Topotecan-Actavis (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Actavis Group PTC ehf. (Iceland)

Manufactured By

S.C. Sindan-Pharma S.R.L. (Romania)

ATC Code

L01CE01 (Topotecan)

Active Substance

Topotecan (Rec.INN registered by WHO)

Dosage Forms

	Topotecan-Actavis	Lyophilisate for preparation of solution for infusion 1 mg: vial 1 pc.
		Lyophilisate for preparation of solution for infusion 4 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion as a yellow porous mass.

Excipients : mannitol – 24 mg, tartaric acid – 5 mg, sodium hydroxide – to pH 3.0±0.2 (2.8-3.2).

Colorless glass vials with a volume of 5 ml (1) – cardboard packs.

Lyophilisate for preparation of solution for infusion as a yellow porous mass.

Excipients : mannitol – 48 mg, tartaric acid – 20 mg, sodium hydroxide – to pH 3.0±0.2 (2.8-3.2).

Colorless glass vials with a volume of 8 ml (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

Antineoplastic drug, topoisomerase I inhibitor. Topoisomerase I is an enzyme directly involved in DNA replication. Topotecan stabilizes the covalent complex of the enzyme and the helically cleaved DNA, which is an intermediate link of the catalytic mechanism.

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

Pharmacokinetics

Distribution

After IV administration of topotecan to adults at doses of 0.5-1.5 mg/m² as a 30-minute daily infusion for 5 days, the area under the concentration-time curve (AUC) increased proportionally to the dose increase.

The binding of topotecan to plasma proteins is 35%. Distribution between blood cells and plasma is uniform. The volume of distribution (V_d) is about 132 L.

Metabolism

It is metabolized in the liver. The main pathway of topotecan metabolism is pH-dependent hydrolysis of the lactone ring, which forms a carboxylic acid with an open ring.

Topotecan did not inhibit the CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, CYP4A isoenzymes, nor did it inhibit the cytosolic enzymes dihydropyrimidine oxidase or xanthine oxidase.

Excretion

After IV administration of topotecan to adults at doses of 0.5-1.5 mg/m² as a 30-minute daily infusion for 5 days, the clearance of topotecan is 64 L/h, which is approximately 2/3 of the hepatic blood flow. The half-life (T_1/2) is 2-3 hours. 20-60% of the dose is excreted in the urine unchanged and in the form of metabolites.

Pharmacokinetics in special clinical cases

In patients with renal failure (CrCl 41-60 ml/min), plasma clearance decreases by 67%. V_d decreases somewhat and thus T_1/2 increases by only 14%. In patients with moderate renal failure, the plasma clearance of topotecan is reduced to 34%.

In patients with hepatic impairment, the plasma clearance of topotecan lactone decreases to 67%, and the total plasma clearance decreases by 10% compared to the control group. The T_1/2 of topotecan increases by approximately 30%, with no significant changes in V_d observed.

When topotecan is prescribed in combination with cisplatin (cisplatin on day 1, Topotecan on days 1 and 5), the clearance of topotecan decreases on day 5 compared to the first day (19.1 L/h/m² compared to 21.3 L/h/m²).

Indications

• Small cell lung cancer;
• Ovarian cancer;
• Recurrent or persistent cervical cancer that is not amenable to surgical treatment and/or radiation combined therapy (stage IVB), as part of combination therapy with cisplatin.

ICD codes

Dosage Regimen

Topotecan is administered as a 30-minute IV infusion.

Adults and elderly patients

Before prescribing the first course of topotecan therapy, the neutrophil count should be ≥1.5×10⁹/L, platelets ≥100×10⁹/L, hemoglobin level ≥9 g/dL.

For small cell lung cancer and ovarian cancer, 1.5 mg/m² of body surface area is prescribed daily for 5 consecutive days with an interval of 3 weeks.

To achieve an effect, it is recommended to conduct at least 4 courses of therapy (the average time to onset of effect in patients with ovarian cancer is 8-11.7 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 topotecan therapy can be carried out only with the following indicators: neutrophils ≥1×10⁹/L, platelets ≥100×10⁹/L, hemoglobin ≥9 g/dL (including after blood transfusion, if necessary).

In case of severe neutropenia (neutrophil count <0.5×10⁹/L) for 7 days or more, or febrile neutropenia, or if treatment is delayed due to neutropenia, the drug dose should be reduced to 1.25 mg/m²/day or if necessary to 1 mg/m²/day or subsequent courses should be carried out with the prophylactic administration of granulocyte colony-stimulating factor (G-CSF), starting from the 6th day of treatment (no earlier than 24 hours after the end of topotecan therapy). If neutropenia persists against the background of G-CSF, the drug doses should be reduced.

If the platelet count decreased during the previous course of chemotherapy to <25×10⁹/L, the doses should be reduced in a similar manner.

If, due to side effects, a dose reduction below 1 mg/m² is required, topotecan therapy should be discontinued.

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

Repeated courses of topotecan therapy can be carried out only with the following indicators: neutrophils ≥1.5×10⁹/L, platelets ≥100×10⁹/L, hemoglobin ≥9 g/dL (including after blood transfusion, if necessary).

In case of febrile neutropenia (increase in body temperature to 38°C (100.4°F) and above with a neutrophil count <1×10⁹/L), for subsequent courses, it is recommended to reduce the dose of topotecan by 20% to 0.6 mg/m².

If the platelet count decreases to <10×10⁹/L, the doses should be reduced in a similar manner.

As an alternative to dose reduction for febrile neutropenia, patients are recommended to administer G-CSF at the end of each subsequent course (before resorting to dose reduction), starting from the 4th day of treatment (no earlier than 24 hours after the end of topotecan therapy). If febrile neutropenia persists against the background of G-CSF, the drug doses for subsequent courses should be reduced by 20% to 0.45 mg/m².

In monotherapy for patients with CrCl > 40 ml/min, no adjustment of the dosage regimen is required. The recommended dose for patients with CrCl from 20 to 39 ml/min is 0.75 mg/m²/day. There are no recommendations for the dosage regimen in patients with reduced CrCl < 20 ml/min.

For combination therapy with topotecan 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 of the cisplatin instructions for use regarding its dose reduction/discontinuation should be followed. In case of cisplatin discontinuation, there is insufficient data regarding the continuation of topotecan monotherapy in patients with cervical cancer.

For patients with impaired liver function (bilirubin level from 1.5 to 10 mg/dL) no dose adjustment is required.

The use of topotecan for the treatment of children is not recommended, because the available experience with the use of the drug in this category of patients is insufficient.

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 µg/ml.

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 frequency of adverse events was classified 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).

From the hematopoietic system very common – neutropenia, febrile neutropenia, leukopenia, thrombocytopenia, anemia; common – pancytopenia; rare – severe bleeding due to thrombocytopenia.

From the respiratory system rare – interstitial lung disease.

From the digestive system very common – diarrhea, nausea, vomiting (including severe), abdominal pain*, constipation, stomatitis, anorexia (including severe); common – hyperbilirubinemia.

From the skin and skin appendages very common – alopecia.

Allergic reactions common – hypersensitivity reactions, including skin rash (including erythematous, maculopapular rash, dermatitis, bullous erythema); rare – anaphylactoid reactions, angioedema, urticaria.

Other very common – increased body temperature, increased fatigue, asthenia, addition of secondary infections; common – weakness, sepsis; very rare – ecchymoses, hemorrhages (mild and not requiring specific treatment). In very rare cases, extravasation has been reported. In case of extravasation, a hematoma or skin hyperemia may occur at the injection site.

* against the background of topotecan use, due to developed neutropenia, there have been reports of neutropenic colitis, including fatal neutropenic colitis.

Contraindications

• Severe suppression of bone marrow function (neutrophil count less than 1.5×10⁹/L, platelets — less than 100 ×10⁹/L);
• Pregnancy and breastfeeding period;
• Childhood (lack of sufficient experience of use);
• Hypersensitivity to topotecan or other components of the drug.

With caution: women of childbearing potential and men during topotecan administration should use reliable methods of contraception.

Use in Pregnancy and Lactation

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

Use in Hepatic Impairment

For patients with impaired liver function (bilirubin level from 1.5 to 10 mg/dL) no dose adjustment is required.

Use in Renal Impairment

In monotherapy for patients with CrCl > 40 ml/min, no adjustment of the dosage regimen is required. The recommended dose for patients with CrCl from 20 to 39 ml/min is 0.75 mg/m²/day. There are no recommendations for the dosage regimen in patients with reduced CrCl < 20 ml/min.

Pediatric Use

The use of topotecan for the treatment of children is not recommended, because the available experience with the use of the drug in this category of patients is insufficient.

Geriatric Use

Use is possible according to the dosage regimen.

Special Precautions

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

It is not recommended to prescribe topotecan monotherapy as first-line therapy. 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, neutrophils and platelets.

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.

Neutropenia induced by the use of topotecan can cause the development of neutropenic colitis (including fatal). In patients with fever, neutropenia, combined pain in the abdomen in the projection of the colon, the possibility of developing neutropenic colitis should be considered. Cases of interstitial lung disease have been reported during therapy with topotecan (including fatal). 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, shortness of breath and/or hypoxia); upon confirmation of newly diagnosed interstitial lung disease, Topotecan should be discontinued.

It weakens the effectiveness of immunization with inactivated vaccines; when using live viral vaccines, it enhances virus replication and the side effects of vaccination. The interval between the administration of topotecan and vaccination with live viral or inactivated viral vaccines varies from 3 to 12 months. If severe thrombocytopenia occurs, 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 working with the drug, generally accepted 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.

Effect on ability to drive vehicles and mechanisms

Some undesirable effects of the drug, such as increased fatigue and weakness, may negatively affect the ability to concentrate and the speed of psychomotor reactions.

The general clinical condition of the patient and the possible development of adverse events should be taken into account when assessing the ability to drive a car and work with mechanisms requiring quick reaction.

Overdose

Symptoms suppression of bone marrow function, stomatitis.

Treatment hospitalization, monitoring of vital functions; symptomatic therapy; if necessary— transfusion of blood components, prescription of broad-spectrum antibiotics. A specific antidote is unknown.

Drug Interactions

With simultaneous use of topotecan with other cytotoxic agents (for example, paclitaxel or etoposide), increased myelosuppression is possible (dose adjustment of topotecan is required).

The nature of the interaction of topotecan with platinum drugs depends on the sequence of platinum administration, namely, whether platinum drugs are prescribed on the 1st or on the 5th day of topotecan use. If platinum drugs are prescribed on the 1st day, then reduced doses of each drug should be used compared to the doses when platinum drugs are prescribed on the 5th day.

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

• Cisplatin on day 1 at a dose of 50 mg/m² and Topotecan at a dose of 0.75 mg/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.
• Carboplatin on day 1: AUC5 (Calvert formula); Topotecan at a dose of 0.5 mg/m² from day 1 to day 5.
• Carboplatin on day 5: AUC5 (⁵¹Cr-EDTA clearance); Topotecan at a dose of 1.0 mg/m² from day 1 to day 5.

Topotecan does not inhibit the cytochrome P450 system isoenzymes. Concomitant use with ondansetron, granisetron, morphine or corticosteroids does not significantly affect the pharmacokinetic parameters of topotecan.

Storage Conditions

In a place protected from light at a temperature not exceeding 25°C (77°F). Keep out of reach of children!

Shelf Life

Shelf life – 36 months.

Dispensing Status

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.