Irinotecan-aar: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IRINOTECAN-AAR

Composition:

Active substance: irinotecan;

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

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

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless or pale yellow solution, free from visible foreign particles.

Pharmacotherapeutic group. Antineoplastic agents. ATC code L01C E02.

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, which is more active than irinotecan against purified topoisomerase I and more cytotoxic against a number of 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 DNA replication fork and results in cytotoxic effects. This cytotoxic effect has been shown to be time-dependent and specific to the S-phase of the cell cycle.

In vitro, irinotecan and SN-38 are not significantly recognized by P-glycoprotein multidrug resistance protein and exert cytotoxic effects on cell lines resistant to doxorubicin and vinblastine.

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

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 with metastatic colorectal cancer who had not previously been treated for this disease. Treatment was administered according to investigational drug regimens of "once every 2 weeks" (see section "Method of administration and dosage") or "once weekly." 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), FA (200 mg/m² body surface area intravenously over 2 hours) and 5-FU (400 mg/m² body surface area intravenously as a bolus, followed by 600 mg/m² body surface area over 22 hours as a continuous intravenous infusion) were administered. On day 2, FA and 5-FU were administered at the same doses and according to the same schedule. In the "once weekly" regimen, for 6 weeks, after administration of irinotecan at a dose of 80 mg/m² body surface area, FA (500 mg/m² body surface area intravenously over 2 hours) and 5-FU (2300 mg/m² body surface area over 24 hours as a continuous intravenous infusion) were administered.

In the study of combination therapy using the two treatment regimens described above, the efficacy of irinotecan was evaluated in 198 patients.

Table 1

	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 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

5-FU – 5-fluorouracil;

FA – folic acid;

NS – 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 those receiving 5-FU/FA alone. Moreover, the median time to definitive deterioration in health status was significantly longer in the combination regimens with irinotecan than in 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 were slightly better (although not statistically significant) in the combination therapy group with irinotecan, suggesting that effective treatment with irinotecan as part of combination therapy 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 irinotecan/5-FU/FA combination resulted in a statistically significant improvement in overall survival. The clinical benefit, assessed by overall survival, was evident in 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 Table 2.

Table 2

	Group 1 Irinitecan/5-FU/FA + placebo	Group 2 Irinitecan/5-FU/FA + Avastin
	Group 1 Irinitecan/5-FU/FA + placebo	Group 2 Irinitecan/5-FU/FA + Avastin
Number of patients	411	402
Overall survival
Median (months)	15.6	20.3
95 % confidence interval (CI)	14.29–16.99	18.46–24.18
Hazard ratio		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
Rate (%)	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 62 202-013 study involving 599 patients with metastatic colorectal cancer who had not previously received treatment was conducted to compare the combination of cetuximab and irinotecan with or without addition of 5-FU/FA infusions (599 patients). In the patient group evaluated for KRAS gene status, patients with tumors characterized by wild-type KRAS gene accounted for 64%. The 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 + FOLFIRI (n = 599)		FOLFIRI (n = 559)	Cetuximab + FOLFIRI (n = 172)	FOLFIRI (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;

FOLFIRI = irinotecan plus 5-FU/FA, infused regimen.

In combination therapy with capecitabine

Results from the phase III randomized controlled trial (CAIRO) confirm 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 to 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 3 weeks. During first-line treatment, median progression-free survival in the group of patients who started 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 the multicenter randomized controlled phase II trial (AIO KRK 0604) confirm the feasibility of using 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); a total of 118 patients were randomized to the capecitabine plus oxaliplatin and bevacizumab 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). The 6-month progression-free survival rate in the group of patients who started treatment 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% (XELOX and bevacizumab) versus 47% (XELIRI and bevacizumab).

Monotherapy as second-line therapy for metastatic colorectal carcinoma

Phase II/III clinical trials using a 3-weekly dosing schedule were conducted in over 980 patients with metastatic colorectal cancer who had previously failed 5-FU-based therapy. The efficacy of irinotecan was evaluated in 765 patients who had documented disease progression on 5-FU at study entry.

Table 4

	Phase III
	Irinatecan compared with supportive care			Irinatecan compared with 5-FU
	Irinatecan, n = 183	Supportive care, n = 90	p-value	Irinatecan, 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

NC – not calculated;

* – 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.

Phase II non-comparative studies were also conducted involving 304 patients who received irinotecan at a dose of 125 mg/m² body surface area as intravenous infusions over 90 minutes 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 starting at 125 mg/m² body surface area was similar to that observed in studies using the irinotecan dosing regimen of once every 3 weeks. The median time to first episode of diarrhea was 11 days.

In combination therapy with cetuximab following failure of cytotoxic therapy with 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; these were 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 to cetuximab monotherapy (111 patients).

In the open-label, single-arm trial IMCL CP02-9923, combination therapy was evaluated (138 patients).

Efficacy results from these studies are presented in Table 5.

Table 5

Study

Objective response rate2

Disease control rate1

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

(22.9)

17.5; 29.1

121 (55.5)

48.6; 62.2

2.8; 4.3

8.6

7.6; 9.6

IMCLCP02-9923

138

(15.2)

9.7; 22.3

(60.9)

52.2; 69.1

2.6; 4.1

8.4

7.2; 10.3

Cetuximab

EMR 62 202-007

111

12 (10.8)

5.7; 18.1

(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).

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 impact on overall survival was demonstrated (hazard ratio 0.91, p-value = 0.48).

Pharmacokinetics

Absorption

At the end of infusion following administration of the recommended dose of 350 mg/m² body surface area, the mean maximum plasma concentration (Cmax) was 7.7 µg/mL for irinotecan and 56 ng/mL for SN-38, while the mean area under the plasma concentration-time curve (AUC) was 34 µg×h/mL and 451 ng×h/mL, respectively. SN-38 typically exhibits marked inter-individual pharmacokinetic variability.

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 3 weeks, the steady-state volume of distribution (Vss) was 157 L/m² body surface area.

In vitro, plasma protein binding is 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 conversion of at least 12% of the dose:

Hydrolysis by carboxylesterase 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 (<0.5% of the irinotecan dose). SN-38 glucuronide is believed to undergo further hydrolysis in the gastrointestinal tract;
Oxidation by cytochrome P450 3A enzymes, leading to cleavage of the outer piperidine ring, resulting in 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 major component in plasma, followed in descending order by the aminopentanoic acid derivative, SN-38 glucuronide, and SN-38. Only SN-38 exerts 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 3 weeks, irinotecan exhibited a biphasic or triphasic elimination profile. The mean plasma clearance of irinotecan was 15 L/h/m². The mean half-life of the first phase in the triphasic model was 12 minutes, the second phase was 2.5 hours, and the terminal half-life was 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 (ULN), irinotecan clearance is reduced by 40%. In patients within this group, administration of 200 mg/m² body surface area of irinotecan results in the same drug exposure in plasma as administration of 350 mg/m² body surface area of irinotecan in patients with normal hepatic 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 regimens 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 are independent of the number of prior treatment cycles and dosing schedule.

Pharmacokinetic/Pharmacodynamic relationship

The severity of the most prominent toxic effects of irinotecan (e.g., leukopenia and diarrhea) is related to the area under the curve (AUC) of the parent drug and its metabolite SN-38. A significant relationship has been observed between hematological toxicity (nadir counts of leukocytes and neutrophils) or diarrhea intensity and AUC values of irinotecan and its 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 variable metabolic activity across populations. The best-characterized genetic variants of UGT1A1 are UGT1A1*28 and UGT1A1*6. These variants, as well as other inherited disorders of UGT1A1 expression (such as Gilbert’s syndrome or Crigler-Najjar syndrome), are associated with reduced enzyme activity.

Patients with impaired UGT1A1 metabolism (e.g., homozygous for UGT1A1*28 or *6 alleles) have an increased risk of developing severe adverse reactions, such as neutropenia and diarrhea, following irinotecan administration due to accumulation of SN-38. According to data from several meta-analyses, this risk is higher in patients receiving irinotecan doses >180 mg/m² (see section "Special precautions for use").

Genotyping for UGT1A1 may be used to identify patients at increased risk of severe neutropenia and diarrhea. Homozygosity for UGT1A1*28 occurs with a frequency of 8–20% in European, African, Middle Eastern, and Latin American populations. The *6 variant is nearly absent in these populations. In East Asian populations, the frequency of *28/*28 is approximately 1–4%, *6/*28 is 3–8%, and *6/*6 is 2–6%. In Central and South Asian populations, the frequency of *28/*28 is approximately 17%, *6/*28 is 4%, and *6/*6 is 0.2%.

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 showed no mutagenic potential.

In rats receiving 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 administration of irinotecan were conducted in mice, rats, and dogs. The main toxic effects were observed in the hematopoietic and lymphatic systems. In dogs, delayed diarrhea was observed, associated with atrophy and focal necrosis of the intestinal mucosa. Alopecia was also observed.

The severity of these effects was dose-dependent and reversible.

Reproduction

Irinotecan showed teratogenic effects in rats and rabbits at doses lower than the human therapeutic dose. In rats with external abnormalities born to irinotecan-treated rats, reduced fertility was observed. This was not observed in morphologically normal rat pups. In pregnant 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 patients who have not received prior chemotherapy for advanced disease;
as monotherapy in patients in whom a treatment regimen containing 5-fluorouracil has proven ineffective.

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

In combination with 5-fluorouracil, folinic acid, and bevacizumab, it is indicated as first-line treatment in patients with metastatic carcinoma of the colon or rectum.

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

Contraindications.

Chronic inflammatory bowel diseases and/or intestinal obstruction (see section "Special precautions");
hypersensitivity to the active substance or to any of the excipients of the medicinal product;
breastfeeding period (see sections "Special precautions" and "Use during pregnancy or breastfeeding");
bilirubin level exceeding the upper limit of normal (ULN) by more than 3 times (see section "Special precautions");
severe bone marrow insufficiency;
patient performance status >2 (according to WHO classification);
concomitant treatment with St. John's wort (see section "Interaction with other medicinal products and other types of interactions");
live attenuated vaccines (see section "Interaction with other medicinal products and other types of interactions").

When used in combination with cetuximab, bevacizumab, or capecitabine, additional contraindications are listed in the instructions for medical use of these medicinal products.

Special safety precautions.

As with other antineoplastic agents, care must be taken when handling and administering Irinotecan-AAP. Protective goggles, mask, and gloves should be used.

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

Disposal

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

Interaction with other medicinal products and other types of interactions.

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

St. John's wort

Decreased plasma levels of the active metabolite of irinotecan, SN-38. In a small pharmacokinetic study (n = 5), where irinotecan at a dose of 350 mg/m² body surface area was administered 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 generalized vaccine reaction with potentially fatal outcome. Concomitant administration 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.

Concomitant use not recommended (see section "Special precautions")

Concomitant administration of irinotecan with strong 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, apalutamide)

Risk of reduced efficacy of irinotecan, SN-38, SN-38 glucuronide, and reduced pharmacodynamic effect. Several studies have shown that concomitant use of antiepileptic drugs that are CYP3A4 inducers reduces the efficacy of irinotecan, SN-38, and SN-38 glucuronide, leading to reduced pharmacodynamic effect. The effect of these antiepileptic drugs resulted 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 more intensive biliary excretion. Additionally, with phenytoin: risk of seizure exacerbation due to reduced absorption of phenytoin caused by cytostatic agents.

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

A study showed that concomitant administration of ketoconazole resulted in an 87% decrease in AUC of the metabolite APC and a 109% increase in AUC of SN-38 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 such combination cannot be avoided.

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

Risk of increased toxicity of irinotecan due to reduced metabolism when administered 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, increased frequency of 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 blockers. Interaction between irinotecan and neuromuscular blockers cannot be excluded. Since irinotecan has anticholinesterase activity, medicinal products with anticholinesterase activity may prolong the neuromuscular blocking effect of succinylcholine and antagonistically affect neuromuscular blockade caused by non-depolarizing agents.

Other combinations

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

Bevacizumab. Results from specific drug interaction studies 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 myelosuppression, may be intensified by other antineoplastic agents with a similar adverse reaction profile.

Special precautions for use.

Irinotecan-AAR should be administered exclusively in a department specialized in cytotoxic chemotherapy. The drug must be used only under the supervision of a qualified physician experienced in anticancer chemotherapy.

Due to the nature and frequency of adverse reactions, the medicinal product should be administered only after careful assessment of the benefit-risk ratio in the following cases:

for treatment of patients with risk factors, particularly patients with a WHO performance status score of 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 combined with high fluid intake at the onset of delayed diarrhea). Such patients should be closely monitored in an inpatient setting.

When irinotecan is used as monotherapy, it is typically administered on a 3-week dosing schedule. However, a weekly dosing regimen may be used for patients who may require closer monitoring or are at particular risk of neutropenia (see section "Pharmacological properties").

Delayed diarrhea

Patients should be warned about the risk of delayed diarrhea, which may occur more than 24 hours after administration of irinotecan and at any time before the start of the next treatment cycle. With monotherapy, the median time to first episode of loose stools was 5 days after infusion of irinotecan. 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/pelvic region, patients with baseline hyperleukocytosis, patients with a performance status ≥2, and women. Without proper treatment, diarrhea may be life-threatening, especially if accompanied by neutropenia.

After the first episode of loose stools, patients should immediately begin drinking large amounts of electrolyte-containing fluids and initiate appropriate anti-diarrheal treatment. Anti-diarrheal therapy should be administered in the department where the drug was administered.

After hospital discharge, patients should receive prescribed medications to allow immediate initiation of diarrhea treatment upon its onset. Additionally, patients should report the occurrence of diarrhea to their physician or to the department where irinotecan was administered.

Current recommended anti-diarrheal treatment consists of high-dose loperamide (4 mg as the initial dose, followed by 2 mg every 2 hours). This treatment should continue for 12 hours after the last episode of loose stools; the treatment regimen must not be modified. Loperamide at these doses must not 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 anti-diarrheal 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 hydration);
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").

Hematological effects

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 who had previously undergone pelvic/abdominal irradiation compared to those who had not. 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 informed 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 an inpatient setting with intravenous broad-spectrum antibiotics.

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

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

Patients with reduced UGT1A1 activity

Patients with poor UGT1A1 metabolism, such as patients with Gilbert's syndrome (e.g., homozygous for UGT1A1*28 or *6 variants), have an increased risk of severe neutropenia and diarrhea following irinotecan treatment. This risk increases with higher doses of irinotecan.

Although the exact initial dose has not been established, consideration should be given to reducing the initial dose of irinotecan in patients with poor UGT1A1 metabolism, particularly those receiving doses > 180 mg/m² or frail patients. Clinical recommendations for dosing in this patient group should be taken into account. Subsequent doses may be increased depending on individual treatment tolerance.

UGT1A1 genotyping may be used to identify patients at increased risk of severe neutropenia and diarrhea, but the clinical benefit of genotyping prior to treatment is uncertain, as UGT1A1 polymorphism does not account for all toxicity observed during irinotecan therapy (see section "Pharmacological properties").

Hepatic impairment

Liver function tests should be performed at baseline and before each treatment cycle.

Patients with bilirubin levels 1.5–3 times above the upper limit of normal (ULN) should have complete blood counts monitored weekly due to decreased irinotecan clearance (see section "Pharmacological properties") and increased risk of hematotoxicity in this population. Patients with bilirubin levels more than 3 times above ULN should refer to the "Contraindications" section.

Nausea and vomiting

Prophylactic antiemetic therapy is recommended before each administration of the drug. Nausea and vomiting are frequently reported with irinotecan use. Patients experiencing vomiting accompanied by delayed diarrhea require immediate hospitalization for appropriate management.

Acute cholinergic syndrome

If acute cholinergic syndrome occurs (defined as early diarrhea in combination with other signs and symptoms such as excessive sweating, abdominal cramps, miosis, and increased salivation), atropine sulfate (0.25 mg subcutaneously) should be administered, unless clinically contraindicated (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, and their frequency is expected to increase with higher doses of irinotecan.

The drug should be used with caution in patients with bronchial asthma. Patients experiencing severe acute cholinergic syndrome should receive prophylactic treatment with atropine sulfate before subsequent doses of the drug.

Respiratory disorders

Rare cases of interstitial lung disease, manifested by pulmonary infiltrates, may occur during irinotecan treatment. Interstitial lung disease may be fatal. Risk factors possibly associated with the development of interstitial lung disease include use of lung-toxic drugs, radiotherapy, and colony-stimulating factors. Patients with risk factors should be carefully monitored for respiratory symptoms before and during irinotecan therapy.

Extravasation

Although irinotecan is not 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 cold compresses applied.

Elderly patients

Due to the higher frequency of decreased biological functions, particularly liver function, the drug dose 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 infection or dehydration due to nausea, vomiting, or diarrhea. Additionally, isolated cases of renal dysfunction due to tumor lysis syndrome have been reported.

Radiation therapy

Patients who have previously undergone pelvic/abdominal irradiation are at increased risk of myelosuppression following irinotecan treatment. Physicians should use this medicinal product with caution 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 of the drug (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 patients who previously received 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, and 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) of CYP3A4 may alter irinotecan metabolism; therefore, such combinations should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

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

Contraception in women of childbearing potential/men

Due to potential genotoxicity, women of reproductive potential should be advised to use highly effective contraception during treatment and for 6 months after the last dose of irinotecan (see section "Pregnancy and breastfeeding").

Due to potential genotoxicity, men of reproductive potential should be advised to use effective contraception during treatment and for 3 months after the last dose 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 (see section "Composition"). Sorbitol is a source of fructose. This medicinal product should not be administered to patients with hereditary fructose intolerance (HFI) unless clinically necessary.

Infants and young children (under 2 years of age) cannot yet be diagnosed with fructose intolerance. Intravenous medications containing fructose may have life-threatening effects in patients with HFI and should not be prescribed to this patient group, except in cases of urgent clinical need and in the absence of alternatives.

A detailed medical history regarding symptoms of HFI should be obtained from each patient before prescribing this medicinal product.

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

Use during pregnancy or breastfeeding.

Contraception

Pregnancy

Data on the use of irinotecan in pregnant women are limited. Animal studies have demonstrated embryotoxic and teratogenic effects of irinotecan. 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 extreme necessity.

Women of childbearing age 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. Therefore, due to the potential for adverse reactions in breastfed infants, breastfeeding should be discontinued during irinotecan treatment (see sections "Contraindications" and "Special precautions for use").

Effect on fertility

Information on the effect of irinotecan on human fertility is lacking. Adverse effects of irinotecan on reproductive function in offspring have been documented in animal studies (see section "Preclinical safety data").

Before starting irinotecan treatment, patients should be offered the possibility of consultation regarding gamete preservation.

Ability to drive and use machines.

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

Method of Administration and Dosage

Method 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.

Preparation of the Intravenous Solution

As with other injectable medicinal products, the solution of Irinotecan-AAR should be prepared under aseptic conditions.

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

Under aseptic conditions, withdraw the required amount of concentrated Irinotecan-AAR solution from the vial using a calibrated syringe and transfer the dose into a 250 ml bag or bottle containing 0.9% sodium chloride solution or 5% glucose solution. Gently invert the container manually to ensure thorough mixing of the infusion solution.

Recommended Dosages

Monotherapy (for previously treated patients)

The recommended dose of the medicinal product is 350 mg/m² body surface area administered as an intravenous infusion over 30–90 minutes every 3 weeks (see sections "Special Warnings" and "Special Precautions").

Combination Therapy (for treatment-naïve patients)

The efficacy and safety of the medicinal product in combination with 5-fluorouracil (5-FU) and folinic acid (FA) are evaluated according to the following regimen (see section "Pharmacological Properties"):

Irinotecan + 5-FU/FA regimen every 2 weeks

The recommended dose of the medicinal product is 180 mg/m² body surface area administered once every 2 weeks as an intravenous infusion over 30–90 minutes, followed by infusion of 5-FU and FA.

For dosage and administration of concomitant cetuximab, refer to the prescribing information for this medicinal product.

The same dose of irinotecan as used in previous treatment cycles involving irinotecan-containing regimens is generally applied. Irinotecan should be administered no sooner than 1 hour after completion of cetuximab infusion.

For dosage and administration of bevacizumab, refer to the prescribing information for bevacizumab.

For dosage and administration of capecitabine combination therapy, see section "Pharmacological Properties" and the relevant sections of the capecitabine prescribing information.

Dose Adjustment

The medicinal product should be administered only after complete resolution of all adverse reactions to grade 0 or 1 according to the NCI-CTC (National Cancer Institute Common Toxicity Criteria) and after complete cessation 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 until treatment-related adverse reactions have resolved.

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

Hematologic toxicity (grade IV neutropenia, febrile neutropenia (grade III–IV neutropenia accompanied by grade II–IV fever), thrombocytopenia, and leukopenia (grade IV));
Non-hematologic toxicity (grade III–IV).

Dose modifications of cetuximab when used in combination with irinotecan should follow the recommendations provided in the cetuximab prescribing information.

For patients aged 65 years and older receiving this medicinal product in combination with capecitabine, the capecitabine dose should be reduced to 800 mg/m² body surface area twice daily according to the capecitabine prescribing information.

Duration of Treatment

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

Special Populations

Patients with Hepatic Impairment

Monotherapy: For patients with a performance status index ≤ 2, the initial dose should be determined based on serum bilirubin levels (when bilirubin levels exceed the ULN by up to 3 times). In such patients with hyperbilirubinemia and prothrombin time prolonged by more than 50%, irinotecan clearance is reduced (see section "Pharmacological Properties"), resulting in an increased risk of hematologic toxicity. Therefore, complete blood counts should be monitored weekly in these patients.

For patients with bilirubin levels exceeding the ULN by up to 1.5 times, the recommended dose is 350 mg/m² body surface area.
For patients with bilirubin levels exceeding the ULN by 1.5–3 times, the recommended dose is 200 mg/m² body surface area.
The medicinal product should not be administered to patients with bilirubin levels exceeding the ULN by more than 3 times (see sections "Contraindications" and "Special Precautions").

There is no information available 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 studies in this patient population have not been conducted (see sections "Pharmacological Properties" and "Special Precautions").

Elderly Patients

No specific pharmacokinetic studies have been performed in elderly patients. However, dosage should be carefully selected in this patient group, as age-related decline in physiological functions is more common. These patients require more intensive monitoring (see section "Special Precautions").

Children

The safety and efficacy of irinotecan in pediatric patients have not been established. Data are lacking.

Method of Administration

Precautions for Dilution of the Medicinal Product Prior to Administration

Instructions for dilution of the medicinal product prior to administration are provided in the section "Method of Administration and Dosage".

Children

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

Overdose.

Symptoms

Cases of overdose, potentially fatal, have been reported with doses approximately twice the recommended therapeutic dose. The most significant adverse reactions 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 of metastatic colorectal cancer, and 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 to occur.

The most common (≥ 1/10) dose-limiting adverse reactions of irinotecan are delayed diarrhea (occurring more than 24 hours after administration of the drug) 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.

A transient acute cholinergic syndrome of severe degree was very commonly observed.

Its main symptoms included early diarrhea and various other symptoms such as abdominal pain, increased 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 Instructions").

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 (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000).

Adverse reactions reported during irinotecan monotherapy (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.

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 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 was observed 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 agents.

Constipation was observed in less than 10% of patients.

Neutropenia was observed in 78.7% of patients, of whom severe grade (neutrophil count < 500 cells/mm³) occurred in 22.6% of patients. In evaluable treatment cycles, neutrophil count was below 1,000 cells/mm³ in 18%, including 7.6% with neutrophil count < 500 cells/mm³.

Complete recovery of counts usually took up to 22 days.

Febrile neutropenia was observed in 6.2% of patients and 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 level < 8 g/dL and 0.9% with hemoglobin level < 6.5 g/dL).

Thrombocytopenia (< 100,000 cells/mm³) was observed 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 severe acute cholinergic syndrome 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 phenomenon and irinotecan administration was not clearly established.

Fever in the absence of infection or concomitant severe neutropenia was recorded 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 observed in 9.2%, 8.1%, and 1.8% of patients, respectively, in the absence of progressive liver metastases.

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

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 recorded 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 the bolus regimen of irinotecan/5-FU/leucovorin. Additionally, with the use of 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 the bolus regimen of irinotecan/5-FU/leucovorin. Additional information on adverse reactions of combination therapy with bevacizumab is provided in the medical instructions for this medicinal product.

Studies were conducted on the use of irinotecan in combination with 5-FU and leucovorin 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 (NCI) 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 use, were reported in 145 patients who received irinotecan at the recommended dose of 180 mg/m² in combination therapy with 5-FU/leucovorin 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.

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

Description of selected adverse reactions (during combination therapy)

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

Nausea and vomiting of severe degree were observed at a lower frequency (in 2.1% and 2.8% of patients, respectively).

Constipation due to irinotecan and/or loperamide use was observed in 3.4% of patients.

Neutropenia was observed in 82.5% of patients, of whom severe grade (neutrophil count < 500 cells/mm³) was recorded in 9.8% of patients. In evaluable treatment cycles, neutrophil count was below 1,000 cells/mm³ in 67.3%, including 2.7% with neutrophil count < 500 cells/mm³. Complete recovery of counts usually took 7–8 days.

Febrile neutropenia was observed in 3.4% of patients and 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 was observed in 97.2% of patients (2.1% with hemoglobin level < 8 g/dL).

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

Acute cholinergic syndrome — transient severe acute cholinergic syndrome was observed in 1.4% of patients receiving combination therapy.

Asthenia was severe in 6.2% of patients receiving combination therapy. The causal relationship between this phenomenon and irinotecan administration was not 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 in these parameters of grade III severity were observed in 0%, 0%, 0%, and 1% of patients, respectively. No cases of grade IV severity 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 studies of weekly irinotecan regimen

In clinical studies of irinotecan use, the following additional adverse reactions related to the drug were reported: 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, cardiac arrest, myocardial infarction, myocardial ischemia, peripheral vascular disorders, vascular disorders), and thromboembolic events (arterial thrombosis, ischemic stroke, cerebrovascular accident, deep vein thrombophlebitis, lower limb venous embolism, pulmonary embolism, thrombophlebitis, thrombosis, and sudden death) (see section "Special Instructions").

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: thrombocytopenia with formation of antiplatelet antibodies.

Metabolism and nutrition 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: arterial hypotension***.

Respiratory, thoracic and mediastinal disorders: interstitial lung diseases, manifesting as pulmonary infiltrates, are uncommon during irinotecan treatment (early effects such as dyspnea have been reported) (see section "Special Instructions"); dyspnea (see section "Special Instructions"), 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, 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: skin reactions.

Musculoskeletal and connective tissue disorders: muscle contractions or spasms.

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.

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 of suspected adverse reactions

Reporting of adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Diluted medicinal product (infusion solution)

An aseptically prepared solution of the medicinal product is chemically and physically stable in infusion solutions (0.9% sodium chloride solution and 5% glucose solution) for 72 hours at 2–8°C, for 40 days when stored in LDPE (low-density polyethylene) or PVC (polyvinyl chloride) containers at 2–8°C or at 25°C in a light-protected place. Under light exposure, chemical and physical stability was demonstrated under the same conditions for 4 days.

From a microbiological standpoint, the solution should be used immediately. If not used immediately, responsibility for the duration and conditions of storage lies with the user, typically the solution should be stored no longer than 12 hours at room temperature or 24 hours at 2–8°C, unless dilution is performed under controlled and validated aseptic conditions.

Storage conditions.

Store in the original packaging in a light-protected place at temperatures not exceeding 30°C. Keep out of reach of children. Do not freeze.

Incompatibilities.

Unknown.

Due to the lack of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Packaging.

2 ml (40 mg) or 5 ml (100 mg) in a vial; 1 or 10 vials with the instructions for medical use in a cardboard box.

Prescription category. By prescription only.

Manufacturer. VENUS REMEDIES LIMITED / VENUS REMEDIES LIMITED.

Manufacturer's address and location of operations.

Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh, 173205, India / Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh, 173205, India.

Marketing Authorization Holder.

AAR PHARMA FZ-LLC / AAR PHARMA FZ-LLC.

Address of Marketing Authorization Holder.

Premises 702, 7th Floor, Building: DSC Tower, Post Box – 478837, Dubai, United Arab Emirates / Premises 702, 7th Floor, Building: DSC Tower, Post Box – 478837, Dubai, United Arab Emirates.