Topotecan accord

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TOPOTECAN ACCORD

Composition:

Active substance: topotecan hydrochloride;

1 ml of concentrate contains 1.0865 mg of topotecan hydrochloride, equivalent to 1 mg of topotecan;

Excipients: tartaric acid, sodium hydroxide or concentrated hydrochloric acid, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear yellow solution.

Pharmacotherapeutic group. Antineoplastic agents. Other antineoplastic agents.

ATC code L01C E01.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

The antitumor activity of topotecan is due to inhibition of topoisomerase I—an enzyme involved directly in DNA replication. Topotecan inhibits topoisomerase I by stabilizing the covalent complex between the enzyme and the cleaved DNA strand, which is an intermediate step in the catalytic mechanism. The cellular consequences of topoisomerase I inhibition by topotecan include induction of protein-associated single-strand DNA breaks.

Children

The use of topotecan has also been studied in children; however, data on safety and efficacy are currently limited.

An open-label study in children (n = 108, age range: up to 16 years) with recurrent or progressive solid tumors evaluated topotecan administered at an initial dose of 2.0 mg/m² as a 30-minute intravenous infusion for 5 consecutive days, repeated every 3 weeks for up to 1 year depending on treatment response. Tumors included Ewing's sarcoma/primitive neuroectodermal tumor, neuroblastoma, osteosarcoma, and rhabdomyosarcoma. Antitumor activity was primarily demonstrated in patients with neuroblastoma. The toxic effects of topotecan in children with recurrent and refractory solid tumors were similar to those observed in adult patients. In this study, 44 (43%) patients received G-CSF (granulocyte colony-stimulating factor) during more than 192 (42.1%) treatment cycles; 65 patients (60%) received red blood cell transfusions and 50 (46%) patients received platelet transfusions during more than 139 and 159 cycles (30.5% and 34.9%), respectively. Due to the dose-limiting toxicity of myelosuppression, the maximum tolerated dose (MTD) was established at 2.0 mg/m²/day with G-CSF and 1.4 mg/m²/day without G-CSF in a pharmacokinetic study in children with refractory solid tumors (see section "Pharmacological Properties. Pharmacokinetics").

Pharmacokinetics.

Distribution

After intravenous administration of topotecan as a 30-minute infusion at doses ranging from 0.5 to 1.5 mg/m² for 5 days, the drug has a high clearance (62 L/h), approximately two-thirds of hepatic blood flow. Topotecan also has a large volume of distribution—approximately 132 L, about three times the total body water—and a relatively short elimination half-life of 2–3 hours. Based on pharmacokinetic parameters, no changes in drug pharmacokinetics occur over the 5-day treatment period. The area under the concentration-time curve (AUC) increased proportionally with dose escalation. Data on changes in pharmacokinetics after multiple dosing are lacking. Plasma protein binding of topotecan is low (35%), with an almost equal distribution between blood cells and plasma.

Metabolism

The elimination of topotecan in humans has been only partially studied. The primary route of clearance is hydrolysis of the lactone ring, forming an open-ring hydroxyacid metabolite.

Metabolism accounts for less than 10% of eliminated topotecan. The N-desmethyl metabolite, which has similar or lower activity than the parent compound in cellular assays, is detectable in urine, plasma, and feces. The AUC ratio (intermediate metabolite/parent compound) was <10% for both total topotecan and lactone topotecan after intravenous administration. O-glucuronide and N-desmethyltopotecan are detected in urine.

Excretion

Total elimination of the drug after administration of five daily doses of topotecan accounted for 71–76% of the intravenously administered dose.

Approximately 51% of the drug is excreted in urine as topotecan and 3% as N-desmethyltopotecan. Fecal excretion of topotecan accounts for 18%, while fecal excretion of N-desmethyltopotecan is approximately 1.7%. Overall, the N-desmethyl metabolite constitutes on average less than 7% (range 4–9%) of the total topotecan recovered in urine and feces. Topotecan-O-glucuronide and N-desmethyltopotecan-O-glucuronide in urine account for less than approximately 2% of the dose.

In vitro studies using human liver microsomes indicate minimal formation of N-desmethyltopotecan.

In vitro, topotecan does not inhibit human cytochrome P450 enzymes—CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A—nor does it inhibit human cytosolic enzymes—dihydropyrimidine dehydrogenase or xanthine oxidase.

When administered in combination with cisplatin (cisplatin on day 1, topotecan for 5 consecutive days), the clearance of topotecan on day 5 was reduced compared to day 1 (19.1 L/h/m² vs. 21.3 L/h/m², respectively).

Special patient groups

Hepatic impairment

In patients with hepatic insufficiency (serum bilirubin levels of 1.5–10 mg/dL), plasma clearance is reduced by approximately 67% compared to the control group. The elimination half-life of topotecan increases by approximately 30%, although no clear evidence of changes in volume of distribution was observed. The total plasma clearance of total topotecan (active and inactive forms) in patients with hepatic insufficiency is reduced by only 10% compared to the control group.

Renal impairment

Plasma clearance in patients with renal insufficiency (creatinine clearance 41–60 mL/min) is reduced by approximately 67% compared to the control group. The volume of distribution is slightly reduced, and the elimination half-life increases by 14%. In patients with moderate renal impairment, plasma clearance of topotecan is reduced by up to 34% compared to the control group. The volume of distribution is also reduced by approximately 25%, resulting in an increase in elimination half-life from 1.9 hours to 4.9 hours.

Age/Body weight

Demographic pharmacokinetic analysis showed that several factors, including age, body weight, and ascites, had no significant effect on the clearance of total topotecan (active and inactive forms).

Children

The pharmacokinetics of topotecan administered as a 30-minute intravenous infusion for 5 days were evaluated in two clinical studies. One study included dose ranges from 1.4 to 2.4 mg/m² in children (aged 2 to 12 years, n = 18), adolescents (aged 12 to 16 years, n = 9), and young adults (aged 16 to 21 years, n = 9) with refractory solid tumors. The second study included dose ranges from 2.0 to 5.2 mg/m² in children (n = 8), adolescents (n = 3), and young adults (n = 3) with leukemia. These studies showed no significant differences in topotecan pharmacokinetics among children, adolescents, and young adults with solid tumors or leukemia; however, the limited data do not allow definitive conclusions.

Preclinical safety data

Like other cytotoxic agents, due to its mechanism of action, topotecan has been shown to be genotoxic to mammalian cells (mouse lymphoma cells and human lymphocytes) in vitro and to bone marrow cells in mice in vivo. It has also been demonstrated that administration of topotecan to rats and rabbits caused embryofetal lethality.

In animal reproductive toxicity studies, no effects on fertility in males or females were observed; however, in females, superovulation and a slight increase in preimplantation loss were noted.

The potential carcinogenicity of topotecan has not been studied.

Clinical characteristics.

Indications.

Monotherapy with topotecan is indicated:

• for patients with metastatic ovarian cancer after first-line chemotherapy or subsequent therapy if a positive effect has not been achieved;
• for patients with recurrent small cell lung cancer in whom retreatment with first-line chemotherapy is not recommended.

Topotecan in combination with cisplatin is indicated for patients with recurrent cervical cancer after radiotherapy, as well as for patients with stage IV-B disease. To confirm treatment with this combination in patients previously treated with cisplatin, the cisplatin-free treatment interval should be evaluated.

Contraindications.

Severe hypersensitivity reactions to the active substance or to any of the excipients.

Pregnancy or breastfeeding.

Severe bone marrow suppression prior to initiation of the first treatment cycle (baseline neutrophil count before administration < 1.5 × 10⁹/L, platelet count < 100 × 10⁹/L).

Safety precautions.

Pregnant healthcare personnel must not handle cytotoxic agents. Preparation of the drug must be performed by trained personnel. Procedures should be carried out in a designated area.

Work surfaces must be covered with absorbent paper on a plastic backing, single-use only. Personnel must wear protective gloves, masks, and gowns. Accidental exposure of the drug to the eyes must be avoided. If exposure occurs, eyes should be immediately and thoroughly rinsed with water.

Handling of instruments used for topotecan administration requires caution. Unused dry product or contaminated materials must be placed in a hazardous waste bag. Sharp objects (needles, syringes, vials, etc.) must be placed in an appropriate, securely sealed container. Personnel responsible for collecting and disposing of such waste must be informed of the associated risks. Waste must be incinerated. Any unused quantities of solution must be flushed into the sewage system with a large amount of water.

Interaction with other medicinal products and other forms of interaction.

Pharmacokinetic interaction studies in vivo in humans have not been conducted.

Topotecan does not inhibit human cytochrome P450 enzymes. No significant effect on the pharmacokinetics of topotecan has been observed when administered concomitantly with granisetron, ondansetron, morphine, or corticosteroids. When topotecan is used in combination with other chemotherapeutic agents, dose reduction of each drug may be necessary to improve tolerability. However, when used in combination with platinum-containing agents, the interaction between these drugs depends on the sequence of administration and on whether the platinum agent is administered on day 1 or day 5 of the treatment cycle. If cisplatin or carboplatin is administered on day 1 of the topotecan treatment cycle, doses of the drugs should be reduced compared to when they are administered on day 5 of the cycle.

In 13 patients with ovarian cancer receiving topotecan (0.75 mg/m²/day for 5 consecutive days) and cisplatin (60 mg/m²/day on day 1), the mean plasma clearance of topotecan on day 5 was slightly reduced compared to day 1. As a result, systemic exposure to total topotecan, as measured by AUC and Cmax, increased by 12% and 23%, respectively, on day 5. Pharmacokinetic data are not available for topotecan (0.75 mg/m²/day for 3 consecutive days) administered with cisplatin (60 mg/m²/day on day 1) in patients with ovarian cancer.

Topotecan is a substrate for both ABCG2 (BCRP) and ABCB1 (P-glycoprotein) transporter proteins, as well as for the breast cancer resistance protein. Inhibitors of ABCG2 and ABCB1 (e.g., elacridar) increase the exposure to oral topotecan when coadministered. The effect of elacridar on the pharmacokinetics of intravenous topotecan is considerably smaller than its effect on oral topotecan.

Special precautions for use.

Hematological toxicity is dose-dependent; therefore, blood parameters, including platelet count, should be monitored regularly (see section "Dosage and administration").

Like other cytotoxic agents, topotecan may cause severe myelosuppression. Cases of myelosuppression leading to sepsis and death due to sepsis have been reported in patients treated with topotecan (see section "Undesirable effects").

Topotecan-induced neutropenia may lead to neutropenic colitis. Fatal cases associated with neutropenic colitis have been reported during clinical trials with topotecan. Neutropenic colitis should be considered in patients presenting symptoms of fever, neutropenia, and concomitant abdominal pain.

Cases of interstitial lung disease, sometimes fatal, have been reported with the use of topotecan (see section "Undesirable effects"). Risk factors include a history of interstitial lung disease, pulmonary fibrosis, lung cancer, radiation exposure to the lungs, and use of pneumotoxic substances and/or colony-stimulating factors. Patients should be closely monitored for symptoms that may indicate interstitial lung disease (such as cough, fever, dyspnea, and/or hypoxia). If interstitial lung disease is diagnosed, treatment with topotecan should be discontinued.

Monotherapy with topotecan and topotecan in combination with cisplatin are frequently associated with clinically significant thrombocytopenia. This should be taken into account when prescribing Topotecan Accord to patients at increased risk of tumour-related hemorrhage.

As expected, patients with poor performance status respond less well to treatment and have a higher incidence of complications such as fever, infections, and sepsis (see section "Undesirable effects"). Therefore, accurate assessment of the patient's performance status during therapy is essential to prevent deterioration.

There is insufficient data on the use of topotecan in patients with severe renal impairment (creatinine clearance < 20 ml/min) or severe hepatic impairment (serum bilirubin ≥ 10 mg/dl) due to liver cirrhosis. Topotecan is not recommended for use in these patient groups (see section "Dosage and administration").

A small group of patients with hepatic impairment (serum bilirubin 1.5–10 mg/dl) received the drug at a dose of 1.5 mg/m²/day administered intravenously over 5 days every three weeks. A reduction in topotecan clearance was observed, although data on dose recommendations for this patient group are lacking (see section "Dosage and administration").

WARNING: In case of contact with skin, wash thoroughly with soap and water; mucous membranes should be thoroughly rinsed with water.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially "sodium-free". However, if the concentrate of Topotecan Accord is diluted using saline solution (0.9% sodium chloride solution), the resulting sodium dose will be higher.

Use during pregnancy or breastfeeding.

Women of childbearing potential / Contraception in men and women

Studies have shown that topotecan causes embryofetal lethality and developmental abnormalities. Like other cytotoxic medicinal products, topotecan may be harmful to the fetus. Women of childbearing potential must therefore be advised to avoid pregnancy during treatment with topotecan and for at least 6 months after discontinuation of treatment.

As with any cytostatic chemotherapy, patients receiving topotecan should be informed that they and their sexual partners must use effective contraceptive methods.

Pregnancy

Topotecan is contraindicated during pregnancy.

If a woman becomes pregnant while receiving topotecan therapy, she should be informed of the potential risk to the fetus.

Breastfeeding

Topotecan is contraindicated in women who are breastfeeding (see section "Contraindications").

Although it is not known whether topotecan is excreted in human milk, breastfeeding should be discontinued at the start of treatment with Topotecan Accord.

Fertility

In reproductive toxicity studies conducted in animals, no effects of topotecan on fertility in males or females were observed. However, as with other cytotoxic agents, topotecan is genotoxic, and effects on fertility, including male fertility, cannot be excluded.

Effects on ability to drive and use machines.

The effect on the ability to drive or operate machinery has not been studied. However, if patients experience prolonged fatigue or asthenia, driving or operating machinery should be done with caution.

Dosage and Administration

Topotecan should only be administered in departments specializing in cytotoxic chemotherapy and only under the supervision of a physician experienced in chemotherapy.

When topotecan is used in combination with cisplatin, it is essential to carefully review the medical instructions for cisplatin use.

Prior to initiating the first treatment cycle with topotecan, patients should have baseline neutrophil counts ≥ 1.5 × 10⁹/L, platelet counts ≥ 100 × 10⁹/L, and hemoglobin levels ≥ 9 g/dL (after blood transfusion, if necessary).

Ovarian Cancer and Small Cell Lung Cancer

Initial Dose

Topotecan is recommended for administration in adults at a dose of 1.5 mg/m² body surface area per day by intravenous infusion over 30 minutes for 5 consecutive days, with treatment cycles repeated every 3 weeks. If the drug is well tolerated, treatment may continue until disease progression.

Subsequent Doses

Topotecan may be re-administered only if neutrophil count is ≥ 1 × 10⁹/L, platelet count is ≥ 100 × 10⁹/L, and hemoglobin level is ≥ 9 g/dL (after blood transfusion, if necessary). To manage neutropenia in oncology patients and maintain neutrophil counts, other medicinal agents (e.g., colony-stimulating factor) are typically co-administered with topotecan or the topotecan dose is reduced.

If dose reduction of topotecan is required for patients with severe neutropenia (neutrophil count ≤ 0.5 × 10⁹/L) lasting 7 or more days, or with severe neutropenia accompanied by fever or signs of infection, or for patients whose treatment was delayed due to neutropenia, the dose should be reduced by 0.25 mg/m²/day to 1.25 mg/m²/day (or further reduced sequentially to 1.0 mg/m²/day, if necessary).

The dose should also be reduced if platelet counts fall below 25 × 10⁹/L. If further dose reduction is required below 1 mg/m²/day to prevent adverse reactions, topotecan administration should be discontinued (based on clinical trial data).

Cervical Cancer

Initial Dose

Topotecan is recommended at a dose of 0.75 mg/m²/day administered by intravenous infusion over 30 minutes on days 1, 2, and 3. Cisplatin should be administered daily by intravenous infusion at a dose of 50 mg/m²/day following topotecan administration. Treatment should be repeated every 21 days for up to 6 cycles or until disease progression.

Subsequent Doses

For subsequent treatment cycles, the drug should not be administered until neutrophil counts reach ≥ 1.5 × 10⁹/L, platelet counts reach ≥ 100 × 10⁹/L, and hemoglobin levels reach ≥ 9 g/dL (after blood transfusion, if necessary).

To manage neutropenia in oncology patients and maintain neutrophil counts, other medicinal agents (e.g., colony-stimulating factor) should typically be co-administered with topotecan or the topotecan dose should be reduced.

If dose reduction of topotecan is required for patients who develop severe neutropenia (neutrophil count ≤ 0.5 × 10⁹/L) lasting 7 or more days, or for patients with severe neutropenia accompanied by fever or signs of infection, or for patients whose treatment was delayed due to neutropenia, the dose should be reduced by 20% to 0.60 mg/m² body surface area/day for subsequent cycles (or further reduced to 0.45 mg/m² body surface area/day, if necessary).

For patients whose platelet counts decrease to < 25 × 10⁹/L during treatment, a similar dose reduction of topotecan is recommended.

Special Patient Groups

Patients with Renal Impairment

Monotherapy (Ovarian Cancer and Small Cell Lung Cancer)

There is insufficient experience with topotecan in patients with severe renal impairment (creatinine clearance < 20 mL/min). The use of topotecan in this patient group is not recommended (see section "Special Precautions").

Limited data suggest that dose reduction is required in patients with moderate renal impairment.

The recommended dose of topotecan as monotherapy in patients with ovarian cancer or small cell lung cancer and creatinine clearance of 20–39 mL/min is 0.75 mg/m²/day for 5 consecutive days.

Combination Therapy (Cervical Cancer)

Treatment with topotecan in combination with cisplatin for cervical cancer should only be initiated if serum creatinine levels are ≤ 1.5 mg/dL.

If serum creatinine levels exceed 1.5 mg/dL during combination therapy (topotecan/cisplatin), careful consideration should be given to dose reduction or continuation of cisplatin treatment. There is insufficient data regarding continuation of topotecan monotherapy in cervical cancer patients if cisplatin treatment is discontinued.

Patients with Hepatic Impairment

A small group of patients with hepatic impairment (serum bilirubin levels of 1.5–10 mg/dL) received intravenous topotecan at 1.5 mg/m²/day for 5 days every 3 weeks. A reduction in topotecan clearance was observed. However, there are insufficient data to make dosing recommendations for this patient group (see section "Special Precautions"). There is insufficient data on the use of topotecan in patients with severe hepatic impairment (serum bilirubin ≥ 10 mg/dL) due to cirrhosis. The use of topotecan in these patient groups is not recommended (see section "Special Precautions").

Dosing Regimen in Combination with Other Medicinal Products

The dose of topotecan may be altered when used in combination with other cytotoxic agents (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). If topotecan is used in combination with cisplatin, the instructions for medical use of cisplatin should be carefully read.

Preparation of the Infusion Solution

1 mL of concentrate for infusion solution contains 1 mg of topotecan; 4 mL of concentrate for infusion solution contains 4 mg of topotecan.

To obtain a final concentration of 25–50 µg/mL, the concentrate for infusion solution must be diluted with either 0.9% sodium chloride solution for intravenous infusion or 5% glucose solution for intravenous infusion.

Children

There is insufficient experience with the use of this medicinal product in children. Available data are provided in the section "Pharmacological Properties."

Overdose

Cases of overdose (at doses 10 times higher than recommended) have been reported with intravenous topotecan. Signs and symptoms observed after overdose are similar to known adverse reactions associated with topotecan use (see section "Adverse Reactions"). Primary complications of overdose include bone marrow suppression and mucositis. Additionally, elevated liver enzyme levels have been reported with intravenous topotecan overdose.

There is no known antidote for overdose. Further treatment should be based on clinical indications or in accordance with recommendations from the national toxicology center, if available.

Adverse Reactions

In clinical trials involving 523 patients with recurrent ovarian cancer and 631 patients with recurrent small cell lung cancer, dose-dependent hematological toxicity was observed, which was predictable and reversible. There was no evidence of cumulative hematological or non-hematological toxicity.

The adverse reaction profile of topotecan used in combination with cisplatin for the treatment of cervical cancer, based on study data, corresponds to that observed when topotecan is used as monotherapy. Overall hematological toxicity in patients receiving topotecan in combination with cisplatin is lower than in patients receiving topotecan alone, but higher than in those receiving cisplatin alone.

Additional adverse reactions were observed when topotecan was used in combination with cisplatin; however, these occurred with cisplatin use alone and cannot be attributed to topotecan. The complete list of adverse reactions associated with cisplatin is provided in the medical instructions for cisplatin.

Adverse reactions are listed below by system organ class and absolute incidence (all reported cases). The frequency of adverse reactions is defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Very common: febrile neutropenia, neutropenia (see "Gastrointestinal disorders"), thrombocytopenia, anemia, leukopenia.

Common: pancytopenia.

Frequency not known: severe bleeding (associated with thrombocytopenia).

Immune system disorders

Common: hypersensitivity reactions, including rash.

Rare: anaphylactic reactions, angioneurotic edema, urticaria.

Infections and infestations

Very common: infections.

Common: sepsis¹.

Metabolism and nutrition disorders

Very common: anorexia (which may be severe).

Respiratory, thoracic and mediastinal disorders

Rare: interstitial lung disease (in some cases fatal).

Gastrointestinal disorders

Very common: nausea, vomiting, and diarrhea (which may be severe), constipation, abdominal pain², mucositis.

Frequency not known: gastrointestinal perforation.

Hepatobiliary disorders

Common: hyperbilirubinemia.

Skin and subcutaneous tissue disorders

Very common: alopecia.

Common: pruritus.

General disorders and administration site conditions

Very common: pyrexia, asthenia, fatigue.

Common: malaise.

Very rare: extravasation of fluid from blood vessels (reactions were mild and generally did not require specific therapy).

Frequency not known: mucosal inflammation.

¹ Fatal cases due to sepsis have been reported in patients receiving topotecan (see section "Special precautions").

² Neutropenic colitis, including fatal neutropenic colitis, has been reported as a complication of topotecan-induced neutropenia (see section "Special precautions").

The frequency of the adverse reactions listed above is more typical in patients with poor general health status.

The frequency of the hematological and non-hematological adverse reactions listed below refers to reactions that are related or possibly related to the use of topotecan.

Hematological.

Neutropenia: severe (neutrophil count < 0.5 × 10⁹/L) occurred in 55% of patients during Cycle 1; lasting ≥ 7 days in 20%; overall in 77% of patients (39% of cycles).

Fever or infection occurred in association with severe neutropenia in 16% of patients during Cycle 1 and overall in 23% of patients (6% of treatment cycles). The median time to onset of severe neutropenia was 9 days, with a median duration of 7 days. Severe neutropenia lasting more than 7 days occurred in 11% of cycles. Among all patients enrolled in clinical trials, including those who developed severe neutropenia and those who did not, fever developed in 11% (4% of cycles) and infectious complications in 26% (9% of cycles). Additionally, sepsis occurred in 5% of all treated patients (1% of cycles).

Severe thrombocytopenia (platelet count < 25 × 10⁹/L) occurred in 25% of patients (8% of cycles); moderate (platelet count 25.0–50.0 × 10⁹/L) in 25% of patients (15% of cycles). Severe thrombocytopenia developed on average on Day 15 and lasted on average 5 days. Platelet transfusions were administered in 4% of cycles. Serious consequences of thrombocytopenia, including fatal events due to tumor hemorrhage, were reported uncommonly.

Moderate to severe anemia (hemoglobin level ≤ 8.0 g/dL) was observed in 37% of patients (14% of cycles). Red blood cell transfusions were administered in 52% of patients (21% of cycles).

Non-hematological.

Common non-hematological adverse reactions included gastrointestinal events such as nausea (52%), vomiting (32%), diarrhea (18%), constipation (9%), and mucositis (14%). The incidence of severe (Grade 3–4) nausea, vomiting, diarrhea, and mucositis was 4%, 3%, 2%, and 1%, respectively.

Mild to moderate abdominal pain was reported in 4% of patients.

Fatigue was observed in approximately 25% and asthenia in 16% of patients treated with topotecan. Severe (Grade 3–4) fatigue and asthenia occurred in 3% of cases.

Total or marked alopecia occurred in 30% of patients, partial alopecia in 15% of patients.

Other adverse reactions reported as related or possibly related to topotecan use included anorexia (12%), malaise (3%), and hyperbilirubinemia (1%).

There were isolated reports of hypersensitivity reactions, including rash, urticaria, angioneurotic edema, and anaphylactic reactions. During clinical trials, rash occurred in 4% of patients and pruritus in 1.5% of patients.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk ratio of the medicine. Healthcare professionals, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: http://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Vials of concentrate should be stored in a dry, light-protected place at a temperature not exceeding 25 °C. Keep out of the reach of children.

Diluted solutions.

The product should be used immediately after dilution, as it contains no antimicrobial preservative. If dilution is performed under aseptic conditions (e.g., on a laminar flow bench), the product should be used within 12 hours at room temperature or within 24 hours if stored at 2–8 °C after the first puncture of the vial.

Incompatibilities. The product should not be mixed with other medicinal products except those specified in the section "Method of administration and dosage."

Packaging. 1 ml or 4 ml of the product in a type I amber glass vial, sealed with a rubber stopper and crimped with an aluminum cap. One glass vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and location of operations.

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

Marketing authorization holder. Accord Healthcare Polska Sp. z o.o. / Accord Healthcare Polska Sp. z o.o.

Inquiries regarding substandard quality of the medicinal product, safety concerns, improper use, or complaints are accepted 24/7 via phone: +380993100335 or by email: [email protected].

Address of the marketing authorization holder. 7 Tasmowa St., Warsaw, 02-677, Poland.