Irinotecan-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IRINOTECAN-VISTA (IRINOTECAN-VISTA)

Composition:

Active substance: irinotecan;

1 ml of concentrate contains 20 mg of irinotecan hydrochloride trihydrate;

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

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless or slightly yellowish solution.

Pharmacotherapeutic group.

Antineoplastic agents. Irinotecan. ATC code: L01X X19.

Pharmacological properties.

Pharmacodynamics.

Irinotecan is an antineoplastic agent, a semisynthetic derivative of camptothecin—an alkaloid from Camptotheca acuminata—and a specific inhibitor of topoisomerase I. Irinotecan and its active metabolite SN-38 bind to the "topoisomerase I–DNA" complex and prevent replication of these single-stranded sequences. Recent studies have demonstrated that the cytotoxicity of irinotecan is associated with double-stranded DNA damage occurring during DNA synthesis, when the replication enzyme interacts with the quaternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38.

Irinotecan is a water-soluble prodrug of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan via carboxylesterase-mediated cleavage of the carbonate bond between camptothecin and the dipiperidino side chain. As an inhibitor of topoisomerase I isolated from human and rodent tumor cell lines, SN-38 is approximately 1000 times more potent than irinotecan. In vitro cytotoxicity analyses indicate that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold. However, plasma area under the concentration-time curve (AUC) values for SN-38 are only 2–8% of those for irinotecan. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxyl anionic form. A pH-dependent equilibrium exists between these two forms: acidic pH favors lactone formation, whereas alkaline pH promotes the hydroxyl anionic form.

In most tissues, carboxylesterase converts irinotecan into SN-38, which is more active against purified topoisomerase I and more cytotoxic than irinotecan against various human and murine tumor cell lines. Inhibition of DNA topoisomerase I by irinotecan or SN-38 leads to single-strand DNA breaks, resulting in blockade of the replication fork and subsequent cytotoxic effects. This cytotoxic effect has been shown to be time-dependent and specific to the S-phase of the cell cycle.

It has been established that irinotecan and SN-38 are not significantly recognized by P-glycoprotein (multidrug resistance protein) in vitro and exert cytotoxic effects on cell lines resistant to doxorubicin and vinblastine. Moreover, irinotecan demonstrates broad-spectrum antitumor activity in vivo against murine tumor models (pancreatic duct adenocarcinoma P03, mammary adenocarcinoma MA16/C, colon adenocarcinomas C38 and C51) and human tumor xenografts (colon adenocarcinoma Co-4, mammary adenocarcinoma Mx-1, gastric adenocarcinomas ST-15 and ST-16). Irinotecan is also effective against tumors expressing P-glycoprotein multidrug resistance protein (vincristine- and doxorubicin-resistant P388 leukemias). In addition to its antitumor activity, the most significant pharmacological effect of Irinotecan-Vista is inhibition of acetylcholinesterase activity.

Clinical study data.

• First-line combination therapy for metastatic colorectal carcinoma.
  • Combined therapy with folinic acid and 5-fluorouracil.
  • A phase III study was conducted in 385 patients with metastatic colorectal cancer who had not previously received treatment for this disease. Treatment was administered according to either a "once every 2 weeks" or a "once weekly" regimen (see section "Dosage and administration"). In the "once every 2 weeks" regimen, on day 1, after administration of irinotecan at a dose of 180 mg/m² body surface area (once every 2 weeks), infusions of folinic acid (200 mg/m² body surface area intravenously over 2 hours) and 5-FU (400 mg/m² body surface area as an intravenous bolus, followed by 600 mg/m² body surface area as a 22-hour intravenous infusion) were performed. On day 2, folinic acid and 5-fluorouracil were administered at the same doses and according to the same schedule. In the "once weekly" regimen, for 6 weeks following administration of irinotecan at a dose of 80 mg/m² body surface area, infusions of folinic acid (500 mg/m² body surface area intravenously over 2 hours) and 5-fluorouracil (2300 mg/m² body surface area as a 24-hour intravenous infusion) were performed. In the combination therapy study using the two regimens described above, the efficacy of irinotecan was evaluated in 198 patients.

	Combined regimens (n = 198)		Weekly (n = 50)		Every 2 weeks (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 time (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

AE: Not significant.

*: According to the analysis performed in the per-protocol population.

With the "once weekly" regimen, the incidence of severe diarrhea was 44.4% in patients receiving irinotecan and 25.6% in patients receiving 5-FU/FA alone. The incidence of severe neutropenia (neutrophil count less than 500 cells/mm³) was 5.8% in patients receiving irinotecan and 2.4% in patients receiving 5-FU/FA alone. Furthermore, the median time to definitive deterioration in health status was significantly longer in the combination regimens including irinotecan compared to the 5-FU/FA alone group (p = 0.046). Quality of life in this phase III study was assessed using the EORTC QLQ-C30 questionnaire. Time to definitive deterioration was consistently longer in the irinotecan treatment group. Gradual changes in the Global Health Status/Quality of Life score in the combination therapy group with irinotecan were slightly better (although not statistically significant), suggesting that effective treatment with irinotecan in combination regimens is feasible without compromising quality of life.

• In combination therapy with bevacizumab.

The evaluation of bevacizumab in combination with irinotecan/5-FU/FA as first-line treatment for metastatic carcinoma of the colon or rectum was assessed in a randomized, double-blind, active-controlled phase III clinical trial (study AVF2107g). The addition of bevacizumab to the combination of irinotecan/5-FU/FA 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. The efficacy results from study AVF2107g are presented in the table below.

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

a - 5 mg/kg every 2 weeks;

b - compared with the control group.

• 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 and irinotecan with or without the addition of infusional 5-fluorouracil/leucovorin (5-FU/LV) (599 patients). In the patient group evaluated for KRAS gene status, patients with tumors characterized by wild-type KRAS accounted for 64%. The efficacy results obtained in this study are presented in the table below.

Variable/Statistical data	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

CI = confidence interval.

• In combination therapy with capecitabine.

Results from a phase III randomized controlled trial (CAIRO) support the use of capecitabine at an initial dose of 1000 mg/m² body surface area (for 2 weeks out of every 3) 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 sequential therapy (n=410) or combination therapy (n=410). Sequential therapy consisted of first-line treatment (capecitabine 1250 mg/m² body surface area twice daily for 14 days), second-line treatment (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 treatment (capecitabine at a dose of

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 treatment (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 3 weeks. During first-line treatment, median progression-free survival in the group of patients initiating treatment was 5.8 months (95% CI: 5.1–6.2 months) for capecitabine monotherapy and 7.8 months (95% CI: 7.0–8.3 months) for XELIRI (p = 0.0002). Interim results from a multicenter, randomized, controlled phase II trial (AIO KRK 0604) support the use of capecitabine at an initial dose of 800 mg/m² body surface area (for 2 weeks out of every 3) 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 2 weeks followed by a 7-day break), irinotecan (200 mg/m² body surface area as a 30-minute infusion on day 1 of each 3-week cycle), and bevacizumab (7.5 mg/kg as a 30–90 minute infusion on day 1 of each 3-week cycle); overall, 118 patients were randomized to the capecitabine plus oxaliplatin and bevacizumab treatment group: capecitabine (1000 mg/m² body surface area twice daily for 2 weeks followed by a 7-day break), oxaliplatin (130 mg/m² body surface area as a 2-hour infusion on day 1 of each 3-week cycle), and bevacizumab (7.5 mg/kg as a 30–90 minute infusion on day 1 of each 3-week cycle). Six-month progression-free survival in the group of patients initiating treatment was 80% in the XELIRI plus bevacizumab group and 74% in the XELOX plus bevacizumab group. Overall response rate (complete and partial response) was 45% (XELOX plus bevacizumab) versus 47% (XELIRI plus bevacizumab).

• Monotherapy as second-line treatment of metastatic colorectal carcinoma. Phase II/III clinical trials using a dosing schedule of once every 3 weeks were conducted in more than 980 patients with metastatic colorectal cancer who had failed prior 5-FU therapy. The efficacy of irinotecan was evaluated in 765 patients who had documented disease progression while on 5-FU at the time of study entry.

	Phase III
	Irinotecan compared to supportive care			Irinotecan compared to 5-FU
	Irinote-can n = 183	Supportive care n = 90	p value	Iri-no-tecan n = 127	5-FU n = 129	p value
Progression-free survival at 6 months (%)	NS	NS		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

ND: not applicable.

* : Statistically significant difference.

In phase II studies involving 455 patients using a dosing regimen of once every 3 weeks, progression-free survival at 6 months was 30%, and median survival was 9 months. Median time to progression was 18 weeks. Additional non-comparative phase II studies were conducted in 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 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-3-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 trials. Overall, 356 patients with metastatic colorectal cancer expressing epidermal growth factor receptors received combination therapy—specifically, patients for whom cytotoxic therapy with irinotecan had failed. The minimum Karnofsky performance status score was 60, but in most patients it was ≥ 80.

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

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

The efficacy results from these studies are presented in the table below.

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
IMCL-CP02-9923	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

CI – confidence interval.

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).

With regard to 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 effect on overall survival was demonstrated (hazard ratio 0.91, p-value = 0.48). Pharmacokinetics/Pharmacodynamics.

The severity of the main toxicities observed with irinotecan (e.g., leukopenia and diarrhea) is related to the exposure level (AUC) of the active substance and its metabolite SN-38. A significant correlation has been established between the severity of hematological toxicity (minimum values to which leukocyte and neutrophil levels decreased) or diarrhea and AUC values for irinotecan and metabolite SN-38 during monotherapy.

• 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 different metabolic intensities among individuals. The first specific variant of the UGT1A1 gene contains a polymorphic region in the promoter area; this variant is known as UGT1A1*28. This variant, as well as other inherited disorders of UGT1A1 expression (such as Gilbert’s syndrome or Crigler-Najjar syndrome), are associated with reduced enzyme activity. Meta-analysis results indicate that patients with Crigler-Najjar syndrome (types 1 and 2) or homozygous carriers of the UGT1A1*28 allele (Gilbert’s syndrome) are at increased risk of developing hematological toxicity (grades 3 and 4) following administration of moderate or high doses of irinotecan (>150 mg/m²). The relationship between UGT1A1 genotype and irinotecan-induced diarrhea has not been established.

Patients known to be homozygous for the UGT1A1*28 allele should receive the standard initial dose of irinotecan. However, these patients should be closely monitored for hematological toxicity. For patients who have experienced hematological toxicity during previous 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 "Dosage and Administration" and "Special Warnings and Precautions for Use").

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

Pharmacokinetics.

After intravenous infusion in humans, plasma concentrations of irinotecan decline in a multi-exponential manner, with a mean elimination half-life of 6 hours. The mean elimination half-life of SN-38 is 10 hours. The mean elimination half-lives of lactone and hydroxyl anionic forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as these forms are in equilibrium.

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, the elimination profile of irinotecan was shown to be biphasic. The mean plasma clearance of irinotecan was 15 L/h/m², and the volume of distribution at steady state (Vss) was 157 L/m² body surface area. The mean elimination half-life in the first phase of the triphasic model was 12 minutes, in the second phase 2.5 hours, and the terminal half-life was 14.2 hours. The elimination of SN-38 is biphasic, with a mean elimination half-life of 13.8 hours. At the end of infusion of the recommended dose of 350 mg/m² body surface area, the mean maximum plasma concentrations were 7.7 µg/mL for irinotecan and 56 ng/mL for SN-38, and the mean values of the area under the pharmacokinetic curve (AUC) were 34 µg•h/mL and 451 ng•h/mL, respectively. SN-38 typically exhibits marked inter-individual variability in pharmacokinetic characteristics. 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 trials. The pharmacokinetic parameters determined 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 CPT-11 dose. The pharmacokinetics of these compounds do not depend on the number of prior treatment cycles or dosing schedule. Within the dose range of 50–350 mg/m², the area under the concentration-time curve (AUC) for irinotecan increases linearly and dose-dependently; the AUC for SN-38 increases more slowly than the dose increase. Maximum SN-38 concentration is reached 1 hour after the end of a 90-minute irinotecan infusion. Irinotecan is moderately bound to plasma proteins (30–68%). SN-38 is extensively bound to plasma proteins (approximately 95%). Irinotecan and SN-38 primarily bind to albumin.

Metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzyme and occurs in the liver. Subsequently, SN-38 forms a glucuronide metabolite via conjugation. SN-38 glucuronide has 1/50 to 1/100 of the cytotoxic activity of SN-38 in in vitro analysis of two cell lines. The distribution of irinotecan in humans is not fully understood. Renal excretion of irinotecan accounts for 11–20%, of SN-38 less than 1%, and of SN-38 glucuronide 3%. Cumulative excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) in bile and urine within 48 hours after administration ranges from 25% (100 mg/m²) to 50% (300 mg/m²). Mass balance and metabolism studies using 14C-labeled irinotecan demonstrated that more than 50% of the intravenously administered dose of irinotecan is excreted unchanged, with 33% of the dose excreted in feces (primarily via bile) and 22% in urine.

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

• Hydrolysis mediated by carboxylesterase, forming 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 subsequent hydrolysis in the intestinal tract;
• Oxidation by cytochrome P450 3A leads to cleavage of the outer piperidine ring, forming an aminopentanoic acid derivative and a primary amine derivative (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Pharmacokinetics in Specific Populations.

Geriatric Patients. Studies have not revealed differences in the pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide between elderly patients and those under 65 years of age. The terminal half-life of irinotecan was 5.5 hours in patients under 65 years and 6 hours in patients over 65 years. AUC0-24 for SN-38 in patients over 65 years was 11% higher than in younger patients. This difference was not statistically significant. Gender. The pharmacokinetics of irinotecan are not influenced by gender.

Race. The pharmacokinetic characteristics of irinotecan in patients of different races have not been studied. Hepatic Impairment. Irinotecan clearance is reduced in patients with hepatic dysfunction, resulting in increased SN-38 concentrations. The extent of this effect depends on the degree of hepatic impairment, assessed by serum levels of total bilirubin and transaminases.

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 exposure as administration of 350 mg/m² body surface area of irinotecan to patients with normal liver function.

Renal Impairment. The effect of renal impairment on the pharmacokinetics of irinotecan has not been studied.

Clinical characteristics.

Indications.

Treatment of patients with advanced colorectal cancer:

• in combination with 5-fluorouracil (5-FU) and folinic acid (FA) in patients who have not received prior chemotherapy for advanced disease;
• monotherapy in patients in whom treatment with 5-fluorouracil has been ineffective.

Irinotecan in combination with cetuximab is indicated for the treatment of patients with metastatic colorectal cancer with wild-type KRAS gene and overexpression of epidermal growth factor receptor (EGFR), who have not previously received chemotherapy, or following ineffective cytotoxic therapy including irinotecan.

Irinotecan in combination with 5-fluorouracil, folinic acid, and bevacizumab is indicated for the treatment of metastatic carcinoma of the colon and rectum as first-line therapy.

In combination with capecitabine (with or without bevacizumab), irinotecan is indicated as first-line therapy in patients with metastatic colorectal cancer.

Contraindications.

• Chronic inflammatory bowel diseases and/or intestinal obstruction (see section "Special precautions");
• hypersensitivity to irinotecan hydrochloride or to any of the excipients;
• breastfeeding period;
• hyperbilirubinemia (serum bilirubin level exceeding the upper normal limit by 3 times);
• severe bone marrow suppression;
• patient's general condition > 2 (according to WHO classification);
• severe neutropenia (less than 1.5 × 10⁹/L);
• concomitant use of St. John's wort (Hypericum perforatum) preparations;
• live attenuated vaccines.

When used in combination with cetuximab, bevacizumab, or capecitabine, additional contraindications are listed in the respective product information for these medicinal products.

Special precautions.

Care should be taken during preparation and administration of irinotecan; protective goggles, mask, and gloves should be used. If the concentrate or prepared infusion solution comes into contact with the skin, it should be immediately and thoroughly washed off with soap and water. If the concentrate or prepared infusion solution contacts mucous membranes, they should be immediately rinsed with water.

Waste disposal.

All materials used for dilution and administration of the medicinal product should be destroyed according to standard procedures for cytotoxic agents.

Interaction with other medicinal products and other types of interactions.

Concomitant use of the following medicinal products with Irinotecan-Vista is contraindicated (see section "Contraindications").

• Live attenuated vaccines (e.g., yellow fever vaccine) – due to the risk of developing systemic diseases with potentially fatal outcomes (e.g., infections). This risk is increased in patients who already have immunosuppression due to the underlying disease. Concomitant administration of live attenuated vaccines is contraindicated during treatment with irinotecan and for 6 months after completion of chemotherapy. Inactivated vaccines (e.g., polio vaccine) may be used, but the immune response to such vaccines may be reduced.
• The concentration of the active metabolite SN-38 is reduced in patients who are concurrently taking St. John's wort (Hypericum perforatum) preparations. In a small pharmacokinetic study (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. Administration of these medicinal products should be discontinued at least 1 week before the first cycle of irinotecan therapy and should not be prescribed during irinotecan treatment. The following medicinal products are not recommended for concomitant use with Irinotecan-Vista.

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

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

Other combinations.

Antineoplastic agents (including fluorocytosine as a prodrug of 5-fluorouracil). Adverse effects of irinotecan, such as myelosuppression, may be enhanced by other antineoplastic agents with a similar adverse effect profile. Caution should be exercised when treating patients who are concurrently taking inhibitors (e.g., ketoconazole) or inducers (e.g., rifampicin, carbamazepine, phenobarbital, or phenytoin) of drug metabolism via cytochrome P450 3A4. Results from several studies have demonstrated that concomitant use of CYP3A-inducing anticonvulsants (e.g., carbamazepine, phenobarbital, or phenytoin) reduces exposure levels of irinotecan, SN-38, and SN-38-glucuronide, leading to decreased pharmacodynamic effect. The effect of such anticonvulsants resulted in a reduction of AUC for SN-38 and SN-38-glucuronide by 50% or more. In addition to induction of cytochrome P450 3A, reduced exposure to irinotecan and its metabolites may also be due to enhanced glucuronidation and more intensive biliary excretion.

Anticonvulsant therapy with non-enzyme-inducing agents should be prescribed cautiously, at least 1 week prior to initiation of irinotecan. Clearance of irinotecan is significantly reduced in patients receiving concomitant therapy with ketoconazole, resulting in increased SN-38 concentration. Ketoconazole should be discontinued at least 1 week before initiation of irinotecan therapy and should not be prescribed during irinotecan treatment.

Phenytoin – due to the risk of seizure exacerbation resulting from reduced gastrointestinal absorption of phenytoin under the influence of cytotoxic agents, or due to the risk of increased toxicity resulting from enhanced metabolic conversion under the influence of phenytoin.

Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, protease inhibitors, clarithromycin, erythromycin, telithromycin). A study demonstrated that concomitant use of ketoconazole resulted in an 87% reduction in AUC of the metabolite APC and a 109% reduction in AUC of the metabolite SN-38 compared to irinotecan monotherapy. Inhibitors of UGT1A1 (e.g., atazanavir, ketoconazole, regorafenib). Concomitant use of atazanavir sulfate, an inhibitor of CYP3A4 and UGT1A1, may increase systemic concentrations of SN-38, the active metabolite of irinotecan. Physicians should consider this possibility when prescribing these two medicinal products concomitantly.

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

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

The following medicinal products should be used with caution when administered concomitantly with Irinotecan-Vista. Anticoagulants are frequently used in cancer patients due to increased risk of thrombosis. In patients requiring vitamin K antagonist anticoagulants, INR (International Normalized Ratio) should be monitored more frequently than usual. This is due to the narrow therapeutic range of these agents, high individual variability in coagulation parameters, and potential interactions between oral anticoagulants and anticancer chemotherapeutic agents. Immunosuppressants (e.g., cyclosporine, tacrolimus) – due to the risk of excessive immunosuppression and lymphocyte proliferation. Neuromuscular blockers: interaction between irinotecan and neuromuscular blocking agents cannot be excluded. Since irinotecan has anticholinesterase activity, prolonged neuromuscular blockade may occur with the use of succinylcholine; antagonistic interaction regarding neuromuscular transmission may also occur when used concomitantly with non-depolarizing muscle relaxants.

Other combinations.

Adverse effects of irinotecan such as myelosuppression and diarrhea may be intensified by other antineoplastic agents with a similar toxicity profile. Use of dexamethasone as an antiemetic increases the likelihood of developing lymphopenia; however, significant opportunistic infections or specific complications characteristic of lymphopenia have not been observed.

Hyperglycemia has been observed in diabetic patients or those with impaired glucose tolerance receiving irinotecan. Hyperglycemia may also develop in some patients due to the use of dexamethasone as an antiemetic. Laxatives used during irinotecan therapy may worsen tolerability of the medicinal product or increase the severity of diarrhea.

Irinotecan may cause secondary dehydration due to vomiting or diarrhea, which may necessitate discontinuation of diuretics during irinotecan treatment or in cases of severe vomiting or diarrhea.

Interactions common to all cytotoxic medicinal products.

There is no information available on the effect of cetuximab on the safety profile of irinotecan or vice versa.

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

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

Special precautions for use.

Irinotecan hydrochloride infusion should be administered only in specialized centers where cytotoxic chemotherapy is performed and only under the supervision of a physician experienced in the use of chemotherapy in oncology.

Considering the nature and frequency of adverse effects, irinotecan hydrochloride should be prescribed only when the expected benefit outweighs the potential risk:

• treatment of patients with risk factors, particularly those with a performance status of 2 (WHO scale);
• in individual cases where patients do not comply with recommendations for preventing adverse effects (particularly the need for immediate and prolonged antidiarrheal therapy along with increased fluid intake). Such patients require careful clinical monitoring.

Delayed diarrhea.

Patients should be informed about the risk of delayed diarrhea, which may occur more than 24 hours after administration of irinotecan and at any time before the next cycle. When used as monotherapy, the median time to the first episode of loose stools was 5 days after drug administration. Patients must immediately inform their physician about the frequency of such episodes and initiate appropriate treatment. Patients at increased risk of developing diarrhea include those previously treated with radiotherapy to the abdominal or pelvic region; patients with prior hyperleukocytosis; patients with poor general condition (performance status > 2 according to WHO classification); and female patients. If diarrhea is not properly treated, it may become life-threatening, particularly when associated with neutropenia.

At the first episode of loose stools, patients should be advised to drink frequently fluids containing electrolytes and to immediately initiate appropriate antidiarrheal therapy.

Recommended antidiarrheal therapy includes high-dose loperamide (4 mg as the first dose, then 2 mg every 2 hours). This therapy should be continued for an additional 12 hours after the last episode of diarrhea, but not longer than 48 hours due to the risk of paralytic ileus. The treatment regimen should not be modified. After hospital discharge, patients should receive prescribed medications to allow immediate initiation of diarrhea treatment upon its onset. Additionally, patients should inform their physician at the department where irinotecan was administered.

In cases of diarrhea associated with neutropenia (neutrophil count < 0.5 × 10⁹/L), in addition to antidiarrheal agents, broad-spectrum antibiotics should be administered prophylactically.

Hospitalization is required for diarrhea management in the following situations, apart from cases requiring antibiotic therapy: diarrhea associated with fever; severe diarrhea (requiring intravenous hydration); diarrhea lasting more than 48 hours despite high-dose loperamide therapy.

Loperamide should not be prescribed prophylactically, even in patients who experienced late diarrhea in previous treatment cycles. In patients who experienced severe diarrhea, a dose reduction of irinotecan is recommended in subsequent treatment cycles. The recommended dose of the drug is 125 mg/m² administered as an intravenous infusion over 90 minutes once weekly for 4 weeks, followed by a 2-week break.

Patients with severe diarrhea are at increased risk of infectious diseases and hematotoxic effects. Such patients should undergo regular complete blood counts.

Hematological disorders.

In clinical studies, the incidence of grade 3–4 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 baseline total serum bilirubin levels ≥ 1.0 mg/dL also had a significantly higher probability of developing grade 3–4 neutropenia during the first treatment cycle compared to patients with bilirubin levels < 1.0 mg/dL. Complete blood counts should be performed weekly during irinotecan treatment. Neutropenia associated with fever (temperature > 38 °C and neutrophil count < 1.0 × 10⁹/L) must be urgently treated in a medical facility with intravenous broad-spectrum antibiotics.

Patients who experienced severe hematological adverse reactions should have their irinotecan dose reduced in subsequent administrations (see section "Dosage and administration"). Patients with severe diarrhea are at increased risk of infections and hematological toxicity. These patients require blood count monitoring.

Hepatic impairment.

Liver function tests should be performed prior to initiation of therapy and before each subsequent cycle. Patients with total serum bilirubin concentrations 1.5 to 3 times above the upper limit of normal should undergo weekly complete blood counts due to reduced irinotecan clearance (see section "Pharmacokinetics") and, consequently, increased risk of hematotoxicity in this patient group. Irinotecan must not be administered to patients with bilirubin levels exceeding the upper limit of normal by more than 3 times—see section "Contraindications".

Nausea and vomiting.

Prophylactic antiemetic treatment is recommended before each irinotecan administration. Nausea and vomiting are frequently reported with irinotecan use. Patients experiencing vomiting in combination with delayed diarrhea should be urgently hospitalized for appropriate treatment.

Acute cholinergic syndrome.

In the absence of clinical contraindications (see section "Adverse reactions"), subcutaneous administration of 0.25 mg atropine sulfate is recommended in case of acute cholinergic syndrome (early diarrhea in combination with various other signs and symptoms such as increased sweating, abdominal cramps, miosis, and hypersalivation). These symptoms, which may occur during or immediately after irinotecan infusion, are associated with the anticholinesterase activity of the parent compound irinotecan. It is expected that higher irinotecan doses will increase the frequency of these symptoms.

Caution is advised in patients with bronchial asthma. Patients who experienced acute and severe cholinergic syndrome should receive prophylactic atropine sulfate prior to subsequent irinotecan infusions.

Respiratory disorders.

Rare cases of interstitial lung disease, manifested as pulmonary infiltrates, may occur during irinotecan treatment. Interstitial lung disease may be fatal. Risk factors for pulmonary infiltrates include use of pneumotoxic agents, radiotherapy, and colony-stimulating factors. In the presence of these risk factors, continuous monitoring of respiratory symptoms before and during irinotecan therapy is required.

Extravasation.

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

Elderly patients.

Due to decreased physiological functions, particularly liver function, caution is required when selecting the irinotecan dose for 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 been reported. These events were usually associated with complications of infection or dehydration due to nausea, vomiting, or diarrhea. Additionally, isolated cases of renal dysfunction due to tumor lysis syndrome have been reported.

Cardiac disorders.

Myocardial ischemia has been observed after irinotecan treatment, primarily in patients with pre-existing heart disease, other known risk factors for cardiac 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, 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).

Immunosuppressive effects, increased susceptibility to infections.

Administration of live or live attenuated vaccines to patients with chemotherapy-induced immunosuppression (including irinotecan) may lead to severe infections and even fatal infections. Live vaccines should be avoided in patients receiving irinotecan. Inactivated or killed vaccines may be used, but the immune response to such vaccines may be diminished.

Radiotherapy.

Patients previously treated with pelvic or abdominal radiotherapy are at increased risk of developing myelosuppression during irinotecan treatment. 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 patient group may require dose adjustment of the drug (see section "Dosage and administration").

Others.

Isolated cases of renal failure, arterial hypotension, or circulatory failure have been observed in patients who experienced diarrhea, vomiting, or sepsis leading to dehydration.

During treatment and for at least 3 months after completion of therapy, patients should use contraceptive methods.

Concomitant use of irinotecan with strong inhibitors (e.g., ketoconazole) or inducers (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, apalutamide, St. John's wort) of CYP3A4 should be avoided, as such combinations may alter irinotecan metabolism (see section "Interaction with other medicinal products and other forms of interaction").

Important information on excipients.

Since the medicinal product contains sorbitol, it should not be administered to patients with hereditary fructose intolerance.

Use during pregnancy or breastfeeding.

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-Vista should not be used during pregnancy, except in cases of extreme necessity.

Women of childbearing potential.

Women of reproductive age should use effective contraception during treatment and for 1 month after treatment. Men should use effective contraception during treatment and for 3 months after completion of therapy.

Effect on fertility.

There is no information on the effect of irinotecan on human fertility. Adverse effects of irinotecan on reproductive function in animal offspring have been documented in animal studies.

Lactation.

Radiolabeled 14C-irinotecan has been detected in the milk of female rats. It is unknown whether irinotecan passes into human breast milk. Therefore, due to the potential for adverse reactions in breastfed infants, breastfeeding should be discontinued during treatment with Irinotecan-Vista (see section "Contraindications").

Ability to affect reaction speed when driving or operating machinery.

Patients should be warned about the possibility of dizziness and visual disturbances occurring within 24 hours during irinotecan treatment and advised to refrain from driving and operating potentially hazardous machinery if use of the medicinal product is necessary.

Method of Administration and Dosage.

Intended for the treatment of adult patients.

Irinotecan solution for infusion is administered via peripheral or central vein. Preparation of the solution for intravenous administration.

As with other injectable medicinal products, Irinotecan-Vista solution should be prepared under aseptic conditions. If visible precipitate is present in the vial before or after reconstitution, the solution must not be used and should be disposed of according to standard procedures for cytotoxic medicinal products. Under aseptic conditions, withdraw the required volume of concentrated Irinotecan-Vista solution from the vial using a calibrated syringe and transfer the dose into a 250 mL bag or bottle containing either 0.9% sodium chloride solution or 5% glucose solution. Gently rotate the container manually to ensure thorough mixing of the solution. 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. When irinotecan hydrochloride is used as monotherapy, the dosing schedule is once every 3 weeks. However, a weekly dosing schedule may be used for patients at risk of developing severe neutropenia and requiring closer monitoring.

Combination therapy (for previously untreated patients).

Irinotecan hydrochloride + 5-FU/FA every 2 weeks: the recommended dose of irinotecan is 180 mg/m² administered as an intravenous infusion over 30–90 minutes once every 2 weeks, followed by infusion of folic acid or 5-fluorouracil.

Doses and administration schedules for cetuximab when used concomitantly with irinotecan should be determined according to approved treatment regimens.

Irinotecan should generally be administered at the same doses as used in the last cycle of the prior regimen containing irinotecan. Irinotecan must not be administered earlier than 1 hour after completion of cetuximab infusion.

Doses and administration schedules for bevacizumab and capecitabine when used concomitantly with irinotecan should be determined according to approved treatment regimens. Dose adjustment.

Irinotecan should be administered only after all adverse effects have resolved to National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 0 or 1, and only after treatment-related diarrhea has been completely resolved. At the beginning of the next infusion cycle, the doses of irinotecan hydrochloride and 5-FU should be reduced based on the highest toxicity grade observed during the previous infusion. If necessary, treatment should be delayed by 1–2 weeks until complete resolution of treatment-related adverse effects.

The dose of irinotecan hydrochloride and 5-FU should be reduced by 15–20% in the event of the following adverse effects:

• Hematological toxicity symptoms (grade IV neutropenia, neutropenia accompanied by fever (neutropenia grade III–IV and fever grade II–IV), thrombocytopenia, and leukopenia (grade IV));
• Non-hematological toxicity symptoms (grade III–IV).

For patients aged 65 years and older receiving irinotecan and capecitabine, the dose of capecitabine should be reduced to 800 mg/m² body surface area twice daily.

Treatment duration: treatment with irinotecan should continue until objective disease progression or until signs of unacceptable toxicity develop.

Patients with hepatic impairment.

As monotherapy: for patients with total serum bilirubin levels more than 3 times the upper limit of normal (ULN) and WHO performance status ≤ 2, the initial dose of irinotecan hydrochloride should be determined. In such patients with hyperbilirubinemia and prothrombin time exceeding 50%, irinotecan clearance is reduced, thereby increasing the risk of hematotoxicity. Therefore, hematological parameters should be monitored weekly in this population.

• For patients with total serum bilirubin concentration up to 1.5 times the ULN, the recommended dose of irinotecan is 350 mg/m².
• For patients with total serum bilirubin concentration between 1.5 and 3 times the ULN, the recommended dose of irinotecan is 200 mg/m².
• Irinotecan should not be administered to patients with total serum bilirubin concentration exceeding 3 times the ULN.

Data on patients with hepatic impairment treated with irinotecan as part of combination therapy are lacking.

Patients with renal impairment.

Irinotecan is not recommended for patients with renal impairment, as studies in this population have not been conducted (see sections "Special precautions" and "Pharmacokinetics").

Elderly patients.

Specific pharmacokinetic studies in elderly patients have not been conducted. However, dose selection should be cautious in individual cases due to age-related decline in physiological functions. This patient group requires close monitoring (see section "Special precautions").

When irinotecan hydrochloride is used as monotherapy, the dosing schedule is once every 3 weeks. However, a weekly dosing schedule may be used for patients requiring closer observation or those at risk of developing severe neutropenia.

Children.

Irinotecan should not be used for the treatment of children.

Overdose.

Symptoms. Overdose is associated with increased severity of adverse effects. Overdose at twice the recommended therapeutic dose may be fatal. The most significant adverse effects observed in overdose include severe-grade neutropenia and severe-grade diarrhea.

Treatment. There is no specific antidote for irinotecan. Intensive supportive therapy should be initiated immediately to prevent dehydration due to diarrhea and to treat infectious complications. Treatment is symptomatic.

Adverse Reactions.

Clinical trials.

Data on adverse reactions were carefully collected during studies in metastatic colorectal cancer; the frequency of their occurrence is presented below. When the medicinal product 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 administration of the medicinal product) and hematological disorders, including neutropenia, anemia, and thrombocytopenia. Neutropenia is the dose-limiting toxic effect. Neutropenia was reversible and not 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-onset diarrhea and various other symptoms such as abdominal pain, sweating, miosis, and increased salivation, which occurred during or within the first 24 hours after irinotecan infusion. These symptoms resolved after administration of atropine (see section "Special precautions for use").

Monotherapy.

The following adverse reactions, possibly or probably related to irinotecan administration, were reported in 765 patients receiving 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). Within each frequency group, adverse reactions are listed in decreasing order of severity.

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

• Infections and infestations.

Common: infections.

• Blood and lymphatic system disorders.

Very common: neutropenia, anemia.

Common: thrombocytopenia, febrile neutropenia.

• Nutrition and metabolism 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 reactions.

Very common: mucositis, pyrexia, asthenia.

• Investigations.

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

Description of selected adverse reactions (during 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 therapy.

Constipation occurred in less than 10% of patients.

Neutropenia occurred in 78.7% of patients, of whom severe grade (neutrophil count < 500 cells/mm³) occurred in 22.6%. In evaluable treatment cycles, neutrophil count was below 1000 cells/mm³ in 18%, including 7.6% with neutrophil count < 500 cells/mm³. Full recovery of counts usually took up to 22 days.

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

Infection episodes occurred in approximately 10.3% of patients (2.5% of all treatment cycles) and were associated with severe neutropenia in about 5.3% of patients (1.1% of all treatment cycles); in 2 cases, this complication led to a fatal outcome.

Anemia was reported 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 (1.8% of all treatment cycles), of whom 0.9% of patients (0.2% of treatment cycles) had platelet counts ≤ 50,000 cells/mm³.

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

Acute cholinergic syndrome.

Transient acute cholinergic syndrome of severe degree occurred in 9% of patients receiving monotherapy.

Asthenia was severe in less than 10% of patients receiving monotherapy. The causal relationship between this event and irinotecan administration was not clearly established. Fever in the absence of infection or concomitant severe neutropenia occurred in 12% of patients receiving monotherapy.

Laboratory tests.

Mild or moderate transient increases in serum transaminases, alkaline phosphatase, or bilirubin levels were observed in 9.2%, 8.1%, and 1.8% of patients, respectively, in the absence of progressive liver metastases.

Mild or moderate transient increase in serum creatinine levels 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 (e.g., acneiform rash in 88% of cases). Information on adverse reactions associated with the combined use of irinotecan and cetuximab is also provided in the instructions for medical use of the respective medicinal products.

The following adverse reactions were reported in patients receiving capecitabine in combination with irinotecan, in addition to those observed during monotherapy with capecitabine or occurring at 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 3 and 4 adverse reactions: febrile neutropenia.

Complete information on capecitabine adverse reactions is provided in the instructions for medical use of this medicinal product.

The following grade 3 and 4 adverse reactions were reported in patients receiving capecitabine in combination with irinotecan and bevacizumab, in addition to those observed during monotherapy with capecitabine or occurring at higher frequency compared to capecitabine monotherapy.

Common, grade 3 and 4 adverse reactions: neutropenia, thrombosis/embolism, arterial hypertension, ischemia/myocardial infarction.

Complete information on adverse reactions of capecitabine and bevacizumab is provided in the instructions for medical use of these medicinal products.

Arterial hypertension of grade 3 was the main significant risk factor associated with the addition of bevacizumab to the treatment regimen of bolus irinotecan/5-FU/FA. Also, with this regimen, the frequency of grade 3–4 diarrhea and leukopenia was slightly increased compared to patients receiving bolus irinotecan/5-FU/FA without bevacizumab.

Additional information on adverse reactions associated with combination therapy including bevacizumab is provided in the instructions for medical use of this medicinal product.

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

Safety data on adverse reactions obtained from clinical trials show that very common adverse reactions of grade 3 or 4 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, gastrointestinal tract, skin and subcutaneous tissue.

The following adverse reactions, possibly or probably related to irinotecan administration, were reported in 145 patients receiving 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 (regimen: 180 mg/m² every 2 weeks):

• Infections and infestations.

Common: infections.

• Blood and lymphatic system disorders.

Very common: thrombocytopenia, neutropenia, anemia.

Common: febrile neutropenia.

• Digestion and metabolism 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 reactions.

Very common: mucositis, asthenia.

Common: pyrexia.

• Investigations.

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

Description of selected adverse reactions (during combination therapy).

Severe diarrhea occurred 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 at lower frequencies (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, of whom severe grade (neutrophil count < 500 cells/mm³) occurred in 9.8%. In evaluable treatment cycles, neutrophil count was below 1000 cells/mm³ in 67.3%, including 2.7% with neutrophil count < 500 cells/mm³. Full recovery of counts usually took 7–8 days.

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

Infection episodes occurred in approximately 2% of patients (0.5% of all treatment cycles) and were associated with severe neutropenia in about 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 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 was not clearly established.

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

Laboratory tests.

Transient increases (grades 1 and 2) in serum AST, ALT, alkaline phosphatase, or bilirubin levels were observed in 15%, 11%, 11%, and 10% of patients, respectively, in the absence of progressive liver metastases. Transient grade 3 increases in these parameters were observed in 0%, 0%, 0%, and 1% of patients, respectively. No grade 4 cases of this adverse reaction were observed. Very rare reports of increased amylase and/or lipase levels were received. Rare cases of hypokalemia and hyponatremia were reported, primarily associated with diarrhea and vomiting.

Other adverse reactions reported in clinical trials of weekly irinotecan regimens.

The following additional adverse reactions associated with the use of irinotecan were reported in clinical trials of weekly irinotecan regimens: pain, sepsis, rectal disorders, gastrointestinal candidiasis, hypomagnesemia, rash, skin symptoms, gait disturbance, confusion, headache, syncope, hot flushes, bradycardia, urinary tract infections, chest pain, increased gamma-glutamyl transferase, hemorrhage, tumor lysis syndrome, cardiovascular disorders (angina pectoris, cardiac arrest, myocardial infarction, myocardial ischemia, peripheral vascular disorders, vascular disorders), and thromboembolic events (arterial thrombosis, ischemic stroke, cerebrovascular accident, deep vein thrombophlebitis, lower extremity venous embolism, pulmonary embolism, thrombophlebitis, thrombosis, and sudden death) (see section "Special 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 of which was confirmed by bacteriological analysis (Clostridium difficile), sepsis, fungal infection*, viral infection**.

Blood and lymphatic system disorders: peripheral thrombocytopenia with formation of antiplatelet antibodies.

Digestion and metabolism 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***.

Vascular disorders: hypotension***.

Respiratory, thoracic and mediastinal disorders: interstitial lung disease, manifesting as pulmonary infiltrates, which are uncommon during irinotecan treatment (cases of early effects such as dyspnea have been reported (see section "Special precautions for use")); hiccups.

Gastrointestinal disorders: intestinal obstruction, ileus: cases of ileus without prior colitis were also reported; megacolon, gastrointestinal hemorrhage, colitis, in some cases colitis complicated by ulcers, bleeding, ileus, or infection; typhlitis, ischemic colitis, ulcerative colitis, gastrointestinal bleeding, 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 reactions: infusion site reactions.

Investigations: increased blood amylase levels, increased lipase levels, hypokalemia, hyponatremia, primarily associated with diarrhea and vomiting, very rare reports of increased serum transaminase levels (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 occurred in patients with infection and/or hypovolemia developed due to severe gastrointestinal toxicity***, renal failure***.

*e.g., Pneumocystis pneumonia, bronchopulmonary aspergillosis, systemic candidiasis. **Herpes zoster, influenza, hepatitis B reactivation, cytomegalovirus colitis.

*** Rare cases of renal failure, 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 medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

The solution of Irinotecan-Vista in infusion solutions (after dilution with 0.9% sodium chloride solution or 5% glucose solution) maintains physical and chemical stability for 12 hours at 15–25 °C and for 48 hours under non-intense lighting conditions at 2–8 °C.

However, to reduce the risk of microbiological contamination, it is recommended to prepare infusion solutions immediately before administration and to administer infusions as soon as possible after preparation. If the solution is not administered immediately after preparation, the responsibility for storage conditions and duration until administration lies with the user. If the solution was not prepared under controlled and validated aseptic conditions, it should be stored at 2–8 °C for no longer than 24 hours.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Incompatibilities. Do not mix with other medicinal products.

The incompatibility of the medicinal product is unknown.

Packaging.

5 mL (100 mg) or 15 mL (300 mg) or 25 mL (500 mg) in a vial;

1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Actavis Italia S.p.A.

Sindan Pharma S.R.L.

Manufacturer's address and location of business activity.

Via Pasteur, 10 - 20014 Nerviano (Milan), Italy.

Bd. Ion Mihalache, 11, Sector 1, 011171, Bucharest, Romania.