Topotecan-Teva, lyophilizate 4 mg

Pharmacotherapeutic group: antitumor drug – alkaloid

ATX code: L01XX17

Pharmacological properties

Pharmacodynamics

Antitumor drug, topoisomerase I inhibitor. Topoisomerase I is an enzyme directly involved in the replication of deoxyribonucleic acid (DNA). Topotecan stabilizes the covalent complex of the enzyme and helical cleaved DNA, which is an intermediate in the catalytic mechanism.

Inhibition of topoisomerase I leads to the breakage of single-helix DNA and stops DNA replication.

Pharmacokinetics

.Distribution

In intravenous (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 in proportion to increasing dose.

The binding of topotecan to plasma proteins is low – 35%. Distribution between blood cells and plasma is homogeneous. Topotecan has a high volume of distribution (V_d) – about 132 l.

When comparing pharmacokinetic parameters, no changes in pharmacokinetics were found during a 5-day course of therapy.

The plasma clearance and V_d values were slightly higher in men than in women. However, these differences were consistent with differences in body surface area.

Metabolism

The main route of metabolism of topotecan is pH-dependent hydrolysis of the lactone ring, in which an open ring carboxylate is formed.

Metabolism is less than 10% of the excreted topotecan. The N-demethylated metabolite of topotecan, which has similar or less activity than topotecan, is detected in the urine, blood plasma and feces. After IV administration, the average AUC of both topotecan and topotecan metabolite was less than 10% for both total topotecan and topotecan in lactone form. In the urine, O-glucuronide of topotecan and N-demethylated topotecan are detected.

In vitro. Topotecan did not inhibit the CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, CYP4A cytochrome P450 system isoenzymes or the cytosolic enzymes dihydropyrimidinoxidase or xanthine oxidase.

Elimation

After intravenous administration the curve of reduction of plasma concentrations of Topotecan has a biexponential character. The pharmacokinetics of topotecan during IV administration is approximately proportional to the administered dose.

When topotecan is administered by injection into adults at doses of 0.5-1.5 mg/m² as a 30-minute daily infusion for 5 days, the plasma clearance of topotecan is high at 62 L/h, which is approximately 2/3 of the hepatic blood flow. The half-life (T_1/2) is relatively short and is 2-3 h.

After a 5-day course of topotecan, the total excretion of topotecan and its metabolites was 71% to 76% of the IV dose administered. Approximately 51% was excreted through the kidneys as topotecan, 3% – as N-demethylated metabolite of topotecan, 18% of topotecan and 1.7% of the N-demethylated metabolite of topotecan were excreted through the intestines. Overall, as a metabolite (N-demethylated metabolite of topotecan) less than 7% of topotecan is excreted through the kidneys and intestines (range 4% to 9%). Urinary concentrations of O-glucuronide topotecan and N-demethylated O-glucuronide topotecan are less than 2% of the administered dose.

When topotecan is administered in combination with cisplatin (cisplatin on day 1, topotecan on days 1-5), topotecan clearance decreases on day 5 compared with day 1 (19.1 L/h/m² versus 21.3 L/h/m², respectively).

In population-based studies, coadministration of granisetron, ondansetron, morphine, or glucocorticosteroids had no significant effect on the pharmacokinetics of topotecan.

Topotecan accumulates in the body in minimal or no amounts with repeated daily intravenous administration, and there are no data on changes in pharmacokinetics with repeated administration.

Pharmacokinetics in Special Clinical Cases

In a population-based study of IV administration of topotecan, a variety of factors, including age, body weight and presence of ascites, had no significant effect on clearance.

Children

The pharmacokinetics of topotecan as a 30-minute infusion over 5 days were evaluated in two studies. One study included a dose range of 1.4 mg/m² to 2.4 mg/m² involving children aged 2 to 12 years (n=18), adolescents 12 to 16 years (n=9) and young adults 16 to 21 years (n=9) with solid tumors difficult to treat. The second study included a dose range of 2.0 mg/m² to 5.2 mg/m² involving children (n=8), adolescents (n=3) and young adults (n=3) with leukemia.

In both studies, there was no apparent difference in the pharmacokinetic parameters of topotecan among different age groups and also according to disease (solid tumor or leukemia). These data are limited enough to present definite conclusions.

Kidney function impairment

In patients with impaired renal function (creatinine clearance (CK) 41-60 mL/min), the plasma clearance of IV injected topotecan was reduced to approximately 67% of that of the control group. V_d decreased slightly and thus T_1/2 increased by only 14%. In patients with moderate renal impairment (CKR 20-39 mL/min), the plasma clearance of topotecan is reduced to 34% of the control value. V_d is reduced by approximately 25%, resulting in an increase in mean T_1/2 from 1.9 h to 4.9 h.

Disorders of liver function

. In patients with impaired liver function (serum bilirubin 1.5 mg/dL to 10 mg/dL), plasma clearance of lactone-formed topotecan after IV administration is reduced to approximately 67% of that of the control group and total plasma clearance is reduced by 10% compared with the control group. T_1/2 of topotecan is increased by approximately 30%, with no significant change in V_d.

Indications

– small cell lung cancer;

– ovarian cancer;

– recurrent or persistent cervical cancer not amenable to surgical treatment and/or radiation therapy (stage IVB), as part of combination therapy with cisplatin.

Active ingredient

Composition

How to take, the dosage

The drug Topotecan-Teva lyophilisate for preparation of a solution for infusion must first be reconstituted and then prepared before use (see Rules for preparation of solution).

Topotecan is administered as a 30-minute IV infusion.

Before the first course of therapy with topotecan, patients’ baseline neutrophil counts should be >1.5*109/l, platelets >100*109/l and a hemoglobin concentration of >9 g/dL (after transfusion, if necessary).

Adult patients and elderly patients

In small cell lung cancer and ovarian cancer prescribes 1.5 mg/m2 body surface daily for 5 consecutive days, 3 weeks apart.

To achieve the effect it is recommended to carry out at least 4 courses of therapy (average time of effect for patients with ovarian cancer is 7.6-11.7 weeks, for patients with small-cell lung cancer – 6.1 weeks. In about 18% of patients with ovarian cancer the effect was achieved after 5 or more courses of therapy).

Recurrent courses of therapy with topotecan can be given only if the patient has the following blood counts: neutrophil count >1*109/l, platelet count >100*109/l and hemoglobin >9 g/dl concentration (incl.

In accordance with standards accepted in oncology practice, the management of patients with neutropenia involves either the use of topotecan with other drugs (e.g. granulocyte colony stimulating factor (G-CSF) or a lower dose of topotecan to maintain acceptable neutrophil levels.

If a decision is made to reduce the dose of topotecan in patients with 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 dose should be reduced by 0.25 mg/msup>2 daily to 1.25 mg/m2/day (thereafter, to 1.0 mg/m2/day if necessary).

If platelet counts decrease in the previous course of chemotherapy <25 *109/l, doses should be reduced in a similar manner.

If a dose reduction below 1.0 mg/m2 is required due to side effects, therapy with topotecan should be discontinued.

In cervical cancer, the recommended daily dose of topotecan is 0.75 mg/m2 on days 1, 2, and 3 of the course. On day 1 of therapy, cisplatin infusion is given at a dose of 50 mg/m2 after administration of topotecan. This regimen is repeated every 21 days for a total of 6 courses. If there are signs of disease progression, topotecan should be stopped.

Recurrent courses of therapy with topotecan can be given only if the patient’s blood counts are as follows: neutrophil count >1.5*109/l, platelet count >100*109/l and a hemoglobin concentration of >9 g/dL (including after blood transfusions.

In accordance with standards accepted in oncology practice, the management of patients with neutropenia involves either the use of topotecan with other drugs (e.g. granulocyte colony stimulating factor (G-CSF) or a lower dose of topotecan to maintain acceptable neutrophil levels.

If a decision is made to reduce the dose of topotecan in patients with severe neutropenia (neutrophil count <0.5*109/l) for 7 days or more, or febrile neutropenia, or if treatment is delayed because of neutropenia, the dose should be reduced by 20% to 0.6 mg/m2 daily (thereafter, to 0.45 mg/m2 daily).

If platelet count <25*109/l decreases, the dose should be reduced in the same manner.

Special patient groups

Children

The use of Topotecan-Teva is not recommended because there is not enough experience with its use in children.

Elderly patients

There is no difference in the effectiveness of the drug in patients over 65 years of age and in younger patients.

Patients with impaired renal function

In monotherapy for patients with CK > 40 ml/min, no dosing adjustments are required. The recommended dose for patients with a CK of 20 to 39 ml/min is 0.75 mg/m2/day for 5 consecutive days of the cycle. There are no recommendations for dosing regimen in patients with decreased CK< 20 mL/min.

The dosing regimen recommendations in patients with a CK of 20 to 39 mL/min are based on studies that included patients with advanced tumorigenesis.

In combination therapy with topotecan with cisplatin for treatment of cervical cancer, initiation of therapy is recommended only in patients whose plasma creatinine concentration does not exceed 1.5 mg/dL. If during treatment, plasma creatinine concentrations exceed 1.5 mg/dL, recommendations for cisplatin dose reduction/cancellation should be followed. If cisplatin is withdrawn, there are insufficient data regarding continuation of topotecan monotherapy in patients with cervical cancer.

Patients with impaired liver function

Monotherapy

. No dose adjustment is required for patients with impaired liver function (serum bilirubin concentrations of 1.5 to 10 mg/dL).

Patients with impaired hepatic function could tolerate a dose of 1.5 mg/m2 for five days every three weeks, although a slight decrease in topotecan clearance was observed.

Combination therapy

When prescribing topotecan with other cytotoxic drugs, dose adjustments may be necessary.

Rules for preparing solution

The contents of the 1 mg vial of Topotecan-Teva should be dissolved in 1.1 ml of sterile water for injection. The resulting reconstituted solution has a concentration of 1 mg/ml, since the vial is filled with a 10% excess in order to ensure reliable quantitative extraction of the active ingredient.

The contents of the 4 mg vial of Topotecan-Teva should be dissolved in 4 ml of sterile water for injection to a concentration of 1 mg/ml (reconstituted solution).

The reconstituted solution obtained after dilution with sterile water for injection should be diluted with 0.9% sodium chloride solution (solution for infusion) or 5% dextrose solution (solution for infusion) to a concentration of 25-50 µg/ml (prepared solution).

If the solutions are prepared under aseptic conditions, they can be stored in refrigerator at 2-8°C for 24 hours, but the terms and conditions of storage in this case are the responsibility of the user.

Interaction

As with other myelosuppressive cytotoxic drugs, myelosuppression is increased when topotecan is used in combination with other cytotoxic agents (e.g., paclitaxel or etoposide), requiring dose reduction.

However, when using topotecan in combination with platinum drugs (e.g., cisplatin or carboplatin), there is a clear dependence of drug-drug interactions on the sequence of administration, i.e., whether the platinum drug is administered on day 1 or day 5 of topotecan. If platinum drugs are administered on day 1 of administration of topotecan, then reduced doses of each drug should be used compared to doses when platinum drugs are administered on day 5.

In intravenous administration of topotecan 13 patients with ovarian cancer (0.75 mg/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 of therapy were slightly lower than on day 1. As a result, systemic exposure of total topotecan, as assessed by AUC and maximum Cmax concentration, was 12% (95% confidence interval (CI): 2% to 24%) and 23% (CI: 7% to 63%) higher on day 5 of therapy, respectively. There were no data on pharmacokinetic interactions after administration of topotecan (0.75 mg/m2/day on 3 consecutive days) and cisplatin (50 mg/m2/day on day 1) in patients with cervical cancer.

Topotecan does not inhibit cytochrome P450 isoenzymes. Co-administration with ondansetron, granisetron, morphine or glucocorticosteroids (infusions are given through different systems or a different route of administration) has no significant effect on the pharmacokinetic parameters of intravenously administered topotecan.

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

Special Instructions

Topotecan treatment should be supervised by a specialist experienced in the use of antitumor drugs.

Hematologic toxicity of topotecan depends on its dose, and regular gross blood counts with determination of hemoglobin concentration, hematocrit, counts of white blood cells, neutrophils and platelets should be performed.

If topotecan is combined with other cytotoxic drugs, the dose should be adjusted.

When pronounced neutropenia develops, close monitoring is necessary for timely diagnosis of infectious complications.

As with other cytotoxic drugs, topotecan can cause severe myelosuppression, leading in some cases to severe infectious complications, including sepsis and associated death.

Neutropenia induced by topotecan treatment can cause neutropenic colitis. Fatal cases of this complication have been reported in clinical trials of topotecan. In patients with fever, neutropenia combined with abdominal pain in the projection of the colon, the possibility of neutropenic colitis should be considered.

In cases of IBL (including fatal) have been reported during topotecan treatment.

Patients with a history of IBD, pulmonary fibrosis, lung cancer, as well as patients who have undergone chest irradiation, received pneumotoxic drugs and/or colony-stimulating factors are at high risk of developing this complication.

Patients should be monitored for symptoms of IBD (e.g., cough, fever, dyspnea and/or hypoxia) if newly identified IBD is confirmed, topotecan should be stopped.

Monotherapy with topotecan and use of topotecan in combination with cisplatin are often associated with the development of clinically significant thrombocytopenia. This should be considered when prescribing topotecan, for example if a patient has a risk for bleeding from the tumor.

In the event of significant thrombocytopenia, extreme caution should be exercised during invasive procedures and regular inspection of the skin and mucous membranes and secretions (for signs of bleeding).

Patients with poor overall systemic status are expected to have a poorer response to treatment and have an increased incidence of complications such as fever, infections, and sepsis. It is important to carefully assess a patient’s general somatic status during therapy to detect deterioration in time.

There is insufficient experience with topotecan in patients with severe renal impairment (CK less than 20 ml/min) or with severe liver function impairment (serum bilirubin > 10 mg/dL) due to cirrhosis. Topotecan is not recommended in this group of patients.

In a small number of patients with impaired liver function (serum bilirubin values between 1.5 and 10 mg/dL), topotecan was used intravenously at a dose of 1.5 mg/m2 for five days every 3 weeks. Decreased clearance of topotecan was observed in this group of patients. However, there are insufficient data to establish recommendations for dosing adjustments for this group of patients.

Women of reproductive age and men should use reliable contraceptive methods during therapy with topotecan.

In animal studies, no reproductive toxicity of topotecan was noted. However, like other cytotoxic drugs, topotoxican is genotoxic and its effect on fertility, including male fertility, cannot be ruled out.

When handling the drug, generally accepted rules for handling cytotoxic drugs must be followed. If you accidentally get the drug on your skin or in your eyes, flush them with copious amounts of water.

Influence on driving and operating ability

The patient’s general clinical condition and possible development of adverse events (especially increased fatigue and weakness) must be considered when assessing ability to drive and operate fast-acting machinery.

Synopsis

Contraindications

– pronounced suppression of bone marrow function (neutrophil count is less than 1.5*109

Side effects

Long-term use does not cause an increase in the toxic effects of the drug. No serious manifestations of cardiotoxicity, neurotoxicity and organ toxicity have been noted.

The undesirable reactions presented below are listed according to the affected organs and organ systems, as well as by frequency of occurrence.

The incidence of adverse events was classified as follows: Very common (≥1/10), common (≥1/100, < 1/10), infrequent (≥1/1000, < 1/100), rare (≥1/10,000, < 1/1000), very rare (< 1/10000, including individual cases), frequency unknown (cannot be estimated based on available data).

The frequency categories were formed mainly on the basis of clinical trials of topotecan.

Disorders of the blood and lymphatic system:

Very common: febrile neutropenia, neutropenia, thrombocytopenia, anemia1, leukopenia; common: pancytopenia; frequency unknown: bleeding, marked and occult bleeding due to thrombocytopenia.

Nervous system disorders:

Often: myalgia.

Disorders of the immune system:

Often: high sensitivity reactions, including rash.

Disorders of the respiratory system, thorax and mediastinum:

Rarely – interstitial lung disease (ILD),.

Disorders of the gastrointestinal tract:

Very common – nausea, vomiting and diarrhea2, constipation, abdominal pain3 , stomatitis, anorexia (including severe).

Often – hyperbilirubinemia.

Very rarely: inflammation of the intestine (colitis).

Prevalence unknown: intestinal obstruction.

Skin and subcutaneous tissue disorders:

Very common: alopecia.

Allergic reactions:

Very common: anaphylactoid reactions.

Rarely: urticaria, difficulty breathing.

Very rare: angioedema.

Prevalence unknown: skin rash (including erythematous, maculopapular, urticaria, dermatitis, bullous erythema).

General disorders and disorders at the site of administration:

Very common – increased body temperature, asthenia, increased fatigue, infections.

Often – weakness, sepsis.

Very rarely – extravasation: hematoma or hyperemia of the skin at the site of injection (in extravasation) (reactions associated with extravasation were mild and usually did not require specific treatment).

Prevalence unknown: dyspnea.

1 cases ranging from medium to severe anemia (3-th and 4-I degree – haemoglobin concentration less than 8.0 g/dL) occurred in 25% of cases (12% of courses). The median time to onset of moderate to severe anemia was day 12 with an average of seven days of therapy. In 46% of the treatment courses that were accompanied by the development of moderate and severe anemia, the duration of anemia was more than seven days. Transfusion of erythrocyte mass was given to 30% of patients (in 13% of courses). Erythropoietin was administered to 10% of patients (in 8% of courses of topotecan therapy).

2 – When topotecan was administered intravenously, diarrhea occurred in 10% of patients over 65 years of age; these reactions were noted, including severe reactions.

3 – cases of neutropenic colitis, including cases with a fatal outcome, were treated as complications of drug-induced neutropenia.

Lack of data on the causal relationship between the following adverse events and administration of hypotecan: arthralgia, increased hepatic transaminase activity, pain (whole body, skeletal bones, chest), headache, neuropathy, skin itching.

Overdose

Symptoms

There have been reported cases of overdose in patients during therapy with topotecan in the form of lyophilisate for preparation of solution for infusion (overdose up to 10-fold of the recommended dose). The observed signs and symptoms of overdose are consistent with the known adverse reactions associated with topotecan. The main complication from overdose is suppression of medullary hematopoiesis and mucositis. In addition, cases of increased liver enzyme activity have been reported after overdose.

Treatment

The antidote for topotecan overdose is unknown. Further treatment should be given as clinically indicated or as recommended by the national poison center, if available.

Pregnancy use

Pregnancy

Topotecan has been shown in preclinical studies to have toxic effects on the fetus and embryo. Like other cytotoxic drugs, Topotecan-Teva may have adverse effects on the fetus when used by pregnant women and is therefore contraindicated for use during pregnancy.

Trustworthy contraceptive methods should be used during therapy with the drug. If pregnancy occurs, inform the attending physician immediately.

Breast-feeding period

The use of the drug is contraindicated in breast-feeding.