Hycamtin (Lyophilisate) Instructions for Use

Marketing Authorization Holder

GlaxoSmithKline Trading, JSC (Russia)

Manufactured By

GlaxoSmithKline Manufacturing, S.p.A. (Italy)

ATC Code

L01CE01 (Topotecan)

Active Substance

Topotecan (Rec.INN registered by WHO)

Dosage Form

Hycamtin

Lyophilisate for preparation of solution for infusion 4 mg: vial 1 or 5 pcs.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion as a porous mass from light yellow to greenish in color; the reconstituted solution is clear, from yellow to yellow-green in color.

Excipients: tartaric acid – 20 mg, mannitol – 48 mg, sodium hydroxide – q.s. to pH 3.0, hydrochloric acid – q.s. to pH 3.0.

Glass vials with a volume of 17 ml (1) – cardboard packs.
Glass vials with a volume of 17 ml (5) – cardboard packs with an integrated cardboard divider.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

Antineoplastic drug, an inhibitor of topoisomerase-I, an enzyme directly involved in DNA replication. Topotecan inhibits the activity of topoisomerase-I by stabilizing the covalent complex of the enzyme and the helix-cleaved DNA, which is an intermediate in the catalytic mechanism.

Inhibition of topoisomerase-I leads to single-strand DNA breaks and cessation of DNA replication.

Pharmacokinetics

Distribution

Topotecan is characterized by a large V_d (about 132 L), approximately 3 times the total body fluid volume, and a relatively short T_1/2 (2-3 h). When comparing pharmacokinetic parameters, no changes in pharmacokinetics were detected during the 5-day course of therapy.

The binding of topotecan to plasma proteins is 35%, and the distribution between blood cells and plasma is uniform.

Plasma clearance and volume of distribution values were somewhat higher in men than in women. However, these differences corresponded to differences in body surface area.

Metabolism

The main pathway of topotecan metabolism is reversible pH-dependent hydrolysis of the lactone ring to form an inactive carboxyl form.

< 10% of the administered topotecan is metabolized. An N-demethylated metabolite of topotecan, possessing similar or less activity than Topotecan, is found in urine, plasma, and feces. After IV administration, the mean AUC ratio of the topotecan metabolite to topotecan was less than 10% for both total topotecan and topotecan in the lactone form. Topotecan O-glucuronide and N-demethylated Topotecan are found in urine.

In vitro, Topotecan does not inhibit the activity of the CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, and CYP4A isoenzymes of the cytochrome P450 system, nor the cytosolic enzymes dihydropyrimidine dehydrogenase and xanthine oxidase.

Excretion

After IV administration, the plasma concentration-time curve of topotecan is biexponential. The pharmacokinetics of topotecan after IV administration are approximately proportional to the administered dose. With repeated daily IV administration, Topotecan accumulates minimally or not at all in the body, and there are no data on changes in pharmacokinetics with repeated administration.

The clearance of topotecan after IV administration in doses from 0.5 mg/m² to 1.5 mg/m² (30-minute daily infusions for 5 consecutive days) was high (64 L/h, i.e., approximately 2/3 of hepatic blood flow).

After a 5-day course of topotecan, the total amount of topotecan and its metabolites eliminated from the body ranged from 71% to 76% of the IV dose. Approximately 51% is excreted by the kidneys as topotecan, 2.5% as the N-demethylated metabolite of topotecan, and 18% of topotecan and 1.5% of the N-demethylated metabolite of topotecan are excreted via the intestine. In total, less than 7% of topotecan (range from 4% to 9%) is excreted via the kidneys and intestine as a metabolite (N-demethylated metabolite of topotecan). Concentrations of topotecan O-glucuronide and N-demethylated topotecan O-glucuronide in urine account for ≤ 2% of the administered dose.

When administered in combination with cisplatin (cisplatin on day 1, Topotecan on days 1-5), the clearance of topotecan on day 5 was lower than on day 1 (19.1 L/h/m² and 21.3 L/h/m², respectively). In population studies, concomitant administration of granisetron, ondansetron, morphine, or glucocorticosteroids did not have a significant effect on the pharmacokinetics of topotecan.

Pharmacokinetics in special patient groups

In a population study of IV topotecan, a number of factors, including age, body weight, and the presence of ascites, did not have a significant effect on clearance.

Children

The pharmacokinetic characteristics of topotecan in children were studied after a 24-hour infusion of topotecan at doses from 2 mg/m² to 7.5 mg/m² or a 72-hour infusion at doses from 0.75 mg/m²/day to 1.95 mg/m²/day. In both studies, the clearance of topotecan was equal to the clearance in adult patients receiving the drug according to similar regimens.

Renal impairment

In patients with renal impairment (CrCl from 40 ml/min to 60 ml/min), the clearance of IV administered topotecan was reduced to approximately 67% of the value in the control group. V_d was slightly reduced, and thus the half-life was increased by 14%. In patients with moderate renal impairment (CrCl from 20 ml/min to 39 ml/min), the plasma clearance of topotecan was reduced to 34% of the control value. V_d was also reduced by approximately 25%, leading to an increase in half-life from 1.9 h to 4.9 h.

Hepatic impairment

In patients with hepatic impairment (serum bilirubin from 1.5 mg/dl to 10 mg/dl), the plasma clearance of topotecan in the lactone form after IV administration is reduced to approximately 67% of the value in the control group. The half-life of topotecan is increased by approximately 30%, but no significant increase in V_d was observed. The clearance of topotecan in patients with hepatic impairment decreased by only 10% compared to controls.

Indications

• Small cell lung cancer;
• Ovarian cancer;
• Recurrent or persistent carcinoma of the cervix uteri, not amenable to surgical treatment and/or radiation therapy (stage IV B), as part of combination therapy with cisplatin.

ICD codes

Dosage Regimen

Hycamtin is administered as a 30-minute IV infusion.

Before prescribing the first course of therapy with Hycamtin, the neutrophil count should be ≥1500/µl, platelets ≥ 100,000/µl, hemoglobin level ≥ 9 g/dl (after transfusion, if necessary).

The drug is prescribed for adults and elderly patients.

For small cell lung cancer and ovarian cancer, 1.5 mg/m² is prescribed daily for 5 consecutive days with a 3-week (21-day) interval before the start of each course.

To achieve an effect, it is recommended to conduct at least 4 courses of therapy (in clinical studies, the average time to onset of effect in patients with ovarian cancer was 7.6-11.7 weeks, in patients with small cell lung cancer – 6.1 weeks. Approximately 18% of patients with ovarian cancer achieved an effect after 5 or more courses of therapy).

Repeated courses of therapy with Hycamtin can be carried out only with the following indicators: neutrophils ≥1000/µl, platelets ≥100,000/µl, hemoglobin ≥9 g/dl (including after transfusion, if necessary).

In case of severe neutropenia (neutrophil count <500/µl) for 7 days or more, or febrile neutropenia, or in case of delayed treatment due to neutropenia, either the drug dose should be reduced to 1.25 mg/m²/day (or later to 1 mg/m²/day), or subsequent courses should be conducted with prophylactic administration of G-CSF. If neutropenia persists against the background of G-CSF, the drug doses should be reduced.

If the platelet count during the previous course of chemotherapy was <25,000/µl, the doses should be reduced in a similar manner.

In clinical studies, topotecan therapy was discontinued if it was necessary to reduce the dose below 1 mg/m².

For cervical cancer, the recommended dose of Hycamtin is 0.75 mg/m² on days 1, 2, and 3. On day 1 of therapy, after administration of Hycamtin, an infusion of cisplatin at a dose of 50 mg/m² is performed. This regimen is repeated every 21 days, for a total of 6 courses. If signs of disease progression appear, Hycamtin should be discontinued.

Repeated courses of therapy with Hycamtin can be carried out only with the following indicators: neutrophil count ≥1500/µl, platelets – ≥100,000/µl, hemoglobin – ≥9 g/dl (after transfusion, if necessary).

In case of severe neutropenia (neutrophil count less than 500/µl) for 7 or more days, or febrile neutropenia, or in case of delayed treatment due to neutropenia, either the drug dose for subsequent courses should be reduced by 20% to 600 mcg/m²/day (or later to 450 mcg/m²/day), or subsequent courses should be conducted with prophylactic administration of G-CSF. If neutropenia persists against the background of G-CSF, the drug doses should be reduced.

If the platelet count decreases to less than 25,000/µl, the doses should be reduced in a similar manner.

The use of Hycamtin for the treatment of children is contraindicated, as the available experience with the drug in this category of patients is insufficient.

In patients with renal impairment with monotherapy with CrCl ≥ 40 ml/min, no dosage adjustment is required. For CrCl from 20 to 39 ml/min, the recommended dose is 750 mcg/m²/day; recommendations are based on studies that included patients with advanced cancer. For CrCl < 20 ml/min, there are no recommendations.

For combination therapy with Hycamtin and cisplatin for the treatment of cervical cancer, it is recommended to start therapy only in patients whose plasma creatinine concentration does not exceed 1.5 mg/dl. If during treatment the plasma creatinine level exceeds 1.5 mg/dl, the recommendations in the cisplatin prescribing information for dose reduction or discontinuation should be followed. In case of cisplatin discontinuation, there is insufficient data regarding the continuation of monotherapy with Hycamtin in patients with cervical cancer.

For patients with hepatic impairment (bilirubin level from 1.5 to 10 mg/dl) with monotherapy, no dose adjustment is required. With combination therapy with other cytotoxic drugs, dose adjustment may be required.

Rules for solution preparation

The contents of the vial should be dissolved in 4 ml of sterile water for injections to a concentration of 1 mg/ml. The resulting solution must be diluted with 0.9% sodium chloride solution or 5% dextrose solution to a concentration of 25-50 mcg/ml.

The reconstituted solution should be used immediately after preparation or stored in a refrigerator at a temperature from 2°C (35.6°F) to 8°C (46.4°F) for 24 hours.

The prepared solution should be used immediately after preparation or stored in a refrigerator at a temperature from 2°C (35.6°F) to 8°C (46.4°F) for 24 hours.

Adverse Reactions

Long-term use does not cause an increase in the toxic effect of the drug. No serious manifestations of cardiotoxicity, neurotoxicity, or organ toxicity were noted.

The adverse events listed below are presented according to the affected organs and organ systems and frequency of occurrence. Frequency is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000, including isolated cases). Frequency categories were formed based on clinical studies of the drug.

From the hematopoietic system: very common – neutropenia, febrile neutropenia, leukopenia, thrombocytopenia, anemia¹, changes in blood parameters²; common – pancytopenia; very rare – side effects affecting blood test results; frequency unknown – bleeding, pronounced and hidden bleeding due to thrombocytopenia.

From the musculoskeletal system: common – myalgia.

From the digestive system: very common – diarrhea³, nausea, vomiting (including severe), abdominal pain⁴, constipation, stomatitis, anorexia (including severe); common – hyperbilirubinemia; very rare – intestinal inflammation (colitis); frequency unknown – intestinal obstruction.

From the immune system: common – hypersensitivity reactions, including rash.

From the respiratory system: rare – interstitial lung disease.

From the skin and subcutaneous tissue: very common – alopecia.

Allergic reactions: very common – anaphylactoid reactions; rare – urticaria, difficulty breathing; very rare – angioedema; frequency unknown – skin rash (including erythematous, maculopapular rash, urticaria, dermatitis, bullous erythema).

General disorders and administration site conditions: very common – fever, increased fatigue, asthenia, infections; common – weakness, sepsis; very rare – extravasation: hematoma or skin hyperemia at the injection site (with extravasation) (reactions associated with extravasation were mild and usually did not require specific treatment); frequency unknown – dyspnea, infections.

¹ Cases of moderate to severe anemia (grades 3 and 4 – Hb < 8 g/dl) occurred in 25% of cases (12% of courses). The median time to onset of moderate and severe anemia was day 12 with a median duration of 7 days. In 46% of courses with moderate and severe anemia, the duration was more than 7 days. Red blood cell transfusions were received by 30% of patients (13% of courses). Erythropoietin was administered to 10% of patients in 8% of courses.

²Low count of cells necessary for blood clotting, which can cause bruising, bleeding, and, rarely, severe bleeding (hemorrhage).

³ With IV administration of topotecan, diarrhea occurred in 10% of patients over 65 years of age.

⁴Cases of neutropenic colitis, including fatal cases, were considered complications of drug-induced neutropenia.

Contraindications

• Severe bone marrow function suppression (neutrophil count less than 1500/µl, platelets — less than 100,000/µl);
• Anemia (Hb < 9 g/dl);
• Pregnancy;
• Lactation (breastfeeding);
• Childhood (insufficient experience);
• History of hypersensitivity to topotecan or other components included in the drug.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and during lactation (breastfeeding).

Women of childbearing potential and men during Hycamtin administration should use reliable methods of contraception. If pregnancy occurs, the treating physician should be informed immediately.

Use in Hepatic Impairment

For patients with hepatic impairment (plasma bilirubin from 1.5 to 10 mg/dl), no special dose adjustment is required. When using Hycamtin at a dose of 1.5 mg/m² for 5 days every 3 weeks, a slight decrease in topotecan clearance was observed.

Use in Renal Impairment

For renal impairment in patients with CrCl≥40 ml/min, no dose adjustment is required. The recommended dose for patients with CrCl 20-39 ml/min is 750 mcg/m²/day. For recommendations regarding the drug dose for patients with CrCl<20 ml/min, the available data are insufficient.

Pediatric Use

Contraindication: childhood (insufficient clinical experience).

Geriatric Use

Use according to the dosage regimen.

Special Precautions

Treatment with topotecan should be carried out under the supervision of a specialist experienced in working with antineoplastic drugs.

The hematological toxicity of topotecan is dose-dependent; it is necessary to regularly perform detailed blood tests with determination of hemoglobin level, hematocrit, leukocyte count, neutrophil and platelet counts.

When combining topotecan with other cytotoxic drugs, its dose must be adjusted.

If severe neutropenia develops, careful monitoring is necessary for timely diagnosis of infectious complications.

As with the use of other cytotoxic drugs, Topotecan can cause severe myelosuppression, leading in some cases to severe infectious complications, including sepsis and associated fatal outcome.

Neutropenia induced by topotecan treatment can cause neutropenic colitis. Cases of this complication with fatal outcome were registered during clinical studies. In patients with fever, neutropenia combined with abdominal pain in the projection of the colon, the possibility of developing neutropenic colitis should be considered.

Cases of interstitial lung disease have been reported during treatment with topotecan, some with fatal outcome. Patients with a history of interstitial lung disease, pulmonary fibrosis, lung cancer, as well as patients who have undergone chest irradiation, taken pneumotoxic drugs and/or colony-stimulating factors, are at high risk of developing this complication. Patients should be monitored for the appearance of symptoms of interstitial lung disease (e.g., cough, fever, dyspnea and/or hypoxia). If newly diagnosed interstitial lung disease is confirmed, Topotecan should be discontinued.

In case of severe thrombocytopenia, extreme caution is required when performing invasive procedures, regular examination of the skin and mucous membranes, as well as secretions to detect signs of bleeding.

When handling the drug, standard rules for handling cytotoxic drugs must be observed. If the drug accidentally gets on the skin or in the eyes, they should be rinsed with plenty of water.

Influence on the ability to drive vehicles and mechanisms

The general clinical condition of the patient and the possible development of adverse events (especially increased fatigue and weakness) should be taken into account when assessing the ability to drive a car and operate machinery requiring increased concentration and speed of psychomotor reactions.

Overdose

Symptoms bone marrow function depression, stomatitis.

Treatment an antidote for topotecan is unknown. Symptomatic therapy is carried out.

Drug Interactions

As with other myelosuppressive cytotoxic drugs, myelosuppression increases when topotecan is used in combination with other cytotoxic substances (for example, paclitaxel or etoposide), which requires a dose reduction. However, when topotecan is used in combinations with platinum drugs (for example, cisplatin or carboplatin), a clear dependence of the drug interaction on the sequence of their administration is observed, i.e., on whether the platinum drug is administered on day 1 or day 5 of topotecan use. If the patient receives the platinum drug on day 1 of topotecan administration, both drugs should be prescribed at lower doses than if the platinum drug is administered on day 5.

With IV administration of topotecan (750 mcg/m²/day for 5 consecutive days) and cisplatin (60 mg/m²/day on day 1), the mean plasma clearance values of topotecan on day 5 may be somewhat lower than on day 1. Thus, the systemic exposure of total topotecan (AUC and C_max) on day 5 may be higher by 12% (95% confidence interval (CI): from 2% to 24%) and 23% (95% CI: from 7% to 63%), respectively. There are no data on pharmacokinetic interaction after administration of topotecan (750 mcg/m²/day for 3 consecutive days) and cisplatin (50 mg/m²/day on day 1) in patients with cervical cancer.

The doses and regimens for topotecan and platinum drugs are given below

• Cisplatin on day 1 at a dose of 60 mg/m² and Topotecan at a dose of 750 mcg/m² from day 1 to day 5.
• Cisplatin on day 5 at a dose of 50 mg/m² and Topotecan at a dose of 1.25 mg/m² from day 1 to day 5.

Topotecan does not inhibit the activity of cytochrome P450 isoenzymes. In population studies, co-administration of granisetron, ondansetron, morphine, or corticosteroids (infusions were administered through different systems or a different route of administration was used) did not have a significant effect on the pharmacokinetics of intravenously administered topotecan.

Topotecan is a substrate for both the breast cancer resistance protein BCRP (ABCG2) and ABCB1 (P-glycoprotein). Elacridar affects the pharmacokinetics of intravenously administered topotecan significantly less than that of orally administered topotecan.

Storage Conditions

The unopened vial should be stored out of the reach of children, protected from light, at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.