4.1. Therapeutic indications

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 (see section 5.1).

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 (see section 5.1).

4.2. Posology and method of administration

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 (see section 6.6).

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 (see sections 4.8 and 5.1).

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 (see section 4.4).

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 1.5 mg/dl. If, during topotecan/cisplatin combination therapy, serum creatinine exceeds 1.5 mg/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 (see section 4.4).

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 (see section 4.4).

Paediatric population

Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration

Topotecan must be reconstituted and further diluted before use (see section 6.6).

4.3. Contraindications

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

− Breast-feeding (see section 4.6).

− 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.

4.4. Special warnings and precautions for use

Haematological toxicity is dose-related and full blood count including platelets should be determined regularly (see section 4.2).

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 (see section 4.8).

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 (see section 4.8). 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 Topotecan Hospira, 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 (see section 4.8). 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 (see section 4.2).

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 (see section 4.2).

Excipient information

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'. However, if a solution of common salt (0.9% w/v sodium chloride solution) is used for the dilution of Topotecan Hospira prior to administration then the dose of sodium received would be higher.

4.5. Interaction with other medicinal products and other forms of interaction

No in vivo human pharmacokinetic interaction studies have been performed.

Topotecan does not inhibit human P450 enzymes (see section 5.2). In a population study using the intravenous route, the co-administration of granisetron, ondansetron, morphine or corticosteroids did not appear to have a significant effect on the pharmacokinetics of total topotecan (active and inactive form).

When combining topotecan with other chemotherapy agents, reduction of the doses of each medicinal product may be required to improve tolerability. However, when combining with platinum agents, there is a distinct sequence-dependent interaction depending on whether the platinum agent is given on day 1 or 5 of the topotecan dosing. If either cisplatin or carboplatin is given on day 1 of the topotecan dosing, a lower dose of each agent must be given to improve tolerability compared to the dose of each agent which can be given if the platinum agent is given on day 5 of the topotecan dosing.

When topotecan (0.75 mg/m2/day for 5 consecutive days) and cisplatin (60 mg/m2/day on day 1) were administered in 13 patients with ovarian cancer, a slight increase in AUC (12%, n = 9) and Cmax (23%, n = 11) was noted on day 5. This increase is considered unlikely to be of clinical relevance.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/ Contraception in males and females

Topotecan has been shown to cause embryo-foetal lethality and malformations in preclinical studies (see section 5.3). As with other cytotoxic medicinal products, topotecan may cause foetal harm and therefore women of childbearing potential should be advised to avoid becoming pregnant during therapy with topotecan.

As with all cytotoxic chemotherapy, patients being treated with topotecan must be advised that they or their partner must use an effective method of contraception.

Women of childbearing potential should use effective contraceptive measures while being treated with topotecan and for 6 months following completion of treatment.

Men are recommended to use effective contraceptive measures and to not father a child while receiving topotecan and for 3 months following completion of treatment.

Pregnancy

If topotecan is used during pregnancy, or if the patient becomes pregnant during therapy with topotecan, the patient must be warned of the potential hazards to the foetus.

Breast-feeding

Topotecan is contraindicated during breast-feeding (see section 4.3). Although it is not known whether topotecan is excreted in human breast milk, breast-feeding should be discontinued at the start of therapy.

Fertility

No effects on male or female fertility have been observed in reproductive toxicity studies in rats (see section 5.3). However, as with other cytotoxic medicinal products, topotecan is genotoxic and effects on fertility, including male fertility, cannot be excluded.

4.7. Effects on ability to drive and use machines

No studies of the effects on the ability to drive and use machines have been performed. However, caution should be observed when driving or operating machines if fatigue and asthenia persist.

4.8. Undesirable effects

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.

Infections and infestations

Very common

Infection

Common

Sepsis1

Blood and lymphatic system disorders

Very common

Febrile neutropenia, neutropenia (see "Gastrointestinal disorders"), thrombocytopenia, anaemia, leucopenia

Common

Pancytopenia

Not known

Severe bleeding (associated with thrombocytopenia)

Immune system disorders

Common

Hypersensitivity reaction including rash

Rare

Anaphylactic reaction, angioedema, urticaria

Metabolism and nutrition disorders

Very common

Anorexia (which may be severe)

Respiratory, thoracic and mediastinal disorders

Rare

Interstitial lung disease (some cases have been fatal)

Gastrointestinal disorders

Very common

Nausea, vomiting and diarrhoea (all of which may be severe), constipation, abdominal pain2, mucositis

Not known

Gastrointestinal perforation

Hepatobiliary disorders

Common

Hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Very common

Alopecia

Common

Pruritus

General disorders and administration site conditions

Very common

Pyrexia, asthenia, fatigue

Common

Malaise

Very rare

Extravasation3

Not known

Mucosal inflammation

1Fatalities due to sepsis have been reported in patients treated with topotecan (see section 4.4).

2Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a complication of topotecan-induced neutropenia (see section 4.4).

3Reactions have been mild and have not generally required specific therapy.

The adverse events listed above have the potential to occur with a higher frequency in patients who have a poor performance status (see section 4.4).

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 (see section 4.4).

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

4.9. Overdose

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 (see section 4.8). 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.