in a hospital setting.

When irinotecan is used as monotherapy, it is usually administered on a schedule of once every three weeks. However, for patients who may require closer monitoring or who are at particular risk of neutropenia, a weekly dosing schedule may be used (see section "Pharmacological properties").

Delayed diarrhea

Patients should be warned about the risk of developing delayed diarrhea, which occurs more than 24 hours after administration of irinotecan and at any time before the start of the next treatment cycle. In monotherapy, the median time to the first episode of loose stools was 5 days after irinotecan administration. Patients must promptly inform their physician about the onset of diarrhea and immediately initiate appropriate therapy. Patients at increased risk of diarrhea include those previously treated with radiotherapy to the abdominal or pelvic area, patients with baseline hyperleukocytosis, patients with a performance status ≥ 2, and women. Without adequate treatment, diarrhea may be life-threatening, especially if it is accompanied by neutropenia.

After the first episode of loose stools, patients should immediately begin drinking large amounts of electrolyte-containing fluids and receive appropriate treatment for diarrhea. Diarrhea treatment should be conducted in the department where irinotecan was administered. After hospital discharge, patients should receive prescribed medications to enable immediate treatment of diarrhea upon its onset. Additionally, patients should report the occurrence of diarrhea to their physician or to the department where irinotecan was administered.

The currently recommended treatment for diarrhea involves high-dose loperamide (4 mg as the initial dose, followed by 2 mg every 2 hours). Treatment should continue for 12 hours after the last episode of loose stools. This treatment regimen should not be modified. Loperamide at these doses should in no case be used for longer than 48 hours due to the risk of paralytic ileus; however, treatment should not last less than 12 hours.

In cases where diarrhea is accompanied by severe neutropenia (neutrophil count < 500 cells/mm³), broad-spectrum antibiotics should be administered prophylactically in addition to antidiarrheal treatment.

In addition to antibiotic use for diarrhea treatment, hospitalization of patients is recommended in the following cases:

• diarrhea accompanied by fever;
• severe diarrhea (requiring intravenous rehydration);
• diarrhea persisting for 48 hours after initiation of high-dose loperamide treatment.

Loperamide should not be used prophylactically, even in patients who experienced delayed diarrhea during previous treatment cycles.

Patients with severe diarrhea should have their dose reduced in subsequent treatment cycles (see section "Dosage and administration").

Effects on the blood system

In clinical studies, the incidence of grade III–IV neutropenia according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) was significantly higher in patients previously irradiated in the pelvic/abdominal region compared to those who did not receive such irradiation. Patients with a baseline total serum bilirubin level of 1.0 mg/dL or higher also had a significantly higher probability of developing grade III–IV neutropenia during the first treatment cycle compared to patients with bilirubin levels below 1.0 mg/dL.

Complete blood counts should be monitored weekly during irinotecan treatment. Patients should be warned about the risk of neutropenia and the significance of fever. Febrile neutropenia (temperature > 38 °C and neutrophil count ≤ 1000 cells/mm³) must be treated immediately in a hospital setting with intravenous broad-spectrum antibiotics.

Patients experiencing severe hematological complications should have their dose reduced in subsequent treatment cycles (see section "Dosage and administration").

Patients with severe diarrhea have an increased risk of infections and manifestations of hematological toxicity. These patients require complete blood count monitoring.

Hepatic impairment

Liver function tests should be performed before the start of therapy and before each cycle.

Patients with bilirubin levels 1.5 to 3 times above the upper limit of normal should have complete blood counts monitored weekly due to reduced irinotecan clearance (see section "Pharmacokinetics") and increased risk of hematotoxicity. Patients with bilirubin levels more than 3 times above the upper limit of normal should refer to the section "Contraindications."

Nausea and vomiting

Anti-emetic agents are recommended prophylactically before the start of each treatment course. Nausea and vomiting are frequently reported with irinotecan use. Patients experiencing vomiting in combination with delayed diarrhea require immediate hospitalization for appropriate treatment.

Acute cholinergic syndrome

In case of acute cholinergic syndrome (defined as early diarrhea in combination with various other signs and symptoms such as increased sweating, abdominal cramps, miosis, and increased salivation), sulfate atropine (0.25 mg subcutaneously) should be administered, provided there are no clinical contraindications (see section "Adverse reactions").

These symptoms, which may occur during or immediately after irinotecan infusion, are associated with the anticholinesterase activity of the parent compound irinotecan. The frequency of these symptoms is expected to increase with higher doses of irinotecan.

Patients with asthma should be treated with caution. Patients experiencing severe acute cholinergic syndrome should receive prophylactic atropine sulfate before subsequent doses of irinotecan.

Respiratory disorders

Rare cases of irinotecan-induced interstitial lung disease, characterized by pulmonary infiltrates and potentially fatal, may occur during treatment. Risk factors possibly associated with the development of interstitial lung disease include the use of lung-toxic agents, radiotherapy, and administration of colony-stimulating factors. Patients with risk factors require careful monitoring for respiratory symptoms before and during irinotecan therapy.

Extravasation

Although irinotecan is not classified as a vesicant, it should be administered with caution, and the infusion site should be monitored for signs of inflammation. In case of extravasation, the area should be flushed and ice applied.

Elderly patients

Due to the higher frequency of decreased physiological functions, particularly liver function, the dose of the drug should be carefully selected in elderly patients (see section "Dosage and administration").

Chronic inflammatory bowel disease and/or bowel obstruction

Irinotecan should not be administered to patients until bowel obstruction has resolved (see section "Contraindications").

Patients with renal impairment

Elevated serum creatinine or blood urea nitrogen levels have been observed. Cases of acute renal failure have occurred. These events were usually associated with complications of infectious diseases or dehydration due to nausea, vomiting, or diarrhea. Additionally, rare cases of renal dysfunction due to tumor lysis syndrome have been reported.

Radiotherapy

Patients previously treated with pelvic or abdominal irradiation are at increased risk of myelosuppression after irinotecan therapy. Physicians should use this medicinal product cautiously in patients who have previously received extensive radiotherapy (e.g., irradiation of > 25% of bone marrow within 6 weeks before starting irinotecan treatment). This group of patients may require dose adjustment (see section "Dosage and administration").

Cardiac disorders

Cases of myocardial ischemia have been observed after irinotecan administration, primarily in patients with pre-existing heart disease, other known risk factors for heart disease, and in patients previously treated with cytotoxic chemotherapy (see section "Adverse reactions"). Therefore, patients with known risk factors require careful monitoring. Measures should be taken to minimize all modifiable risk factors (e.g., smoking, arterial hypertension, hyperlipidemia).

Vascular disorders

In patients with multiple risk factors in addition to the primary malignancy, irinotecan use has rarely been associated with thromboembolic complications (pulmonary embolism, venous thrombosis, and arterial thromboembolism).

Other

Concomitant use of irinotecan with a strong inhibitor (e.g., ketoconazole) or inducer (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, apalutamide) of CYP3A4 may alter irinotecan metabolism; therefore, such concomitant use should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Uncommon cases of renal failure, arterial hypotension, or circulatory disturbances have been reported in patients experiencing episodes of dehydration related to diarrhea and/or vomiting or sepsis.

Contraception in women of childbearing potential and men

Women who may become pregnant should use highly effective contraceptive methods during treatment and for 6 months after the last dose of irinotecan due to the potential genotoxicity of irinotecan (see section "Pregnancy and breastfeeding").

Men with partners of childbearing potential should use effective contraceptive methods during treatment and for 3 months after the last dose of irinotecan due to the potential genotoxicity of irinotecan (see section "Pregnancy and breastfeeding").

Breastfeeding

Due to the potential for adverse reactions in breastfed infants, breastfeeding should be discontinued during irinotecan treatment (see sections "Contraindications" and "Pregnancy and breastfeeding").

This medicinal product contains sorbitol. Sorbitol is a source of fructose. Patients with hereditary fructose intolerance should not use this medicinal product unless absolutely necessary.

Infants and children under 2 years of age cannot yet be diagnosed with hereditary fructose intolerance. Intravenous preparations containing fructose may cause life-threatening adverse reactions in patients with hereditary fructose intolerance; therefore, they should not be administered to this patient group except in cases of extreme clinical necessity and lack of alternatives.

A detailed history regarding symptoms of hereditary fructose intolerance should be obtained from each patient before prescribing this medicinal product.

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Women of childbearing potential/contraception in men and women

Women who may become pregnant should use highly effective contraceptive methods during treatment and for 6 months after the last dose of irinotecan due to the potential for genotoxicity of irinotecan (see section "Special precautions for use").

Male patients with partners of childbearing potential should use effective contraceptive methods during treatment and for 3 months after the last dose of irinotecan due to the potential for genotoxicity of irinotecan (see section "Special precautions for use").

Pregnancy

There are no data on the use of irinotecan in pregnant women. Animal studies have demonstrated that irinotecan has embryotoxic and teratogenic effects. Therefore, considering the results of animal studies and the mechanism of action of irinotecan, irinotecan should not be used during pregnancy except in cases of absolute necessity.

Women of childbearing potential should not start irinotecan treatment until pregnancy has been excluded. Pregnancy should be avoided if either partner is receiving irinotecan.

Breastfeeding

Available data are limited but suggest that irinotecan and its metabolites are excreted in breast milk. Due to the potential for adverse reactions in breastfed children, breastfeeding should be discontinued during irinotecan treatment (see sections "Contraindications" and "Special precautions for use").

Effects on fertility

There is no information on the effect of irinotecan on human fertility. Animal studies have documented an adverse effect of irinotecan on fertility of offspring (see section "Preclinical safety data"). The need for gamete preservation should be considered before starting irinotecan treatment.

Ability to drive and use machines.

The medicinal product has a moderate effect on the ability to drive and use machinery. Patients should be warned about the possibility of dizziness or visual disturbances occurring within 24 hours after irinotecan administration and advised to refrain from driving and operating machinery if these symptoms occur.

Administration and Dosage

Route of Administration

The medicinal product is intended for treatment of adult patients only. The infusion solution should be administered into a peripheral or central vein.

Recommended Doses

Monotherapy (for previously treated patients)

The recommended dose is 350 mg/m² body surface area administered as an intravenous infusion over 30–90 minutes every three weeks.

Combination Therapy (for treatment-naïve patients)

The safety and efficacy of irinotecan in combination with 5-FU and LV were evaluated according to the regimen (see section "Pharmacodynamics").

• Regimen – irinotecan + 5-FU/LV every two weeks

The recommended dose of the medicinal product is 180 mg/m² body surface area, administered once every two weeks as an intravenous infusion over 30–90 minutes, followed by 5-FU and LV infusion.

Dosage and administration instructions for concomitant cetuximab are provided in the cetuximab product information.

The same irinotecan dose as used in the last cycle of irinotecan-based therapy should generally be applied. Irinotecan should be administered no sooner than 1 hour after completion of cetuximab infusion.

Dosage and administration information for bevacizumab is provided in the bevacizumab product information.

Dosage and administration information for combination with capecitabine are provided in section "Pharmacodynamics" and in the relevant sections of the capecitabine product information.

Dose Modifications

The medicinal product should be administered only after adequate resolution of all adverse reactions to grade 0 or 1 according to NCI-CTC criteria and after complete resolution of treatment-related diarrhea.

At the beginning of the next infusion, the dose of the medicinal product and 5-FU (if used) should be reduced based on the most severe adverse reactions observed during the previous infusion. Treatment initiation should be delayed by 1–2 weeks to allow resolution of treatment-related adverse reactions.

The dose of the medicinal product and/or 5-FU (if used) should be reduced by 15–20% in case of the following adverse reactions:

• Hematotoxicity (grade IV neutropenia, febrile neutropenia [grade III–IV neutropenia accompanied by grade II–IV fever], thrombocytopenia, and leukopenia [grade IV]);
• Non-hematological toxicity (grade III–IV).

Dose modification recommendations for cetuximab when used in combination with irinotecan are provided in the cetuximab product information.

Dose modification recommendations for bevacizumab when used in combination with irinotecan are provided in the bevacizumab product information.

For patients aged 65 years and older receiving combination therapy with capecitabine, a reduced dose of capecitabine to 800 mg/m² body surface area twice daily is recommended, according to the capecitabine product information. Refer also to the capecitabine product information.

Duration of Treatment

Treatment with the medicinal product should continue until objective disease progression or development of signs of unacceptable toxicity.

Special Patient Populations

Patients with Hepatic Impairment

Monotherapy: For patients with ECOG performance status ≤ 2, the initial dose should be determined based on serum bilirubin levels (if bilirubin is elevated up to 3 times the upper limit of normal). In such patients with hyperbilirubinemia and prothrombin time prolonged by more than 50%, irinotecan clearance is reduced (see section "Pharmacokinetics"), increasing the risk of hepatotoxicity. Therefore, weekly monitoring of complete blood count is recommended in these patients.

• For patients with bilirubin levels up to 1.5 times the upper limit of normal, the recommended dose is 350 mg/m² body surface area.
• For patients with bilirubin levels between 1.5 and 3 times the upper limit of normal, the recommended dose is 200 mg/m² body surface area.
• The medicinal product should not be administered to patients with bilirubin levels exceeding 3 times the upper limit of normal (see sections "Contraindications" and "Special Warnings and Precautions for Use").

There is no information on the use of irinotecan in combination with other agents in patients with hepatic impairment.

Patients with Renal Impairment

Irinotecan should not be used in patients with renal impairment, as no studies have been conducted in this patient population (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Elderly Patients

No specific pharmacokinetic studies have been conducted in elderly patients. However, dose selection should be cautious in this population due to the higher likelihood of decreased physiological functions. These patients require more intensive monitoring (see section "Special Warnings and Precautions for Use").

Pediatric Patients

The safety and efficacy of irinotecan in pediatric patients have not been established. There is no data on the use of irinotecan in children.

Administration

Precautions to be taken before handling or administering the medicinal product

Irinotecan is a cytotoxic agent. Instructions for dilution of the medicinal product prior to administration are provided in the section "Special Precautions for Handling."

Pediatric Patients

The medicinal product is intended for treatment of adult patients only.

Overdose

Symptoms

Cases of overdose have been reported at doses approximately twice the recommended therapeutic doses and may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhea.

Management

There is no known antidote for irinotecan. Intensive supportive therapy should be initiated to prevent dehydration due to diarrhea and to treat any infectious complications.

Adverse Reactions

Clinical Studies

Data on adverse reactions were carefully collected during studies in metastatic colorectal cancer; the frequency of their occurrence is presented below. When the drug is used for indications other than colorectal cancer, similar adverse reactions are expected.

The most common (≥ 1/10) dose-limiting adverse reactions of irinotecan are delayed diarrhea (occurring more than 24 hours after drug administration) and hematological disorders, including neutropenia, anemia, and thrombocytopenia.

Neutropenia is the dose-limiting toxic effect. Neutropenia was reversible and non-cumulative; during monotherapy or combination therapy, the median time to reach the nadir of neutrophil count was 8 days.

Transient acute cholinergic syndrome of severe degree was very frequently observed. Its main symptoms were early diarrhea and various other symptoms such as abdominal pain, increased sweating, miosis, and increased salivation, occurring during or within the first 24 hours after irinotecan infusion. These symptoms resolved after administration of atropine (see section "Special Warnings and Precautions for Use").

Monotherapy

The following adverse reactions, possibly or probably related to irinotecan administration, were reported in 765 patients who received the recommended dose of 350 mg/m² as monotherapy. The frequency of adverse reactions is classified as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), and very rare (< 1/10000).

Adverse reactions reported during irinotecan monotherapy (schedule: 350 mg/m² every 3 weeks):

Infections and infestations

Common: infections.

Blood and lymphatic system disorders

Very common: neutropenia, anemia.

Common: thrombocytopenia, febrile neutropenia.

Metabolism and nutrition disorders

Very common: decreased appetite.

Nervous system disorders

Very common: cholinergic syndrome.

Gastrointestinal disorders

Very common: diarrhea, vomiting, nausea, abdominal pain.

Common: constipation.

Skin and subcutaneous tissue disorders

Very common: alopecia (reversible).

General disorders and administration site conditions

Very common: mucositis, fever, asthenia.

Investigations

Common: increased blood creatinine, increased transaminases (ALT and AST), increased bilirubin, increased alkaline phosphatase in blood.

Description of selected adverse reactions (in monotherapy)

Severe diarrhea was observed in 20% of patients who followed recommendations for diarrhea control. In evaluable treatment cycles, severe diarrhea occurred in 14%. The median time to onset of loose stools after irinotecan infusion was 5 days.

Nausea and vomiting were severe in approximately 10% of patients receiving antiemetic prophylaxis.

Constipation was observed in less than 10% of patients.

Neutropenia occurred in 78.7% of patients, with severe grade (neutrophil count < 500 cells/mm³) in 22.6% of patients. In evaluable treatment cycles, neutrophil count was below 1000 cells/mm³ in 18%, including 7.6% with neutrophil count < 500 cells/mm³.

Complete recovery usually took up to 22 days.

Febrile neutropenia occurred in 6.2% of patients and in 1.7% of all treatment cycles.

Infections occurred in approximately 10.3% of patients (2.5% of all treatment cycles) and were associated with severe neutropenia in approximately 5.3% of patients (1.1% of all treatment cycles); in two cases, this complication led to a fatal outcome.

Anemia was observed in approximately 58.7% of patients (8% with hemoglobin < 8 g/dL and 0.9% with hemoglobin < 6.5 g/dL).

Thrombocytopenia (< 100,000 cells/mm³) occurred in 7.4% of patients and in 1.8% of all treatment cycles, with platelet count ≤ 50,000 cells/mm³ in 0.9% of patients and in 0.2% of treatment cycles.

In almost all patients, recovery took up to 22 days.

Acute cholinergic syndrome: transient acute cholinergic syndrome of severe degree was observed in 9% of patients receiving the drug as monotherapy.

Asthenia was severe in less than 10% of patients receiving the drug as monotherapy. The causal relationship between this event and irinotecan administration has not been clearly established.

Fever in the absence of infection or concomitant severe neutropenia occurred in 12% of patients receiving the drug as monotherapy.

Laboratory findings: slight or moderate transient increases in serum levels of transaminases, alkaline phosphatase, or bilirubin were recorded in 9.2%, 8.1%, and 1.8% of patients, respectively, in the absence of progressive liver metastases.

Slight or moderate transient increase in serum creatinine level was observed in 7.3% of patients.

Combination Therapy

The adverse reactions described in this section relate to irinotecan.

There is no evidence that cetuximab affects the safety profile of irinotecan or vice versa. During combination therapy with cetuximab, additional adverse reactions expected with cetuximab use were reported (such as acneiform dermatitis in 88% of cases). Information on adverse reactions of combined use of irinotecan and cetuximab is also provided in the medical instructions for this medicinal product.

The following adverse reactions were reported in patients receiving capecitabine in combination with irinotecan, in addition to those observed during capecitabine monotherapy or occurring with higher frequency compared to capecitabine monotherapy.

Very common – all grades of severity: thrombosis/embolism. Common – all grades of severity: hypersensitivity reactions, ischemia/myocardial infarction. Common – grade III and IV adverse reactions: febrile neutropenia. Complete information on capecitabine adverse reactions is provided in the medical instructions for this medicinal product.

The following grade III and IV adverse reactions were reported in patients receiving capecitabine in combination with irinotecan and bevacizumab, in addition to those observed during capecitabine monotherapy or occurring with higher frequency compared to capecitabine monotherapy: Common – grade III and IV adverse reactions: neutropenia, thrombosis/embolism, arterial hypertension, ischemia/myocardial infarction. Complete information on adverse reactions of capecitabine and bevacizumab is provided in the medical instructions for these medicinal products.

The development of grade III arterial hypertension was the main significant risk associated with adding bevacizumab to bolus dose regimen of irinotecan/5-FU/FA. Additionally, with this treatment regimen, a slight increase in the frequency of grade III/IV chemotherapy-related adverse reactions—diarrhea and leukopenia—was observed compared to patients receiving only bolus dose irinotecan/5-FU/FA. Other information on adverse reactions of combination therapy with bevacizumab is provided in the medical instructions for this medicinal product.

Studies have been conducted on the use of irinotecan in combination with 5-FU and FA for the treatment of metastatic colorectal cancer.

Safety data on adverse reactions obtained during clinical trials show that very common adverse reactions of grade III or IV according to the National Cancer Institute scale, possibly or probably related to therapy, occurred in the following MedDRA organ system classes: blood and lymphatic system disorders, gastrointestinal disorders, skin and subcutaneous tissue disorders.

The following adverse reactions, possibly or probably related to irinotecan use, were reported in 145 patients who received irinotecan at the recommended dose of 180 mg/m² in combination therapy with 5-FU/FA every 2 weeks.

Adverse reactions reported during combination therapy with irinotecan (schedule: 180 mg/m² every 2 weeks):

Infections and infestations

Common: infections.

Blood and lymphatic system disorders

Very common: thrombocytopenia, neutropenia, anemia.

Common: febrile neutropenia.

Metabolism and nutrition disorders

Very common: decreased appetite.

Nervous system disorders

Very common: cholinergic syndrome.

Gastrointestinal disorders

Very common: diarrhea, vomiting, nausea.

Common: abdominal pain, constipation.

Skin and subcutaneous tissue disorders

Very common: alopecia (reversible).

General disorders and administration site conditions

Very common: mucositis, asthenia.

Common: fever.

Investigations

Very common: increased transaminases (ALT and AST), increased bilirubin, increased alkaline phosphatase in blood.

Description of selected adverse reactions (in combination therapy)

Severe diarrhea was observed in 13.1% of patients who followed recommendations for diarrhea control. In evaluable treatment cycles, severe diarrhea occurred in 3.9%.

Severe nausea and vomiting were observed less frequently (in 2.1% and 2.8% of patients, respectively).

Constipation due to irinotecan and/or loperamide occurred in 3.4% of patients.

Neutropenia occurred in 82.5% of patients, with severe grade (neutrophil count < 500 cells/mm³) in 9.8% of patients. In evaluable treatment cycles, neutrophil count was below 1000 cells/mm³ in 67.3%, including 2.7% with neutrophil count < 500 cells/mm³. Complete recovery usually took up to 7–8 days.

Febrile neutropenia occurred in 3.4% of patients and in 0.9% of all treatment cycles.

Infections occurred in approximately 2% of patients (0.5% of all treatment cycles) and were associated with severe neutropenia in approximately 2.1% of patients (0.5% of all treatment cycles); in one case, this complication led to a fatal outcome.

Anemia occurred in 97.2% of patients (2.1% with hemoglobin < 8 g/dL).

Thrombocytopenia (< 100,000 cells/mm³) occurred in 32.6% of patients and in 21.8% of all treatment cycles. No cases of severe thrombocytopenia (< 50,000 cells/mm³) were observed.

Acute cholinergic syndrome: transient acute cholinergic syndrome of severe degree occurred in 1.4% of patients receiving combination therapy.

Asthenia was severe in 6.2% of patients receiving combination therapy. The causal relationship between this event and irinotecan administration has not been clearly established.

Fever in the absence of infection or concomitant severe neutropenia occurred in 6.2% of patients receiving combination therapy.

Laboratory findings: transient increases (grades I and II) in serum levels of AST, ALT, alkaline phosphatase, or bilirubin were observed in 15%, 11%, 11%, and 10% of patients, respectively, in the absence of progressive liver metastases. Transient increases of grade III severity were observed in 0%, 0%, 0%, and 1% of patients, respectively. No cases of grade IV severity were observed.

Very rare reports of increased amylase and/or lipase levels were received.

Rare cases of hypokalemia and hyponatremia were reported, mostly associated with diarrhea and vomiting.

Other adverse reactions reported in clinical trials of weekly irinotecan regimen

Additional adverse reactions associated with irinotecan use were reported in clinical trials: pain, sepsis, rectal disorders, gastrointestinal candidiasis, hypomagnesemia, rash, skin symptoms, gait disturbance, confusion, headache, syncope, flushing, bradycardia, urinary tract infections, chest pain, increased gamma-glutamyl transferase, extravasation, tumor lysis syndrome, cardiovascular disorders (angina, cardiac arrest, myocardial infarction, myocardial ischemia, peripheral vascular disorders, vascular disorders), and thromboembolic events (arterial thrombosis, ischemic stroke, cerebrovascular disorders, deep vein thrombosis, peripheral vascular embolism, pulmonary embolism, thrombophlebitis, thrombosis, and sudden death) (see section "Special Warnings and Precautions for Use").

Post-marketing Surveillance

The frequency of adverse reactions during post-marketing surveillance is unknown (cannot be estimated from available data).

Infections and infestations: pseudomembranous colitis, one case confirmed by bacteriological analysis (Clostridium difficile), sepsis, fungal infection^A, viral infection^B.

Blood and lymphatic system disorders: peripheral thrombocytopenia with anti-platelet antibodies.

Gastrointestinal and metabolic disorders: dehydration (due to diarrhea and vomiting), hypovolemia.

Immune system disorders: hypersensitivity reactions, anaphylactic reaction.

Nervous system disorders: speech disorders, mostly reversible and in some cases associated with cholinergic syndrome observed during or immediately after irinotecan infusion, paresthesia, involuntary muscle contractions.

Cardiac disorders: arterial hypertension (during or after infusion), cardiac failure^C.

Vascular disorders: arterial hypotension^C.

Respiratory, thoracic and mediastinal disorders: interstitial lung diseases, manifesting as pulmonary infiltrates, occurring infrequently during irinotecan treatment (cases of early effects such as dyspnea have been reported) (see section "Special Warnings and Precautions for Use"); hiccups.

Gastrointestinal disorders: intestinal obstruction; ileus: cases of ileus without preceding colitis were also reported; megacolon; gastrointestinal hemorrhage; colitis, in some cases complicated by ulcers, bleeding, ileus, or infection; typhlitis; ischemic colitis; ulcerative colitis; symptomatic or asymptomatic elevation of pancreatic enzymes; intestinal perforation.

Hepatobiliary disorders: steatohepatitis, hepatic steatosis.

Skin and subcutaneous tissue disorders: skin reactions.

General disorders and administration site conditions: infusion site reactions, breast pain, pain.

Investigations: increased blood amylase, increased lipase, hypokalemia, hyponatremia, mostly associated with diarrhea and vomiting, very rare reports of increased serum transaminases (AST and ALT) in the absence of progressive liver metastases.

Musculoskeletal and connective tissue disorders: muscle contractions or cramps.

Renal and urinary disorders: renal function impairment and acute renal failure usually observed in patients with infection and/or hypovolemia resulting from severe gastrointestinal toxicity^C, renal failure^C.

^A e.g., Pneumocystis jirovecii pneumonia, bronchopulmonary aspergillosis, systemic candidiasis.

^B Herpes zoster, influenza, hepatitis B reactivation, cytomegalovirus colitis.

^C Rare cases of renal failure, arterial hypotension, or cardiac failure were observed in patients who experienced dehydration due to diarrhea and/or vomiting or sepsis.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life

3 years.

Diluted medicinal product (infusion solution)

The aseptically prepared drug solution is physically and chemically stable with infusion solutions (0.9% sodium chloride solution and 5% glucose solution) for 28 days when stored in PENG or PVC containers at 5°C to 30°C in a light-protected place. Under light exposure, physicochemical stability is maintained for 3 days.

From a microbiological standpoint, the diluted preparation should be used immediately. If not administered immediately after dilution, the user is responsible for storage duration and conditions. Usually, the preparation should be stored for no more than 24 hours at 2–8°C, unless dilution was performed under controlled and validated aseptic conditions.

Storage conditions

Store in the original packaging in a light-protected place. Do not freeze. Keep out of reach of children.

Incompatibilities

Do not mix with other medicinal products in the same vial, except with 0.9% sodium chloride solution or 0.5% glucose solution.

Packaging

5 ml (100 mg) or 15 ml (300 mg) in a vial, 1 vial per pack.

Prescription status

Prescription only.

Manufacturer

Accord Healthcare Polska Sp. z o.o. Importer's Warehouse / Accord Healthcare Polska Sp. z o.o. Magazyn Importera.

Manufacturer's address

ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing Authorization Holder

Accord Healthcare Polska Sp. z o.o. / Accord Healthcare Polska Sp. z o.o.

Address of the Marketing Authorization Holder

7 Tasmowa St., Warsaw, 02-677, Poland.

Date of last review