Topotecano Generis

Topotecano Generis capsules are indicated as monotherapy for the treatment of adult patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate.

Topotecan monotherapy is indicated for the treatment of:

- patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy.

- patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate.

Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment-free interval to justify treatment with the combination.

Topotecano Generis capsules should only be prescribed and therapy supervised by a physician experienced in the use of chemotherapeutic agents.

Posology

Prior to administration of the first course of topotecan, patients must have a baseline neutrophil count of >1.5 x 10⁹/l, a platelet count of >100 x 10⁹/l and a haemoglobin level of >9 g/dl (after transfusion if necessary).

Initial dose

The recommended dose of Topotecano Generis capsules is 2.3 mg/m² body surface area per day administered for five consecutive days with a three-week interval between the start of each course. If well tolerated, treatment may continue until disease progression.

The capsule(s) must be swallowed whole, and must not be chewed crushed or divided.

Topotecano Generis capsules may be taken with or without food.

Subsequent doses

Topotecan should not be re-administered unless the neutrophil count is >1 x 10⁹/l, the platelet count is >100 x 10⁹/l, and the haemoglobin level is >9 g/dl (after transfusion if necessary).

Standard oncology practice for the management of neutropenia is either to administer topotecan with other medicinal products (e.g. G-CSF) or to reduce the dose to maintain neutrophil counts.

If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count <0.5 x 10⁹/l) for seven days or more or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose should be reduced by 0.4 mg/m²/day to 1.9 mg/m²/day (or subsequently down to 1.5 mg/m²/day if necessary).

Doses should be similarly reduced if the platelet count falls below 25 x 10⁹/l. In clinical studies, topotecan was discontinued if the dose needed to be reduced below 1.5 mg/m²/day.

For patients who experience Grade 3 or 4 diarrhoea, the dose should be reduced by 0.4 mg/m²/day for subsequent courses. Patients with Grade 2 diarrhoea may need to follow the same dose modification guidelines.

Proactive management of diarrhoea with anti-diarrhoeal agents is important. Severe cases of diarrhoea may require administration of oral or intravenous electrolytes and fluids, and interruption of topotecan therapy.

Special populations

Patients with renal impairment

The recommended monotherapy dose of oral topotecan in patients with small cell lung carcinoma with creatinine clearance between 30 and 49 ml/min is 1.9 mg/m²/day for five consecutive days. If well tolerated, the dose may be increased to 2.3 mg/m²/day in subsequent cycles.

Limited data in Korean patients with creatinine clearance less than 50 ml/min suggest a further lowering of dose may be required.

Insufficient data are available to make a recommendation for patients with a creatinine clearance <30 ml/min.

Patients with hepatic impairment

Pharmacokinetics of Topotecano Generis capsules have not been specifically studied in patients with impaired hepatic function. There are insufficient data available with Topotecano Generis capsules to make a dose recommendation for this patient group.

Paediatric population

Elderly

No overall differences in effectiveness were observed between patients aged over 65 years and younger adult patients. However in the two studies in which both oral and intravenous topotecan were administered, patients over 65 years old receiving oral topotecan experienced an increase in drug-related diarrhoea compared to those younger than 65 years of age.

The use of topotecan should be confined to units specialised in the administration of cytotoxic chemotherapy. Topotecan should only be administered under the supervision of a physician experienced in the use of chemotherapy.

Posology

When topotecan is used in combination with cisplatin, the full prescribing information for cisplatin should be consulted.

Prior to administration of the first course of topotecan, patients must have a baseline neutrophil count of >1.5 x 10⁹/l, a platelet count of > 100 x 10⁹/l and a haemoglobin level of > 9 g/dl (after transfusion if necessary).

Ovarian and small cell lung carcinoma

Initial dose

The recommended dose of topotecan is 1.5 mg/m² body surface area per day administered by intravenous infusion over 30 minutes daily for five consecutive days with a three-week interval between the start of each course. If well tolerated, treatment may continue until disease progression.

Subsequent doses

Topotecan should not be re-administered unless the neutrophil count is > 1 x 10⁹/l, the platelet count is > 100 x 10⁹/l, and the haemoglobin level is > 9 g/dl (after transfusion if necessary).

Standard oncology practice for the management of neutropenia is either to administer topotecan with other medicinal products (e.g. G-CSF) or to reduce the dose to maintain neutrophil counts.

If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count < 0.5 x 10⁹/l) for seven days or more or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose should be reduced by 0.25 mg/m²/day to 1.25 mg/m²/day (or subsequently down to 1.0 mg/m²/day if necessary).

Doses should be similarly reduced if the platelet count falls below 25 x 10⁹/l. In clinical studies, topotecan was discontinued if the dose had been reduced to 1.0 mg/m²/day and a further dose reduction was required to manage adverse effects.

Cervical carcinoma

Initial dose

The recommended dose of topotecan is 0.75 mg/m²/day administered as a 30-minute intravenous infusion on days 1, 2 and 3. Cisplatin is administered as an intravenous infusion on day 1 at a dose of 50 mg/m²/day and following the topotecan dose. This treatment schedule is repeated every 21 days for six courses or until progressive disease.

Subsequent doses

Topotecan should not be re-administered unless the neutrophil count is > 1.5 x 10⁹/l, the platelet count is > 100 x 10⁹/l, and the haemoglobin level is > 9 g/dl (after transfusion if necessary).

Standard oncology practice for the management of neutropenia is either to administer topotecan with other medicinal products (e.g. G-CSF) or to reduce the dose to maintain neutrophil counts.

If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count < 0.5 x 10⁹/l) for seven days or more or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose should be reduced by 20% to 0.60 mg/m²/day for subsequent courses (or subsequently down to 0.45 mg/m²/day if necessary).

Doses should be similarly reduced if the platelet count falls below 25 x 10⁹/l.

Special populations

Patients with renal impairment

Monotherapy (ovarian and small cell lung carcinoma):

There is insufficient experience with the use of topotecan in patients with severely impaired renal function (creatinine clearance <20 ml/min). Use of topotecan in this group of patients is not recommended.

Limited data indicate that the dose should be reduced in patients with moderate renal impairment. The recommended monotherapy dose of topotecan in patients with ovarian or small cell lung carcinoma and a creatinine clearance between 20 and 39 ml/min is 0.75 mg/m²/day for five consecutive days.

Combination therapy (cervical carcinoma):

In clinical studies with topotecan in combination with cisplatin for the treatment of cervical cancer, therapy was only initiated in patients with serum creatinine less than or equal to 1.5mg/dl. If, during topotecan/cisplatin combination therapy, serum creatinine exceeds 1.5mg/dl, it is recommended that the full prescribing information be consulted for any advice on cisplatin dose reduction/continuation. If cisplatin is discontinued, there are insufficient data regarding continuing monotherapy with topotecan in patients with cervical cancer.

Patients with hepatic impairment

A small number of hepatically impaired patients (serum bilirubin between 1.5 and 10 mg/dl) were given intravenous topotecan at 1.5 mg/m²/day for five days every three weeks. A reduction in topotecan clearance was observed. However, there are insufficient data available to make a dose recommendation for this patient group.

There is insufficient experience with the use of topotecan in patients with severely impaired hepatic function (serum bilirubin > 10 mg/dl) due to cirrhosis. Topotecan is not recommended to be used in this patient group.

Paediatric population

2 but no recommendation on a posology can be made.

Method of administration

Topotecan must be reconstituted and further diluted before use.

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

- Breast-feeding.

- Severe bone marrow depression prior to starting first course, as evidenced by baseline neutrophils <1.5 x 10⁹/l and/or a platelet count of <100 x 10⁹/l.

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

− Breast-feeding.

− Severe bone marrow depression prior to starting first course, as evidenced by baseline neutrophils <1.5 x 10⁹/l and/or a platelet count of < 100 x 10⁹/l.

Haematological toxicity is dose-related and full blood count including platelets should be determined regularly.

As with other cytotoxic medicinal products, topotecan can cause severe myelosuppression. Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients treated with topotecan.

Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical studies with topotecan. In patients presenting with fever, neutropenia and a compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered.

Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been fatal. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation and use of pneumotoxic substances and/or colony stimulating factors. Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, dyspnoea and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed.

Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated with clinically relevant thrombocytopenia. This should be taken into account when prescribing Topotecano Generis, e.g. if patients at increased risk of tumour bleeds are considered for therapy.

As would be expected, patients with poor performance status (PS >1) have a lower response rate and an increased incidence of complications such as fever, infection and sepsis. Accurate assessment of performance status at the time therapy is given is important, to ensure that patients have not deteriorated to PS 3.

Topotecan is partly eliminated via renal excretion and renal impairment might lead to increased exposure to topotecan. Dosing recommendations for patients receiving oral topotecan with creatinine clearance less than 30 ml/min have not been established. Use of topotecan in these patients is not recommended.

A small number of hepatically impaired patients (serum bilirubin between 1.5 and 10 mg/dl) were given intravenous topotecan at 1.5 mg/m²/day for five days every three weeks. A reduction in topotecan clearance was observed. However, there are insufficient data available to make a dose recommendation for this patient group. There is insufficient experience of the use of topotecan in patients with severely impaired hepatic function (serum bilirubin >10 mg/dl). Use of topotecan in these patients is not recommended.

Diarrhoea, including severe diarrhoea requiring hospitalisation, has been reported during treatment with oral topotecan. Diarrhoea related to oral topotecan can occur at the same time as drug-related neutropenia and its sequelae. Communication with patients prior to drug administration regarding these side effects and proactive management of early and all signs and symptoms of diarrhoea is important. Cancer treatment-induced diarrhoea (CTID) is associated with significant morbidity and may be life-threatening. Should diarrhoea occur during treatment with oral topotecan, physicians are advised to aggressively manage diarrhoea. Clinical guidelines describing the aggressive management of CTID include specific recommendations on patient communication and awareness, recognition of early warning signs, use of anti-diarrhoeals and antibiotics, changes in fluid intake and diet, and need for hospitalisation.

Intravenous topotecan should be considered in the following clinical situations: uncontrolled emesis, swallowing disorders, uncontrolled diarrhoea, clinical conditions and medication that may alter gastrointestinal motility and drug absorption.

Haematological toxicity is dose-related and full blood count including platelets should be determined regularly .

As with other cytotoxic medicinal products, topotecan can cause severe myelosuppression. Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients treated with topotecan.

Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical studies with topotecan. In patients presenting with fever, neutropenia and a compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered.

Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been fatal. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation and use of pneumotoxic substances and/or colony stimulating factors. Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, dyspnoea and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed.

Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated with clinically relevant thrombocytopenia. This should be taken into account when prescribing Topotecano Generis, e.g. if patients at increased risk of tumour bleeds are considered for therapy.

As would be expected, patients with poor performance status (PS>1) have a lower response rate and an increased incidence of complications such as fever, infection and sepsis. Accurate assessment of performance status at the time therapy is given is important, to ensure that patients have not deteriorated to PS 3.

There is insufficient experience of the use of topotecan in patients with severely impaired renal function (creatinine clearance < 20 ml/min) or severely impaired hepatic function (serum bilirubin > 10 mg/dl) due to cirrhosis. Use of topotecan in these patient groups is not recommended.

A small number of hepatically impaired patients (serum bilirubin between 1.5 and 10 mg/dl) were given intravenous topotecan at 1.5 mg/m²/day for five days every three weeks. A reduction in topotecan clearance was observed. However, there are insufficient data available to make a dose recommendation for this patient group.

In clinical studies involving patients with relapsed small cell lung cancer, the dose-limiting toxicity of oral topotecan monotherapy was found to be haematological. Toxicity was predictable and reversible. There were no signs of cumulative haematological or non-haematological toxicity.

The frequencies associated with the haematological and non-haematological adverse events presented are for adverse events considered to be related/possibly related to oral topotecan therapy.

Adverse reactions are listed below, by system organ class and absolute frequency (all reported events). Frequencies are defined as: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The adverse events listed above have the potential to occur with a higher frequency in patients who have a poor performance status.

Safety data are presented based on an integrated data set of 682 patients with relapsed lung cancer administered 2,536 courses of oral topotecan monotherapy (275 patients with relapsed SCLC and 407 with relapsed non-SCLC).

Haematological

Neutropenia

Severe neutropenia (Grade 4 - neutrophil count <0.5 x 10⁹/l) occurred in 32% of patients in 13% of courses. Median time to onset of severe neutropenia was day 12 with a median duration of 7 days. In 34% of courses with severe neutropenia, the duration was >7 days. In course 1 the incidence was 20%, by course 4 the incidence was 8%. Infection, sepsis and febrile neutropenia occurred in 17%, 2%, and 4% of patients, respectively. Death due to sepsis occurred in 1% of patients. Pancytopenia has been reported. Growth factors were administered to 19% of patients in 8% of courses.

Thrombocytopenia

Severe thrombocytopenia (Grade 4 - platelets <10 x 10⁹/l) occurred in 6% of patients in 2% of courses. Median time to onset of severe thrombocytopenia was day 15 with a median duration of 2.5 days. In 18% of courses with severe thrombocytopenia the duration was >7 days. Moderate thrombocytopenia (Grade 3 - platelets between 10.0 and 50.0 x 10⁹/l) occurred in 29% of patients in 14% of courses. Platelet transfusions were given to 10% of patients in 4% of courses. Reports of significant sequelae associated with thrombocytopenia including fatalities due to tumour bleeds have been infrequent.

Anaemia

Moderate to severe anaemia (Grade 3 and 4 - Hb ≤8.0 g/dl) occurred in 25% of patients (12% of courses). Median time to onset of moderate to severe anaemia was day 12 with a median duration of 7 days. In 46% of courses with moderate to severe anaemia, the duration was >7 days. Red blood cell transfusions were given in 30% of patients (13% of courses). Erythropoietin was administered to 10% of patients in 8% of courses.

Non-haematological

The most frequently reported non-haematological effects were nausea (37%), diarrhoea (29%), fatigue (26%), vomiting (24%), alopecia (21%) and anorexia (18%). All cases were irrespective of associated causality. For severe cases (CTC Grade 3/4) reported as related/possibly related to topotecan administration the incidence was diarrhoea 5% , fatigue 4%, vomiting 3%, nausea 3% and anorexia 2%.

The overall incidence of drug-related diarrhoea was 22%, including 4% with Grade 3 and 0.4% with Grade 4. Drug-related diarrhoea was more frequent in patients >65 years of age (28%) compared to those less than 65 years of age (19%).

Complete alopecia related/possibly related to topotecan administration was observed in 9% of patients and partial alopecia related/possibly related to topotecan administration in 11% of patients.

Therapeutic interventions associated with non-haematological effects included anti-emetic agents, given to 47% of patients in 38% of courses and anti-diarrhoeal agents, given to 15% of patients in 6% of courses. A 5-HT3 antagonist was administered to 30% of patients in 24% of courses. Loperamide was administered to 13% of patients in 5% of courses. The median time to onset of Grade 2 or worse diarrhoea was 9 days.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

In dose-finding studies involving 523 patients with relapsed ovarian cancer and 631 patients with relapsed small cell lung cancer, the dose-limiting toxicity of topotecan monotherapy was found to be haematological. Toxicity was predictable and reversible. There were no signs of cumulative haematological or non-haematological toxicity.

The safety profile of topotecan when given in combination with cisplatin in the cervical cancer clinical studies is consistent with that seen with topotecan monotherapy. The overall haematological toxicity is lower in patients treated with topotecan in combination with cisplatin compared to topotecan monotherapy, but higher than with cisplatin alone.

Additional adverse events were seen when topotecan was given in combination with cisplatin; however, these events were seen with cisplatin monotherapy and were not attributable to topotecan. The prescribing information for cisplatin should be consulted for a full list of adverse events associated with cisplatin use.

The integrated safety data for topotecan monotherapy are presented below.

Adverse reactions are listed below by system organ class and absolute frequency (all reported events). Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The adverse events listed above have the potential to occur with a higher frequency in patients who have a poor performance status.

The frequencies associated with the haematological and non-haematological adverse events listed below represent the adverse event reports considered to be related/possibly related to topotecan therapy.

Haematological

Neutropenia: Severe (neutrophil count <0.5 x 10⁹/l) during course 1 in 55% of patients, with duration >seven days in 20 % and overall in 77 % of patients (39 % of courses). In association with severe neutropenia, fever or infection occurred in 16 % of patients during course 1 and overall in 23 % of patients (6 % of courses). Median time to onset of severe neutropenia was nine days and the median duration was seven days. Severe neutropenia lasted beyond seven days in 11 % of courses overall. Among all patients treated in clinical studies (including both those with severe neutropenia and those who did not develop severe neutropenia), 11 % (4 % of courses) developed fever and 26 % (9 % of courses) developed infection. In addition, 5 % of all patients treated (1 % of courses) developed sepsis.

Thrombocytopenia: Severe (platelets <25 x 10⁹/l) in 25 % of patients (8 % of courses); moderate (platelets between 25.0 and 50.0 x 10⁹/l) in 25 % of patients (15 % of courses). Median time to onset of severe thrombocytopenia, was day 15 and the median duration was five days.

Platelet transfusions were given in 4 % of courses. Reports of significant sequelae associated with thrombocytopenia including fatalities due to tumour bleeds, have been infrequent.

Anaemia:

Moderate to severe (Hb ≤8.0 g/dl) in 37 % of patients (14 % of courses). Red cell transfusions were given in 52 % of patients (21 % of courses).

Non-haematological

Frequently reported non-haematological effects were gastrointestinal, such as nausea (52 %), vomiting (32 %), diarrhoea (18 %), constipation (9 %) and mucositis (14 %). The incidence of severe (Grade 3 or 4) nausea, vomiting, diarrhoea and mucositis was 4, 3, 2 and 1 % respectively.

Mild abdominal pain was reported in 4 % of patients.

Fatigue was observed in approximately 25 % and asthenia in 16 % of patients receiving topotecan. Severe (Grade 3 or 4) fatigue and asthenia both occurred with an incidence of 3 %.

Total or pronounced alopecia was observed in 30 % of patients and partial alopecia in 15 % of patients.

Other severe events that were recorded as related or possibly related to topotecan treatment were anorexia (12 %), malaise (3 %) and hyperbilirubinaemia (1 %).

Hypersensitivity reactions including rash, urticaria, angioedema and anaphylactic reactions have been reported rarely. In clinical studies, rash was reported in 4 % of patients and pruritus in 1.5 % of patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

IrelandHPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: [email protected]

Overdoses have been reported in patients being treated with topotecan capsules (up to 5 fold of the recommended dose) and intravenous topotecan (up to 10 fold of the recommended dose). The signs and symptoms observed following overdose were consistent with the known undesirable events associated with topotecan. The primary complications of overdose are bone marrow suppression and mucositis. In addition, elevated hepatic enzymes have been reported with intravenous topotecan overdose.

There is no known antidote for topotecan overdose. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

Overdoses have been reported in patients being treated with intravenous topotecan (up to 10 fold of the recommended dose) and topotecan capsules (up to 5 fold of the recommended dose). The signs and symptoms observed following overdose were consistent with the known undesirable events associated with topotecan. The primary complications of overdose are bone marrow suppression and mucositis. In addition, elevated hepatic enzymes have been reported with intravenous topotecan overdose.

There is no known antidote for topotecan overdose. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents: ATC code: L01XX17.

Mechanism of action

The anti-tumour activity of topotecan involves the inhibition of topoisomerase-I, an enzyme intimately involved in DNA replication as it relieves the torsional strain introduced ahead of the moving replication fork. Topotecan inhibits topoisomerase-I by stabilising the covalent complex of enzyme and strand-cleaved DNA which is an intermediate of the catalytic mechanism. The cellular sequela of inhibition of topoisomerase-I by topotecan is the induction of protein-associated DNA single-strand breaks.

Clinical efficacy and safety

Relapsed SCLC

A Phase III study (Study 478) compared oral topotecan plus best supportive care (BSC) (n = 71) with BSC alone (n = 70) in patients who had relapsed following first-line therapy (median time to progression [TTP] from first-line therapy: 84 days for oral topotecan plus BSC, 90 days for BSC alone) and for whom re-treatment with intravenous chemotherapy was not considered appropriate. In the oral topotecan plus BSC group there was a statistically significant improvement in overall survival compared with the BSC alone group (Log-rank p = 0.0104). The unadjusted hazard ratio for the oral topotecan plus BSC group relative to the BSC alone group was 0.64 (95% CI: 0.45, 0.90). Median survival in patients treated with oral topotecan plus BSC was 25.9 weeks (95% CI: 18.3, 31.6) compared to 13.9 weeks (95% CI: 11.1, 18.6) for patients receiving BSC alone (p = 0.0104).

Patient self-reports of symptoms using an unblinded assessment showed a consistent trend for symptom benefit for oral topotecan plus BSC.

One Phase II study (Study 065) and one Phase III study (Study 396) were conducted to evaluate the efficacy of oral topotecan versus intravenous topotecan in patients who had relapsed >90 days after completion of one prior regimen of chemotherapy (see Table 1). Oral and intravenous topotecan were associated with similar symptom palliation in patients with relapsed sensitive SCLC in patient self-reports on an unblinded symptom scale assessment in each of these two studies.

Table 1 Summary of survival, response rate, and time to progression in SCLC patients treated with oral or intravenous topotecan

N = total number of patients treated

CI = confidence interval

Paediatric population

The safety and effectiveness of oral topotecan in paediatric patients have not been established.

Pharmacotherapeutic group: antineoplastic agents: other antineoplastic agents, ATC code: L01XX17.

Mechanism of action

The anti-tumour activity of topotecan involves the inhibition of topoisomerase-I, an enzyme intimately involved in DNA replication as it relieves the torsional strain introduced ahead of the moving replication fork. Topotecan inhibits topoisomerase-I by stabilising the covalent complex of enzyme and strand-cleaved DNA which is an intermediate of the catalytic mechanism. The cellular sequela of inhibition of topoisomerase-I by topotecan is the induction of protein-associated DNA single-strand breaks.

Clinical efficacy and safety

Relapsed ovarian cancer

In a comparative study of topotecan and paclitaxel in patients previously treated for ovarian carcinoma with platinum-based chemotherapy (n = 112 and 114, respectively), the response rate (95 % CI) was 20.5 % (13 %, 28 %) versus 14 % (8 %, 20 %) and median time to progression 19 weeks versus 15 weeks (hazard ratio 0.7 [0.6, 1.0]), for topotecan and paclitaxel, respectively. Median overall survival was 62 weeks for topotecan versus 53 weeks for paclitaxel (hazard ratio 0.9 [0.6, 1.3]).

The response rate in the whole ovarian carcinoma programme (n = 392, all previously treated with cisplatin or cisplatin and paclitaxel) was 16 %. The median time to response in clinical studies was 7.6-11.6 weeks. In patients refractory to or relapsing within 3 months after cisplatin therapy (n = 186), the response rate was 10 %.

These data should be evaluated in the context of the overall safety profile of the medicinal product, in particular of the significant haematological toxicity.

A supplementary retrospective analysis was conducted on data from 523 patients with relapsed ovarian cancer. Overall, 87 complete and partial responses were observed, with 13 of these occurring during cycles 5 and 6 and 3 occurring thereafter. Of the patients who received more than 6 cycles of therapy, 91 % completed the study as planned or were treated until disease progression, with only 3 % withdrawn for adverse events.

Relapsed SCLC

A phase III study (Study 478) compared oral topotecan plus best supportive care (BSC) (n=71) with BSC alone (n=70) in patients who had relapsed following first-line therapy (median time to progression [TTP] from first-line therapy: 84 days for oral topotecan plus BSC, 90 days for BSC alone) and for whom re-treatment with intravenous chemotherapy was not considered appropriate. In the oral topotecan plus BSC group there was a statistically significant improvement in overall survival compared with the BSC alone group (Log-rank p=0.0104). The unadjusted hazard ratio for the oral topotecan plus BSC group relative to the BSC alone group was 0.64 (95% CI: 0.45, 0.90). Median survival in patients treated with oral topotecan plus BSC was 25.9 weeks (95 % C.I. 18.3, 31.6) compared to 13.9 weeks (95 % CI: 11.1, 18.6) for patients receiving BSC alone (p=0.0104).

Patient self-reports of symptoms using an unblinded assessment showed a consistent trend for symptom benefit for oral topotecan plus BSC.

One Phase II study (Study 065) and one Phase III study (Study 396) were conducted to evaluate the efficacy of oral topotecan versus intravenous topotecan in patients who had relapsed >90 days after completion of one prior regimen of chemotherapy (see Table 1). Oral and intravenous topotecan were associated with similar symptom palliation in patients with relapsed sensitive SCLC in patient self-reports on an unblinded symptom scale assessment in each of these two studies.

Table 1. Summary of survival, response rate, and time to progression in SCLC patients treated with oral topotecan or intravenous topotecan

N = total number of patients treated.

CI = Confidence interval.

In another randomised Phase III trial which compared intravenous (IV) topotecan to cyclophosphamide, doxorubicin and vincristine (CAV) in patients with relapsed, sensitive SCLC, the overall response rate was 24.3% for topotecan compared to 18.3% for the CAV group. Median time to progression was similar in the two groups (13.3 weeks and 12.3 weeks, respectively).

Median survivals for the two groups were 25.0 and 24.7 weeks, respectively. The hazard ratio for survival with IV topotecan relative to CAV was 1.04 (95% CI: 0.78 - 1.40).

The response rate to topotecan in the combined small cell lung cancer programme (n = 480) for patients with relapsed disease sensitive to first-line therapy was 20.2 %. Median survival was 30.3 weeks (95 % CI: 27.6, 33.4).

In a population of patients with refractory SCLC (those not responding to first-line therapy), the response rate to topotecan was 4.0%.

Cervical carcinoma

In a randomised, comparative Phase III study conducted by the Gynaecologic Oncology Group (GOG 0179), topotecan plus cisplatin (n=147) was compared with cisplatin alone (n=146) for the treatment of histologically confirmed persistent, recurrent or Stage IVB carcinoma of the cervix where curative treatment with surgery and/or radiation was not considered appropriate. Topotecan plus cisplatin had a statistically significant benefit in overall survival relative to cisplatin monotherapy after adjusting for interim analyses (Log-rank p =0.033).

Table 2. Study results Study GOG-0179

In patients (n=39) with recurrence within 180 days after chemoradiotherapy with cisplatin, the median survival in the topotecan plus cisplatin arm was 4.6 months (95% CI:: 2.6, 6.1) versus 4.5 months (95% C.I.: 2.9, 9.6) for the cisplatin arm, with an hazard ratio of 1.15 (0.59, 2.23). In those patients (n=102) with recurrence after 180 days, the median survival in the topotecan plus cisplatin arm was 9.9 months (95% CI:: 7, 12.6) versus 6.3 months (95%CI:: 4.9, 9.5) for the cisplatin arm, with a hazard ratio of 0.75 (0.49, 1.16).

Paediatric population

Topotecan was also evaluated in the paediatric population; however, only limited data on efficacy and safety are available.

In an open-label study involving children (n = 108, age range: infant to 16 years) with recurrent or progressive solid tumours, topotecan was administered at a starting dose of 2.0 mg/m² given as a 30-minute infusion for 5 days repeated every 3 weeks for up to one year depending on response to therapy. Tumour types included were Ewing's sarcoma/primitive neuroectodermal tumour, neuroblastoma, osteoblastoma and rhabdomyosarcoma. Anti-tumour activity was demonstrated primarily in patients with neuroblastoma. Toxicities of topotecan in paediatric patients with recurrent and refractory solid tumours were similar to those historically seen in adult patients. In this study, forty-six (43%) patients received G-CSF over 192 (42.1%) courses; sixty-five (60%) received transfusions of packed red blood cells and fifty (46%) of platelets over 139 and 159 courses (30.5% and 34.9%) respectively. Based on the dose-limiting toxicity of myelosuppression, the maximum tolerated dose (MTD) was established at 2.0 mg/m²day with G-CSF and 1.4 mg/m²/day without G-CSF in a pharmacokinetic study in paediatric patients with refractory solid tumours.

Distribution

The pharmacokinetics of topotecan after oral administration have been evaluated in cancer patients following doses of 1.2 to 3.1 mg/m²/day and 4 mg/m²/day administered daily for 5 days. The bioavailability of oral topotecan (total and lactone) in humans is approximately 40%. Plasma concentrations of total topotecan (i.e. lactone and carboxylate forms) and topotecan lactone (active moiety) peak at approximately 2.0 hours and 1.5 hours, respectively, and decline bi-exponentially with mean terminal half-life of approximately 3.0 to 6.0 hours. Total exposure (AUC) increases approximately proportionally with dose. There is little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change in pharmacokinetics after multiple doses. Preclinical studies indicate plasma protein binding of topotecan is low (35%) and distribution between blood cells and plasma was fairly homogeneous.

Biotransformation

A major route of clearance of topotecan is by hydrolysis of the lactone ring to form the ring-opened carboxylate. Other than hydrolysis, topotecan is cleared predominantly renally, with a minor component metabolised to the N-desmethyl metabolite (SB-209780) identified in plasma, urine and faeces.

Elimination

Overall recovery of topotecan-related material following five daily doses of topotecan was 49 to 72% (mean 57%) of the administered oral dose. Approximately 20% was excreted as total topotecan and 2% was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted for 33% while faecal elimination of N-desmethyl topotecan was 1.5%. Overall, the N-desmethyl metabolite contributed a mean of less than 6% (range 4-8%) of the total topotecan-related material accounted for in the urine and faeces. O-glucuronides of both topotecan and N-desmethyl topotecan have been identified in the urine. The mean metabolite: parent plasma AUC ratio was less than 10% for both total topotecan and topotecan lactone.

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

Following co-administration of the ABCB1 (P-gp) and ABCG2 (BCRP) inhibitor, elacridar (GF120918) at 100 to 1000 mg with oral topotecan, the AUC_0-∞ of topotecan lactone and total topotecan increased approximately 2.5-fold.

Administration of oral cyclosporine A (15 mg/kg), an inhibitor of transporters ABCB1 (P-gp) and ABCC1 (MRP-1) as well as the metabolising enzyme CYP3A4, within 4 hours of oral topotecan increased the dose normalised AUC0-24h of topotecan lactone and total topotecan approximately 2.0- and 2.5-fold, respectively.

The extent of exposure was similar following a high-fat meal and in the fasted state, while t_max was delayed from 1.5 to 3 hours (topotecan lactone) and from 3 to 4 hours (total topotecan).

Special populations

Hepatic impairment

The pharmacokinetics of oral topotecan have not been studied in patients with hepatic impairment.

Renal impairment

Results of a cross-study analysis suggest that the exposure to topotecan lactone, the active moiety following topotecan administration, increases with decreased renal function. Geometric mean topotecan lactone dose-normalised AUC_(0-∞) values were 9.4, 11.1 and 12.0 ng*h/ml in subjects with creatinine clearance values of more than 80 ml/min, 50 to 80 ml/min and 30 to 49 ml/min, respectively. In this analysis, creatinine clearance was calculated using the Cockcroft-Gault method. Similar results were obtained if glomerular filtration rate (ml/min) was estimated using the MDRD formula corrected for body weight. Patients with creatinine clearance >60 ml/min have been included in efficacy/safety studies of topotecan. Therefore, use of the normal starting dose in patients with a mild decrease in renal function is considered established.

Korean patients with renal impairment had generally higher exposure than non-Asian patients with the same degree of renal impairment. The clinical significance of this finding is unclear. Geometric mean topotecan lactone dose-normalised AUC_(0-∞) values for Korean patients were 7.9, 12.9 and 19.7 ng*h/ml in subjects with creatinine clearance values of more than 80 ml/min, 50 to 80 ml/min and 30 to 49 ml/min, respectively. There are no data from Asian patients with renal impairment other than Koreans.

Gender

A cross-study analysis in 217 patients with advanced solid tumours indicated that gender did not affect the pharmacokinetics of Topotecano Generis capsules to a clinically relevant extent.

Distribution

Following intravenous administration of topotecan at doses of 0.5 to 1.5 mg/m² as a 30-minute infusion daily for five days, topotecan demonstrated a high plasma clearance of 62 l/h (SD 22), corresponding to approximately 2/3 of liver blood flow. Topotecan also had a high volume of distribution, about 132l (SD 57), and a relatively short half-life of 2-3 hours. Comparison of pharmacokinetic parameters did not suggest any change in pharmacokinetics over the 5 days of dosing. Area under the curve increased approximately in proportion to the increase in dose. There is little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change in the pharmacokinetics after multiple doses. Preclinical studies indicate plasma protein binding of topotecan is low (35%) and distribution between blood cells and plasma was fairly homogeneous.

Biotransformation

The elimination of topotecan has only been partly investigated in man. A major route of clearance of topotecan was by hydrolysis of the lactone ring to form the ring-opened carboxylate.

Metabolism accounts for <10% of the elimination of topotecan. An N-desmethyl metabolite, which was shown to have similar or less activity than the parent in a cell-based assay, was found in urine, plasma and faeces. The mean metabolite: parent AUC ratio was < 10 % for both total topotecan and topotecan lactone. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been identified in the urine.

Elimination

Overall recovery of topotecan-related material following five daily doses of topotecan was 71 to 76 % of the administered IV dose. Approximately 51% was excreted as total topotecan and 3 % was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted for 18 % while faecal elimination of N-desmethyl topotecan was 1.7 %. Overall, the N-desmethyl metabolite contributed a mean of < 7% (range 4-9 %) of the total topotecan-related material accounted for in the urine and faeces. The topotecan-O-glucuronide and N-desmethyl topotecan-O-glucuronide in the urine were < 2.0 %.

In vitro data using human liver microsomes indicate the formation of small amounts of N-demethylated topotecan. In vitro, topotecan did not inhibit human P450 enzymes CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A or CYP4A, nor did it inhibit the human cytosolic enzymes dihydropyrimidine or xanthine oxidase.

When given in combination with cisplatin (cisplatin day 1, topotecan days 1 to 5), the clearance of topotecan was reduced on day 5 compared to day 1 (19.1 l/h/m² compared to 21.3 l/h/m² [n=9]).

Special populations

Hepatic impairment

Plasma clearance in patients with hepatic impairment (serum bilirubin between 1.5 and 10 mg/dl) decreased to about 67 % when compared with a control group of patients. Topotecan half-life was increased by about 30 % but no clear change in volume of distribution was observed. Plasma clearance of total topotecan (active and inactive form) in patients with hepatic impairment only decreased by about 10 % compared with the control group of patients.

Renal impairment

Plasma clearance in patients with renal impairment (creatinine clearance 41-60 ml/min.) decreased to about 67 % compared with control patients. Volume of distribution was slightly decreased and thus half-life only increased by 14 %. In patients with moderate renal impairment topotecan plasma clearance was reduced to 34 % of the value in control patients. Mean half-life increased from 1.9 hours to 4.9 hours.

Age/weight

In a population study, a number of factors including age, weight and ascites had no significant effect on clearance of total topotecan (active and inactive form).

Paediatric population

The pharmacokinetics of topotecan given as a 30-minute infusion for 5 days were evaluated in two studies. One study included a dose range of 1.4 to 2.4 mg/m² in children (aged 2 up to 12 years, n = 18), adolescents (aged 12 up to 16 years, n = 9), and young adults (aged 16 to 21 years, n = 9) with refractory solid tumours. The second study included a dose range of 2.0 to 5.2 mg/m² in children (n = 8), adolescents (n = 3), and young adults (n = 3) with leukaemia. In these studies there were no apparent differences in the pharmacokinetics of topotecan among children, adolescents and young adult patients with solid tumours or leukaemia, but data are too limited to draw definite conclusions.

Resulting from its mechanism of action, topotecan is genotoxic to mammalian cells (mouse lymphoma cells and human lymphocytes) in vitro and mouse bone marrow cells in vivo. Topotecan was also shown to cause embryo-foetal lethality when given to rats and rabbits.

In reproductive toxicity studies with topotecan in rats there was no effect on male or female fertility; however, in females super-ovulation and slightly increased pre-implantation loss were observed.

The carcinogenic potential of topotecan has not been studied.

Resulting from its mechanism of action, topotecan is genotoxic to mammalian cells (mouse lymphoma cells and human lymphocytes) in vitro and mouse bone marrow cells in vivo. Topotecan was also shown to cause embryo-foetal lethality when given to rats and rabbits.

In reproductive toxicity studies with topotecan in rats there was no effect on male or female fertility; however, in females super-ovulation and slightly increased pre-implantation loss were observed.

The carcinogenic potential of topotecan has not been studied.

Topotecano Generis capsules should not be opened or crushed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Topotecano Generis is provided as a sterile concentrate containing 4 mg topotecan in 4 ml solution (1 mg/ml).

Parenteral products should be visually inspected for particulate matter and discolouration prior to administration. Topotecano Generis is a yellow/yellow green solution. If visible particles are observed, the product should not be administered.

Further dilution with either sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for injection is required, to obtain a final concentration of between 25 and 50 micrograms/ml prior to administration to the patient.

The normal procedures for proper handling and disposal of anticancer medicinal products should be adopted, namely:

− Personnel should be trained to prepare and administer the medicinal product.

− Pregnant staff should be excluded from working with this medicinal product.

− Personnel handling this medicinal product should wear protective clothing including mask, goggles and gloves.

− All items for administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags for high-temperature incineration. Liquid waste may be flushed with large amounts of water.

− Accidental contact with the skin or eyes should be treated immediately with copious amounts of water. If there is lasting irritation, a doctor should be consulted.

- Any unused product or waste material should be disposed of in accordance with local requirements.