Irinotecan shilpa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IRINOTECAN SHILPA (IrinotecanShilpa)

Composition:

Active substance: irinotecan;

1 ml of concentrate contains 20 mg of irinotecan hydrochloride trihydrate,
equivalent to 17.33 mg of irinotecan;

Excipients: sorbitol 400, lactic acid, sodium hydroxide, hydrochloric acid, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear light yellow solution, free from visible mechanical particles.

Pharmacotherapeutic group. Antineoplastic agents. Irinotecan.

ATC code: L01X X19.

Pharmacological Properties.

Pharmacodynamics.

Experimental study data.

Irinotecan is a semisynthetic derivative of camptothecin. It is an antineoplastic agent acting as a specific inhibitor of DNA topoisomerase I. Under the action of carboxylesterase in most tissues, irinotecan is metabolized to SN-38, a compound that 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 damage, which blocks the 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.

Irinotecan and SN-38 are not significantly recognized in vitro by P-glycoprotein, a multidrug resistance protein, and exert cytotoxic effects on cell lines resistant to doxorubicin and vinblastine. Furthermore, 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 antitumor activity, the most significant pharmacological effect of irinotecan is inhibition of acetylcholinesterase activity.

Clinical study data.

• First-line combination therapy for metastatic colorectal carcinoma.
  • Combination therapy with folinic acid (FA) and 5-fluorouracil (5-FU).

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 two investigational regimens: "once every 2 weeks" (see section "Administration and dosage") or "once weekly." In the "once every 2 weeks" regimen, on day 1, after administration of irinotecan hydrochloride 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 as a 22-hour intravenous infusion) were infused. 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 hydrochloride 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 as a 24-hour intravenous infusion) were infused.

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

Table 1

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 in combination with 5-FU/FA, 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 in combination with 5-FU/FA, and 2.4% in patients receiving 5-FU/FA alone. In addition, the median time to definitive deterioration in health status was significantly longer in the combination therapy group with 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. The evolution of Global Health Status/quality of life scores over time in the combination therapy group with irinotecan was slightly better (although not statistically significant), suggesting that irinotecan can be effectively used in combination therapy 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. Efficacy results from study AVF2107g are presented in Table 2 below.

Table 2

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 addition of 5-FU/FA infusions (599 patients). In the patient population evaluated for KRAS gene status, patients with tumors characterized as wild-type for this gene accounted for 64%. The efficacy results obtained in this study are presented in Table 3 below.

Table 3

CI – confidence interval.

• In combination therapy with capecitabine.

Results from the phase III randomized controlled trial (CAIRO) support the use of capecitabine at an initial dose of 1000 mg/m² body surface area (administered 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), followed by 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, the 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).

Results from the interim analysis of a multicenter, randomized, controlled phase II trial (AIO KRK 0604) support the feasibility of using capecitabine at an initial dose of 800 mg/m² body surface area (administered 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 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). The 6-month progression-free survival rate in the group of patients initiating 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 plus bevacizumab) versus 47% (XELIRI plus bevacizumab).

• Monotherapy as second-line treatment 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

NC – 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.

Additionally, non-comparative phase II studies were conducted involving 304 patients who received the medicinal product at a dose of 125 mg/m² body surface area as intravenous infusions lasting 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 at the initial dose of 125 mg/m² body surface area was similar to that observed in studies using the dosing regimen of once every 3 weeks. The median time to first episode of diarrhea was 11 days.

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

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

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

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

The efficacy results obtained in these studies are presented in Table 5 below.

Table 5

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).

Based on 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 exposure levels (AUC) of the active substance and its metabolite SN-38. A significant correlation was established between the severity of hematological toxicity (minimum leukocyte and neutrophil counts) or diarrhea and AUC values for 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, leading to variable effects on metabolism in patients. One 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 for the UGT1A1*28 allele (Gilbert’s syndrome) are at increased risk of developing hematological toxicity (grades 3 and 4) following administration of medium 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, such patients should be closely monitored for hematological toxicity. For patients who have previously experienced hematological toxicity during prior treatment cycles, consideration should be given to reducing the initial dose of irinotecan. The exact extent of initial 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 precautions").

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

Pharmacokinetics.

In a phase I study involving 60 patients who received irinotecan every 3 weeks 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 or triphasic. The mean plasma clearance of the drug 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. SN-38 elimination follows a biphasic pattern, with a mean terminal half-life of 13.8 hours. At the end of infusion following the recommended dose of 350 mg/m² body surface area, mean maximum plasma concentrations were 7.7 µg/mL for irinotecan and 56 ng/mL for SN-38, while 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 pronounced inter-individual pharmacokinetic variability.

Population pharmacokinetic analysis of irinotecan was performed in a cohort of 148 patients with metastatic colorectal cancer. These patients received irinotecan at various doses and dosing schedules in phase II studies. 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 the administered CPT-11 dose. The pharmacokinetics of these compounds are independent of the number of prior treatment cycles and dosing schedule.

Protein binding in plasma in vitro was approximately 65% for irinotecan and approximately 95% for SN-38.

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

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

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

Unchanged irinotecan constitutes the main fraction of the drug in plasma. In descending order of concentration, the next components are the aminopentanoic acid derivative, SN-38 glucuronide, and SN-38. Only SN-38 exhibits significant cytotoxic activity.

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

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;
• as monotherapy in patients for whom a treatment regimen with 5-FU has proven ineffective.

Irinotecan in combination with cetuximab is indicated for the treatment of metastatic colorectal cancer with wild-type KRAS gene expressing epidermal growth factor receptors in patients who have not previously received treatment for metastatic disease or for whom prior cytotoxic therapy with irinotecan has proven ineffective.

Irinotecan in combination with 5-FU, FA, and bevacizumab is indicated as first-line therapy in patients with metastatic carcinoma of the colon or rectum.

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

Contraindications.

• Chronic inflammatory bowel disease and/or bowel obstruction (see section "Special precautions").
• History of severe hypersensitivity reactions to irinotecan hydrochloride trihydrate or to any of the excipients of Irinotecan Shilpa.
• Pregnancy or breastfeeding.
• Serum bilirubin levels exceeding the upper limit of normal by more than 3 times.
• Severe bone marrow insufficiency.
• Patient's general condition > 2 (according to WHO classification).
• Concomitant treatment with St. John's wort.
• Concomitant use of live attenuated vaccines (e.g., yellow fever vaccine).

Safety precautions.

During preparation and administration of irinotecan, caution should be exercised and protective eyewear, 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 comes into contact with mucous membranes, they should be immediately rinsed with water.

Disposal

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

Special precautions for storage

The solution of Irinotecan Shilpa in infusion solutions (0.9% w/v sodium chloride solution and 5% w/v glucose solution) maintains physical and chemical stability for up to 28 days when protected from light and stored in low-density polyethylene or PVC containers at 5 °C or 30 °C. It has been demonstrated that in the absence of light protection, the solution maintains physicochemical stability for up to 3 days.

Nevertheless, 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 prior to administration lies with the user. If the solution has not been prepared under controlled and validated aseptic conditions, it should be stored at 2–8 °C for no longer than 24 hours.

Interaction with other medicinal products and other types of interactions.

Interaction between irinotecan and neuromuscular blocking agents cannot be excluded. Since irinotecan has anticholinesterase activity, drugs with similar anticholinesterase activity may prolong neuromuscular blockade by suxamethonium and antagonize neuromuscular blockade by non-depolarizing agents.

Results from several studies have demonstrated that concomitant use of anticonvulsant enzyme inducers of CYP3A (e.g., carbamazepine, phenobarbital, or phenytoin) reduces exposure to irinotecan, SN-38, and SN-38-glucuronide, leading to diminished pharmacodynamic effects. The effect of these anticonvulsants was a reduction in 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.

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 the metabolite SN-38 compared to irinotecan monotherapy.

Caution should be exercised when treating patients who are concomitantly taking inhibitors (e.g., ketoconazole) or inducers (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, or apalutamide) of drug metabolism via cytochrome P450 3A4. Concomitant use of irinotecan with inducers/inhibitors of this metabolic pathway may alter the intensity of irinotecan metabolism; therefore, such concomitant use should be avoided (see section "Special precautions").

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

Atazanavir sulfate. Concomitant administration of irinotecan with atazanavir sulfate (an inhibitor of CYP3A4 and UGT1A1) may increase systemic exposure to the active metabolite of irinotecan, SN-38. Physicians should consider this possibility when prescribing these two drugs concomitantly.

Interactions typical for all cytotoxic agents.

Patients with tumors have an increased risk of thromboembolic events. Therefore, anticoagulants are usually prescribed for such patients. If vitamin K antagonist anticoagulants are indicated, the International Normalized Ratio (INR) should be monitored more frequently than usual. This is due to the narrow therapeutic range of these agents, high individual variability in blood coagulability, and potential interactions between oral anticoagulants and anticancer chemotherapeutic agents.

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

• Live attenuated vaccines (e.g., yellow fever vaccine) – due to the risk of generalized vaccine reaction with potentially fatal outcomes (e.g., infections). This risk is increased in patients with immunosuppression due to the underlying disease. Inactivated vaccines should be used if available (e.g., polio), although the immune response to such vaccines may be reduced.
• St. John's wort (Hypericum perforatum) – due to reduced plasma levels of 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.

Concomitant use of the following medicinal products with Irinotecan Shilpa is not recommended.

Concomitant administration of irinotecan with strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) (e.g., carbamazepine, phenobarbital, phenytoin, or apalutamide) may alter the intensity of irinotecan metabolism; therefore, such concomitant use should be avoided (see section "Special precautions").

The following medicinal products should be used concomitantly with Irinotecan Shilpa with caution.

• Cyclosporine, tacrolimus – due to the risk of excessive immunosuppression and risk of lymphocyte proliferation.

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

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

Other combinations.

Antineoplastic agents (including flucytosine as a prodrug of 5-fluorouracil). Adverse effects of irinotecan, such as myelosuppression, may be intensified by other antineoplastic agents with a similar adverse effect profile.

Special precautions for use.

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

Due to the nature and frequency of adverse reactions, irinotecan 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 of 2.
• In rare individual cases, when patients are unlikely to comply with recommendations for managing adverse reactions (e.g., the need for immediate and prolonged treatment of delayed diarrhea combined with high fluid intake upon onset of delayed diarrhea). Such patients should be closely monitored in an inpatient setting.

Delayed diarrhea.

Patients should be warned about the risk of developing delayed diarrhea, which occurs more than 24 hours after administration of irinotecan and may occur 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 irinotecan administration. Patients must promptly inform their physician about the onset of diarrhea and immediately initiate appropriate therapy.

Patients at increased risk of developing diarrhea include those who previously received abdominal or pelvic radiotherapy, patients with baseline hyperleukocytosis, patients with a performance status ≥ 2, and women. Without adequate treatment, diarrhea may become life-threatening, particularly when associated with 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 initiated at the department where irinotecan was administered. After hospital discharge, patients should receive prescribed medications to allow immediate initiation of diarrhea treatment upon its onset. Additionally, patients should inform the medical staff at the department where they received irinotecan about the occurrence of diarrhea.

The currently recommended anti-diarrheal treatment consists of high-dose loperamide (4 mg as the first dose, followed by 2 mg every 2 hours). Treatment should continue for 12 hours after the last episode of loose stools. This regimen should not be modified. Loperamide at these doses should never 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 therapy.

In addition to antibiotic therapy, hospitalization of patients is recommended in the following cases:

• Diarrhea associated with fever;
• Severe diarrhea (requiring intravenous rehydration);
• Diarrhea persisting for 48 hours after initiation of high-dose loperamide treatment.

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

Patients experiencing severe diarrhea should have their dose reduced in subsequent treatment cycles (see section "Method of administration and dosage").

Hematological effects.

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 who had previously received 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 3–4 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 therapy. 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 a hospital setting with intravenous broad-spectrum antibiotics.

Patients experiencing severe hematological complications should have their dose reduced in subsequent treatment cycles (see section "Method of administration and dosage"). Patients with severe diarrhea have an increased risk of infections and manifestations of hematological toxicity. Complete blood counts should be performed in these patients.

Hepatic impairment.

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

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

Nausea and vomiting.

Prophylactic antiemetic therapy is recommended before each course of irinotecan treatment. Nausea and vomiting are frequently reported with the use of this drug. Patients experiencing vomiting in combination with delayed diarrhea require immediate hospitalization for appropriate management.

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 increased salivation).

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

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

Respiratory disorders.

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

Extravasation.

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

Elderly patients.

Due to the higher frequency of decreased biological functions, particularly liver function, in elderly patients, Irinotecan Shilpa dosage should be carefully selected (see section "Method of administration and dosage").

Chronic inflammatory bowel disease and/or bowel obstruction.

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

Renal function impairment.

Elevations in serum creatinine or blood urea nitrogen have been observed. Cases of acute renal failure have been reported. These events were usually associated with infectious complications or dehydration due to nausea, vomiting, or diarrhea. Additionally, isolated cases of renal impairment due to tumor lysis syndrome have been reported.

Radiotherapy.

Patients who previously received pelvic/abdominal irradiation have an increased risk of myelosuppression after irinotecan administration. Physicians should use this medicinal product cautiously in patients who have previously undergone extensive radiotherapy (e.g., irradiation of > 25% of bone marrow within 6 weeks prior to starting irinotecan therapy). Dose adjustments may be required in this patient group (see section "Method of administration and dosage").

Cardiac disorders.

Cases of myocardial ischemia have been observed after irinotecan administration, primarily in patients with pre-existing cardiac 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 close monitoring. Measures should be taken to minimize all modifiable risk factors (e.g., smoking, arterial hypertension, hyperlipidemia).

Vascular disorders.

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

Immunosuppressants/increased susceptibility to infections.

Administration of live or live attenuated vaccines to patients with immunosuppression due to chemotherapeutic agents (including irinotecan) may lead to serious 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.

Other factors.

Since this medicinal product contains sorbitol, it should not be used in patients with hereditary fructose intolerance.

Rare cases of renal failure, arterial hypotension, or circulatory failure have been reported in patients with dehydration due to diarrhea and/or vomiting, as well as in patients with sepsis.

Patients should use contraceptive methods during treatment and for at least three months after completion of therapy.

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

Use during pregnancy or breastfeeding.

Women of reproductive potential/use of contraception in men and women.

Women of childbearing potential should use effective contraceptive measures during treatment with irinotecan and for 1 month after treatment. Men should use effective contraception during treatment and for 3 months after completion of therapy.

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, based on animal study results and the mechanism of action of irinotecan, Irinotecan Shilpa should not be used during pregnancy unless absolutely necessary.

Breastfeeding.

14C-labeled irinotecan has been detected in the milk of lactating 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 irinotecan therapy (see section "Contraindications").

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.

Ability to affect reaction speed when driving or operating machinery.

Patients should be warned about the possibility of dizziness or visual disturbances within 24 hours after administration of irinotecan and advised not to drive or operate machinery if these symptoms occur.

Method of Administration and Dosage.

This medicinal product is intended for use only in adults. The infusion solution should be administered into a peripheral or central vein.

Preparation of the Solution for Intravenous Administration.

As with other injectable drugs, the Irinotecan Shilpa solution should be prepared under aseptic conditions. If visible precipitation 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 volume of Irinotecan Shilpa solution from the vial using a calibrated syringe and transfer the dose into an infusion bag or bottle containing 250 mL of 0.9% sodium chloride solution or 5% glucose solution. Mix thoroughly by manually rotating the container.

Recommended Dosages.

For monotherapy, irinotecan is generally administered once every 3 weeks. However, for patients who may require closer monitoring or who are at increased risk of developing severe neutropenia, a weekly administration schedule may be considered (see section "Pharmacological Properties").

Monotherapy (for previously treated patients): the recommended dose of Irinotecan Shilpa is 350 mg/m² body surface area administered by intravenous infusion over 30–90 minutes every 3 weeks (see section "Special Instructions").

Combination therapy (for previously untreated patients): the efficacy and safety of irinotecan in combination with 5-FU and LV were evaluated using the following dosing schedule (see section "Pharmacodynamics") – irinotecan and 5-FU/LV every 2 weeks. The recommended dose of Irinotecan Shilpa is 180 mg/m² body surface area administered by intravenous infusion over 30–90 minutes once every 2 weeks, followed by infusion of LV or 5-FU. The same dose of irinotecan as used in the last cycles of irinotecan-containing therapy should generally be applied. Irinotecan should be administered no sooner than 1 hour after the end of cetuximab infusion.

Dose Adjustment.

Irinotecan should be administered only after all adverse reactions have adequately resolved to grade 0 or 1 according to the NCI-CTC scale (National Cancer Institute Common Terminology Criteria for Adverse Events) and after treatment-related diarrhea has completely ceased.

At the beginning of the next infusion cycle, the dose of Irinotecan Shilpa and 5-FU (if used) should be reduced based on the most severe adverse reaction observed during the previous infusion.

Treatment initiation should be delayed by 1–2 weeks to allow resolution of treatment-related adverse reactions.

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

• hematologic toxicity (grade 4 neutropenia, febrile neutropenia (neutropenia grade 3–4 and fever grade 2–4), thrombocytopenia, and leukopenia (grade 4));
• non-hematologic toxicity (grade 3–4).

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

Duration of Treatment.

Irinotecan therapy should continue until objective evidence of disease progression or until unacceptable toxicity occurs.

Special Patient Populations.

Patients with Hepatic Impairment.

Monotherapy.

• For patients with a performance status index ≤ 2, the initial dose of irinotecan should be determined based on serum bilirubin levels (when bilirubin levels exceed the upper limit of normal by no more than 3 times). In such patients with hyperbilirubinemia and prothrombin time greater than 50%, irinotecan clearance is reduced (see section "Pharmacokinetics"), increasing the risk of hematologic toxicity. Therefore, complete blood counts should be monitored weekly in these patients.
• For patients with bilirubin levels exceeding the upper limit of normal by up to 1.5 times, the recommended dose of irinotecan is 350 mg/m² body surface area.
• For patients with bilirubin levels exceeding the upper limit of normal by 1.5–3 times, the recommended dose of Irinotecan Shilpa is 200 mg/m² body surface area.
• Irinotecan Shilpa should not be used in patients with bilirubin levels exceeding the upper limit of normal by more than 3 times (see sections "Contraindications" and "Special Instructions").

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 on the use of the drug in this patient population have not been conducted (see sections "Special Instructions" and "Pharmacokinetics").

Elderly Patients.

No specific pharmacokinetic studies have been conducted in elderly patients. However, dosage should be carefully selected in this population due to the higher likelihood of decreased physiological functions. These patients require more intensive monitoring (see section "Special Instructions").

As with other antineoplastic agents, Irinotecan Shilpa should be prepared and administered with caution. The use of protective goggles, mask, and gloves is mandatory.

In case of contact of concentrate or infusion solution with the skin, the area should be immediately rinsed and thoroughly washed with water and soap; in case of contact with mucous membranes, the area should be immediately flushed with water.

Disposal.

All materials used for reconstitution and administration of the drug must be disposed of according to the standard procedures of the healthcare facility for cytotoxic agents.

Children. Irinotecan Shilpa is intended for use only in adults.

Overdose.

Cases of overdose, which may be fatal, have been reported following administration of doses approximately twice the recommended therapeutic dose. The most significant adverse reactions were severe neutropenia and severe diarrhea. There is no known antidote for irinotecan. Intensive supportive treatment should be administered to prevent dehydration due to diarrhea and to treat possible infectious complications.

Adverse Reactions.

Clinical trial data.

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

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

Neutropenia is the dose-limiting toxic effect. Neutropenia was reversible and not cumulative; during monotherapy or combination therapy, the median time to reach the nadir neutrophil count was 8 days.

Severe transient acute cholinergic syndrome was very commonly observed.

Its main symptoms included early-onset diarrhea and various other symptoms such as abdominal pain, sweating, miosis, and increased salivation, occurring during or within the first 24 hours after irinotecan infusion. These symptoms resolved following administration of atropine (see section "Special instructions").

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 (≥ 1/10,000 to < 1/1000), and very rare (< 1/10,000). Within each frequency group, adverse reactions are listed in order of decreasing severity.

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 blood alkaline phosphatase levels.

Description of selected adverse reactions (during monotherapy).

Severe diarrhea occurred in 20% of patients who followed diarrhea management recommendations. 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, with severe grade (neutrophil count < 500 cells/mm³) observed in 22.6% of patients. In evaluable treatment cycles, neutrophil count was below 1000 cells/mm³ in 18%, including 7.6% with neutrophil count < 500 cells/mm³.

Complete recovery of counts usually took up to 22 days.

Fever with severe neutropenia occurred in 6.2% of patients and in 1.7% of all treatment cycles.

Infectious 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 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), including 0.9% of patients (0.2% of treatment cycles) with platelet count ≤ 50,000 cells/mm³.

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

Acute cholinergic syndrome.

Severe transient acute cholinergic syndrome 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 refer 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 with 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 capecitabine monotherapy 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 capecitabine monotherapy 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.

The development of grade 3 arterial hypertension was the main significant risk associated with adding bevacizumab to the bolus regimen of irinotecan/5-FU/leucovorin. Additionally, with this treatment regimen, a slight increase in the frequency of grade 3/4 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 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 for the treatment of metastatic colorectal cancer.

Safety data 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 system, skin and subcutaneous tissue.

The following adverse reactions, possibly or probably related to irinotecan and reported in 145 patients receiving irinotecan at the recommended dose of 180 mg/m² in combination therapy with 5-FU/leucovorin every 2 weeks, are listed below.

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 blood alkaline phosphatase levels.

Description of selected adverse reactions (during combination therapy).

Severe diarrhea occurred in 13.1% of patients who followed diarrhea management recommendations. In evaluable treatment cycles, severe diarrhea occurred in 3.9%.

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

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

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

Fever with severe neutropenia occurred in 3.4% of patients and in 0.9% of all treatment cycles.

Infectious 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 1 case, this complication led to fatal outcome.

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

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

Acute cholinergic syndrome.

Severe transient acute cholinergic syndrome 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.

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

Laboratory tests.

Transient increases (grade 1 and 2) in serum levels of AST, ALT, alkaline phosphatase, or bilirubin were observed in 15%, 11%, 11%, and 10% of patients, respectively, in the absence of progressive liver metastases. Transient increases of grade 3 severity in these parameters were observed in 0%, 0%, 0%, and 1% of patients, respectively. No cases of grade 4 severity for 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 using weekly irinotecan regimen.

In clinical trials of irinotecan use, the following additional adverse reactions related to drug use were reported: pain, sepsis, rectal disorders, gastrointestinal candidiasis, hypomagnesemia, rash, skin reactions, gait disturbance, confusion, headache, syncope, hot flashes, 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 diseases), and thromboembolic events (arterial thrombosis, ischemic stroke, cerebrovascular accident, deep 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.

Blood and lymphatic system disorders: peripheral 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.

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

Respiratory, thoracic and mediastinal disorders: interstitial lung diseases, manifested as pulmonary infiltrates, occurring infrequently during irinotecan treatment (cases of 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, gastrointestinal bleeding, symptomatic or asymptomatic increase in pancreatic enzyme levels, intestinal perforation.

Skin and subcutaneous tissue disorders: skin reactions.

General disorders and administration site conditions: 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 spasms.

Renal and urinary disorders: renal function impairment and acute renal failure usually observed in patients with infection and/or hypovolemia developed due to severe gastrointestinal toxicity*, renal failure*.

Vascular disorders: hypotension*.

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

Shelf life. 3 years.

Storage conditions.

Store in original packaging at temperatures not exceeding 30 °C. Keep out of reach of children.

Incompatibilities.

Do not mix with other medicinal products. Drug incompatibility is unknown.

Packaging.

5 ml or 15 ml of concentrate for infusion solution in amber glass vials closed with a rubber stopper and aluminum cap with flip-off component. One vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. Shilpa Medicare Limited.

Manufacturer's address and place of business. Unit 4, Pharmaceutical Formulations SEZ, Plots S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahbubnagar, Telangana, 509301, India.