Topotecan Eagle

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Topotecan Eagle 3 mg/1 ml concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One ml of concentrate for solution for infusion contains 3 mg topotecan (as hydrochloride). 
 
Each 1 ml single dose vial contains 3 mg of topotecan. 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion. 
 
A clear light yellow to orange solution, pH ≤ 1.2. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Topotecan monotherapy is indicated for the treatment of 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 
 
Posology 
 
When 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). 
 
Small Cell Lung Carcinoma 
 
Initial dose 
The recommended dose of topotecan is 1.5 mg/m2 body surface area/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). 
 

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Standard oncology practice for the management of neutropenia is either to administer topotecan with 
other medications (e.g. G-CSF) or to dose reduce 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 trials, 
topotecan was discontinued if the dose had been reduced to 1.0 mg/m2 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 30 minute intravenous 
infusion daily 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 more than or equal to 
1.5 x 109/l, the platelet count is more than or equal to 100 x 109/l, and the haemoglobin level is more 
than or equal to 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 dose reduce to maintain neutrophil counts. 
 
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count less than 
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. 
 
Dosage in renally impaired patients 
Monotherapy (Small cell lung carcinoma) 
Insufficient data are available to make a recommendation for patients with a creatinine clearance 
< 20 ml/min. Limited data indicate that the dose should be reduced in patients with moderate renal 
impairment. The recommended monotherapy dose of topotecan in patients with 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. 
 
Paediatric population 
The experience in children is limited, therefore no recommendation for treatment of paediatric patients 
with topotecan can be given (see sections 5.1 and 5.2). 
 
Method of administration 
 

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The use of topotecan should be confined to units specialised in the administration of cytotoxic 
chemotherapy and should only be administered under the supervision of a physician experienced in 
the use of chemotherapy (see section 6.6). 
 
The concentration of topotecan in the 1 ml vial is higher (3 mg/ml) than with other topotecan products. 
It is important that Topotecan Eagle is further diluted before use (see section 6.6). 
 
Concentration must be noticed or life-threatening overdose may occur. 
 
Topotecan Eagle contains a higher dose concentration (3 mg/ml) than other topotecan products 
for intravenous infusion (usually 1 mg/ml). Topotecan Eagle must be diluted to a final 
concentration between 25 µg/ml and 50 µg/ml (see section 6.6 for dilution instructions). 
 
4.3 Contraindications 
 
Topotecan is contraindicated in patients who 
− have a history of severe hypersensitivity to the active substance or to any of the excipients 
− are breast feeding (see section 4.6) 
− already have 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 
 
Topotecan Eagle requires appropriate dilution before use. The concentration of topotecan in 
Topotecan Eagle differs from other topotecan products (see section 6.6 for further instructions on 
dilution). 
 
Concentration must be noticed or life-threatening overdose may occur. 
 
Topotecan Eagle contains a higher dose concentration (3 mg/ml) than other topotecan products 
for intravenous infusion (usually 1 mg/ml). Topotecan Eagle must be diluted to a final 
concentration between 25 µg/ml and 50 µg/ml (see section 6.6 for dilution instructions). 
 
Haematological toxicity is dose-related and full blood count including platelets should be monitored 
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 trials 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, 
e.g. in case patients at increased risk of tumour bleeds are considered for therapy. 
 
As 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). 

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Accurate assessment of performance status at the time therapy is given is important, to ensure that 
patients have not deteriorated to performance status 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. Topotecan is not recommended to be used in these patient groups. 
 
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 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. 
 
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 an intravenous population study, 
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). 
 
In combining topotecan with other chemotherapy agents, reduction of the doses of each medicinal 
product may be required to improve tolerability. However, in 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 five 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 
 
Contraception in males and females 
As with all cytotoxic chemotherapy, effective contraceptive methods must be advised when either 
partner is treated with topotecan. 
 
Women of childbearing potential 
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. 
 
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. 
 
Breastfeeding 
Topotecan is contra-indicated 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. 

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4.7 Effects on ability to drive and use machines 
 
No studies on 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 trials 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 adverse event profile for topotecan when given in combination with cisplatin in the cervical 
cancer clinical trials 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 not attributable to topotecan. 
The prescribing information for cisplatin should be consulted for a full list of adverse events 
associated 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), 
including isolated reports and not known (cannot be estimated from the available data). 
 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
 
 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) 
 
 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 pain1, mucositis 
 1 Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a 
 complication of topotecan-induced neutropenia (see section 4.4) 
 
 Skin and subcutaneous tissue disorders 
 Very common: alopecia 
 Common: pruritus 
 
 Metabolism and nutrition disorders 
 Very common: anorexia (which may be severe) 
 
 Infections and infestations 
 Very common: infection 
 Common: sepsis2 

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 2 Fatalities due to sepsis have been reported in patients treated with topotecan (see section 4.4) 
 
 General disorders and administration site conditions 
 Very common: pyrexia, asthenia, fatigue 
 Common: malaise 
 Very rare: extravasation3 
 3 Extravasation has been reported very rarely. Reactions have been mild and have not generally 
 required specific therapy. 
 
 Immune system disorders 
 Common: hypersensitivity reaction including rash 
 Rare: anaphylactic reaction, angioedema, urticaria 
 
 Hepato-biliary disorders 
 Common: hyperbilirubinaemia 
 
The incidence of 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 was seen in 55 % of the patients 
and 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 trials (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 less than 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 %), and diarrhoea (18 %), constipation (9 %) and mucositis (14 %). Severe (grade 3 or 4) nausea, 
vomiting, diarrhoea and mucositis incidence was 4, 3, 2 and 1 % respectively. 
 
Mild abdominal pain was also reported amongst 4 % of patients. 
 
Fatigue was observed in approximately 25 % and asthenia in 16 % of patients whilst receiving 
topotecan. Severe (grade 3 or 4) fatigue and asthenia incidence was 3 and 3 % respectively. 
 
Total or pronounced alopecia was observed in 30 % of patients and partial alopecia in 15 % of 
patients. 
 

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Other severe events occurring in patients 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 trials, rash was reported in 4 % of patients and pruritus in 1.5 % of patients. 
 
4.9 Overdose 
 
There is no known antidote for topotecan overdose. The primary complications of overdose are 
anticipated to be bone marrow suppression and mucositis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX17. 
 
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. 
 
Relapsed SCLC 
 
A phase III trial (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 + BSC, 90 days for BSC) and for 
whom retreatment with intravenous chemotherapy was not considered appropriate. Oral topotecan plus 
BSC group had a statistically significant improvement in overall survival compared with the BSC 
alone group (Log-rank p = 0.0104). The unadjusted hazard ratio for oral topotecan plus BSC group 
relative to BSC alone group was 0.64 (95 % CI: 0.45, 0.90). The median survival for patients treated 
with topotecan + BSC was 25.9 weeks (95 % C.I. 18.3, 31.6) compared to 13.9 weeks (95 % C.I. 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 + BSC. 
 
One Phase 2 study (Study 065) and one Phase 3 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. 
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Table 1. Summary of survival, response rate and time to progression in SCLC patients treated with oral 
or intravenous topotecan 

Study 065 Study 396 

Oral topotecan Intravenous topotecan Oral topotecan 
Intravenous 

topotecan  

(N = 52) (N = 54) (N = 153) (N = 151) 
Median survival (weeks) 
 (95 % CI) 

32.3 
(26.3, 40.9) 

25.1 
(21.1, 33.0) 

33.0 
(29.1, 42.4) 

35.0 
(31.0, 37.1) 

 Hazard ratio (95 % CI) 0.88 (0.59, 1.31) 0.88 (0.7, 1.11) 
Response rate (%) 
 (95 % CI) 

23.1 
(11.6, 34.5) 

14.8 
(5.3, 24.3) 

18.3 
(12.2, 24.4) 

21.9 
(15.3, 28.5) 

Difference in response 
rate (95 % CI) 8.3 (-6.6, 23.1) -3.6 (-12.6, 5.5) 

Median time to 
progression (weeks) 
 (95 % CI) 

14.9 
 

(8.3, 21.3) 

13.1 
 

(11.6, 18.3) 

11.9 
 

(9.7, 14.1) 

14.6 
 

(13.3, 18.9) 
 Hazard ratio (95 % CI) 0.90 (0.60, 1.35) 1.21 (0.96, 1.53) 

N = total number of patients treated. 
CI = Confidence interval. 
 
In another randomised phase III trial which compared intravenous topotecan to cyclophosphamide, 
Adriamycin (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 of 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 %. The 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 trial conducted by the Gynaecological 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). 
 

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Table 2. Study results Study GOG-0179 
ITT population 

 Cisplatin  
50mg/m2 d.1 

q21 d. 

Cisplatin  
50mg/m2 d.1 +  

Topotecan 0.75mg/m2 dx3  
q21 

Survival (months) (n = 146) (n = 147) 
Median (95 % C.I.) 6.5 (5.8, 8.8) 9.4 (7.9, 11.9) 
Hazard ratio (95 % C.I.) 0.76 (0.59-0.98) 
Log rank p-value 0.033 

   
Patients without prior Cisplatin chemoradiotherapy 

 Cisplatin Topotecan/Cisplatin 
Survival (months) (n = 46) (n = 44) 
Median (95 % C.I.) 8.8 (6.4, 11.5) 15.7 (11.9, 17.7) 
Hazard ratio (95 % C.I.) 0.51 (0.31, 0.82) 

   
Patients with prior Cisplatin chemoradiotherapy 

 Cisplatin Topotecan/Cisplatin 
Survival (months) (n = 72) (n = 69) 
Median (95 % C.I) 5.9 (4.7, 8.8) 7.9 (5.5, 10.9) 
Hazard ratio (95 % C.I.) 0.85 (0.59, 1.21) 

 
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 % C.I.: 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 
(n = 102) with recurrence after 180 days, the median survival in the topotecan plus cisplatin arm was 
9.9 months (95 % C.I.: 7, 12.6) versus 6.3 months (95 % C.I.: 4.9, 9.5) for the cisplatin arm with an 
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 trial 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. Antitumour 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/m2/day with G-CSF and 1.4 mg/m2/day 
without G-CSF in a pharmacokinetic study in paediatric patients with refractory solid tumours (see 
section 5.2). 
 
5.2 Pharmacokinetic properties 
 
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 132 l, (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 

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in the PK after multiple doses. Preclinical studies indicate plasma protein binding of topotecan is low 
(35 %) and distribution between blood cells and plasma was fairly homogeneous. 
 
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 less than 10 % for both total topotecan 
and topotecan lactone. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has 
been identified in the urine. 
 
Overall recovery of medicinal product-related material following five daily doses of topotecan was 
71 to 76 % of the administered intravenous 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 less than 7 % (range 4-9 %) of the total medicinal 
product related material accounted for in the urine and faeces. The topotecan-O-glucuronide and 
N-desmethyl topotecan-O-glucuronide in the urine were less than 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]) (see 
section 4.5). 
 
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. 
 
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. 
 
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 mg/m2 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 mg/m2 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. 
 

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5.3 Preclinical safety data 
 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Hydrochloric acid (E507) (for pH adjustment) 
Water for injections 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Vial before opening 
18 months. 
 
Diluted solution 
From a microbiological point of view, the solution should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 20°C - 25°C and ambient lighting conditions. 
 
6.4 Special precautions for storage 
 
Do not store above 25°C. 
 
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions of once-opened and diluted medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
1 ml concentrate in type 1 clear glass vial, together with grey butyl rubber stopper and aluminium seal 
with blue polypropylene flip-off cap, and with yellow vial ring collar. 
Each pack contains 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
General precautions 
The normal procedures for proper handling and disposal of anticancer medicinal products should be 
adopted, namely: 
− Personnel should be trained to dilute the medicinal product. 
− Pregnant staff should be excluded from working with this medicinal product. 
− Personnel handling this medicinal product during dilution should wear protective clothing 

including mask, goggles and gloves. 

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− 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. 

 
Instructions for dilution 
 
Concentration must be noticed or life-threatening overdose may occur. 
 
Topotecan Eagle concentrate is clear yellow to orange in colour and contains 3 mg/ml of topotecan, 
which is a higher concentration than found in other topotecan products for intravenous infusion. 
 
The user is requested to report any medication errors. 
 
The following dosing tables should be used as reference: 
 
Instructions for Preparation for Intravenous Administration for Small Cell Lung Cancer 

For recommended dose 
'1.5 mg/m2' 

For reduced dose 
'1.25 mg/m2' 

For reduced dose 
'1.0 mg/m2' Body  

surface area 
(m2) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required  

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

1 0.50 1.50 0.42 1.26 0.33 0.99 

1.1 0.55 1.65 0.46 1.38 0.37 1.11 

1.2 0.60 1.80 0.50 1.50 0.40 1.20 

1.3 0.65 1.95 0.54 1.62 0.43 1.29 

1.4 0.70 2.10 0.58 1.74 0.47 1.41 

1.5 0.75 2.25 0.63 1.89 0.50 1.50 

1.6 0.80 2.40 0.67 2.01 0.53 1.59 

1.7 0.85 2.55 0.71 2.13 0.57 1.71 

1.8 0.90 2.70 0.75 2.25 0.60 1.80 

1.9 0.95 2.85 0.79 2.37 0.63 1.89 

2 1.00 3.00 0.83 2.49 0.67 2.01 

2.1 1.05 3.15 0.88 2.64 0.70 2.10 

2.2 1.10 3.30 0.92 2.76 0.73 2.19 

2.3 1.15 3.45 0.96 2.88 0.77 2.31 

2.4 1.20 3.60 1.00 3.00 0.80 2.40 

2.5 1.25 3.75 1.04 3.12 0.83 2.49 
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Instructions for Preparation for Intravenous Administration for Cervical Cancer 
For recommended dose  

'0.75 mg/m2' 
For reduced dose  

'0.60 mg/m2' 
For reduced dose  

'0.45 mg/m2' Body 
surface area 

(m2) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

1 0.25 0.75 0.20 0.60 0.15 0.45 

1.1 0.28 0.84 0.22 0.66 0.17 0.51 

1.2 0.30 0.90 0.24 0.72 0.18 0.54 

1.3 0.33 0.99 0.26 0.78 0.20 0.60 

1.4 0.35 1.05 0.28 0.84 0.21 0.63 

1.5 0.38 1.14 0.30 0.90 0.23 0.69 

1.6 0.40 1.20 0.32 0.96 0.24 0.72 

1.7 0.43 1.29 0.34 1.02 0.26 0.78 

1.8 0.45 1.35 0.36 1.08 0.27 0.81 

1.9 0.48 1.44 0.38 1.14 0.29 0.87 

2 0.50 1.50 0.40 1.20 0.30 0.90 

2.1 0.53 1.59 0.42 1.26 0.32 0.96 

2.2 0.55 1.65 0.44 1.32 0.33 0.99 

2.3 0.58 1.74 0.46 1.38 0.35 1.05 

2.4 0.60 1.80 0.48 1.44 0.36 1.08 

2.5 0.63 1.89 0.50 1.50 0.38 1.14 
 
Further dilution of Topotecan Eagle is required with either sodium chloride 9 mg/ml (0.9 % w/v) 
solution for injection or glucose 50 mg/ml (5 % w/v) solution for injection in order to reach a final 
topotecan concentration of between 25 µg/ml and 50 µg/ml in the solution for infusion to the patient. 
Dilution should be performed under strict aseptic conditions (e.g. an LAF bench). 
 
Disposal 
Topotecan Eagle 3 mg/1 ml is for single use only. Any unused product or waste material should be 
disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Eagle Laboratories Limited 
The Clock House 
Station Approach 
Marlow, Bucks, SL7 1NT 
United Kingdom 
Tel: +1 (201) 326-5324 
Fax: +1 (201) 391-2430 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/11/744/001 
 
 

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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 
22/12/2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/. 

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http://www.emea.europa.eu/�


16 

1. NAME OF THE MEDICINAL PRODUCT 
 
Topotecan Eagle 15 mg/5 ml concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One ml of concentrate for solution for infusion contains 3 mg topotecan (as hydrochloride). 
 
Each 5 ml multi dose vial contains 15 mg of topotecan. 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion. 
 
A clear light yellow to orange solution, pH ≤ 1.2. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Topotecan monotherapy is indicated for the treatment of 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 
 
Posology 
 
When 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). 
 
Small Cell Lung Carcinoma 
 
Initial dose 
The recommended dose of topotecan is 1.5 mg/m2 body surface area/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). 
 

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Standard oncology practice for the management of neutropenia is either to administer topotecan with 
other medicinal products (e.g. G-CSF) or to dose reduce 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 trials, 
topotecan was discontinued if the dose had been reduced to 1.0 mg/m2 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 30 minute intravenous 
infusion daily 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 more than or equal to 
1.5 x 109/l, the platelet count is more than or equal to 100 x 109/l, and the haemoglobin level is more 
than or equal to 9 g/dl (after transfusion if necessary). 
 
Standard oncology practice for the management of neutropenia is either to administer topotecan with 
other medications (e.g. G-CSF) or to dose reduce to maintain neutrophil counts. 
 
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count less than 
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. 
 
Dosage in renally impaired patients 
Monotherapy (Small cell lung carcinoma) 
Insufficient data are available to make a recommendation for patients with a creatinine clearance 
< 20 ml/min. Limited data indicate that the dose should be reduced in patients with moderate renal 
impairment. The recommended monotherapy dose of topotecan in patients with 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. 
 
Paediatric population 
The experience in children is limited, therefore no recommendation for treatment of paediatric patients 
with topotecan can be given (see sections 5.1 and 5.2). 
 
Method of administration 
 

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The use of topotecan should be confined to units specialised in the administration of cytotoxic 
chemotherapy and should only be administered under the supervision of a physician experienced in 
the use of chemotherapy (see section 6.6). 
 
The concentration of topotecan in the 5 ml vial is higher (3 mg/ml) than with other topotecan products. 
It is important that Topotecan Eagle is further diluted before use (see section 6.6). 
 
Concentration must be noticed or life-threatening overdose may occur. 
 
Topotecan Eagle contains a higher dose concentration (3 mg/ml) than other topotecan products 
for intravenous infusion (usually 1 mg/ml). Topotecan Eagle must be diluted to a final 
concentration between 25 µg/ml and 50 µg/ml (see section 6.6 for dilution instructions). 
 
4.3 Contraindications 
 
Topotecan is contraindicated in patients who 
− have a history of severe hypersensitivity to the active substance or to any of the excipients 
− are breast feeding (see section 4.6) 
− already have 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 
 
Topotecan Eagle requires appropriate dilution before use. The concentration of topotecan in 
Topotecan Eagle differs from other topotecan products (see section 6.6 for further instructions on 
dilution). 
 
Concentration must be noticed or life-threatening overdose may occur. 
 
Topotecan Eagle contains a higher dose concentration (3 mg/ml) than other topotecan products 
for intravenous infusion (usually 1 mg/ml). Topotecan Eagle must be diluted to a final 
concentration between 25 µg/ml and 50 µg/ml (see section 6.6 for dilution instructions). 
 
Haematological toxicity is dose-related and full blood count including platelets should be monitored 
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 trials 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, 
e.g. in case patients at increased risk of tumour bleeds are considered for therapy. 
 
As 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). 

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Accurate assessment of performance status at the time therapy is given is important, to ensure that 
patients have not deteriorated to performance status 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. Topotecan is not recommended to be used in these patient groups. 
 
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 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. 
 
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 an intravenous population study, 
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). 
 
In combining topotecan with other chemotherapy agents, reduction of the doses of each medicinal 
product may be required to improve tolerability. However, in 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 five 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 
 
Contraception in males and females 
As with all cytotoxic chemotherapy, effective contraceptive methods must be advised when either 
partner is treated with topotecan. 
 
Women of childbearing potential 
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. 
 
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. 
 
Breastfeeding 
Topotecan is contra-indicated 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. 

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4.7 Effects on ability to drive and use machines 
 
No studies on 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 trials 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 adverse event profile for topotecan when given in combination with cisplatin in the cervical 
cancer clinical trials 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 not attributable to topotecan. 
The prescribing information for cisplatin should be consulted for a full list of adverse events 
associated 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), 
including isolated reports and not known (cannot be estimated from the available data). 
 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
 
 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) 
 
 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 pain1, mucositis 
 1 Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a 
 complication of topotecan-induced neutropenia (see section 4.4) 
 
 Skin and subcutaneous tissue disorders 
 Very common: alopecia 
 Common: pruritus 
 
 Metabolism and nutrition disorders 
 Very common: anorexia (which may be severe) 
 
 Infections and infestations 
 Very common: infection 
 Common: sepsis2 

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 2 Fatalities due to sepsis have been reported in patients treated with topotecan (see section 4.4) 
 
 General disorders and administration site conditions 
 Very common: pyrexia, asthenia, fatigue 
 Common: malaise 
 Very rare: extravasation3 
 3 Extravasation has been reported very rarely. Reactions have been mild and have not generally 
 required specific therapy. 
 
 Immune system disorders 
 Common: hypersensitivity reaction including rash 
 Rare: anaphylactic reaction, angioedema, urticaria 
 
 Hepato-biliary disorders 
 Common: hyperbilirubinaemia 
 
The incidence of 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 was seen in 55 % of the patients 
and 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 trials (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 less than 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 %), and diarrhoea (18 %), constipation (9 %) and mucositis (14 %). Severe (grade 3 or 4) nausea, 
vomiting, diarrhoea and mucositis incidence was 4, 3, 2 and 1 % respectively. 
 
Mild abdominal pain was also reported amongst 4 % of patients. 
 
Fatigue was observed in approximately 25 % and asthenia in 16 % of patients whilst receiving 
topotecan. Severe (grade 3 or 4) fatigue and asthenia incidence was 3 and 3 % respectively. 
 
Total or pronounced alopecia was observed in 30 % of patients and partial alopecia in 15 % of 
patients. 
 

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Other severe events occurring in patients 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 trials, rash was reported in 4 % of patients and pruritus in 1.5 % of patients. 
 
4.9 Overdose 
 
There is no known antidote for topotecan overdose. The primary complications of overdose are 
anticipated to be bone marrow suppression and mucositis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX17. 
 
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. 
 
Relapsed SCLC 
 
A phase III trial (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 + BSC, 90 days for BSC) and for 
whom retreatment with intravenous chemotherapy was not considered appropriate. Oral topotecan plus 
BSC group had a statistically significant improvement in overall survival compared with the BSC 
alone group (Log-rank p = 0.0104). The unadjusted hazard ratio for oral topotecan plus BSC group 
relative to BSC alone group was 0.64 (95 % CI: 0.45, 0.90). The median survival for patients treated 
with topotecan + BSC was 25.9 weeks (95 % C.I. 18.3, 31.6) compared to 13.9 weeks (95 % C.I. 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 + BSC. 
 
One Phase 2 study (Study 065) and one Phase 3 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. 
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Table 1. Summary of survival, response rate and time to progression in SCLC patients treated with oral 
or intravenous topotecan 

Study 065 Study 396 

Oral topotecan Intravenous topotecan Oral topotecan 
Intravenous 

topotecan  

(N = 52) (N = 54) (N = 153) (N = 151) 
Median survival (weeks) 
 (95 % CI) 

32.3 
(26.3, 40.9) 

25.1 
(21.1, 33.0) 

33.0 
(29.1, 42.4) 

35.0 
(31.0, 37.1) 

 Hazard ratio (95 % CI) 0.88 (0.59, 1.31) 0.88 (0.7, 1.11) 
Response rate (%) 
 (95 % CI) 

23.1 
(11.6, 34.5) 

14.8 
(5.3, 24.3) 

18.3 
(12.2, 24.4) 

21.9 
(15.3, 28.5) 

Difference in response 
rate (95 % CI) 8.3 (-6.6, 23.1) -3.6 (-12.6, 5.5) 

Median time to 
progression (weeks) 
 (95 % CI) 

14.9 
 

(8.3, 21.3) 

13.1 
 

(11.6, 18.3) 

11.9 
 

(9.7, 14.1) 

14.6 
 

(13.3, 18.9) 
 Hazard ratio (95 % CI) 0.90 (0.60, 1.35) 1.21 (0.96, 1.53) 

N = total number of patients treated. 
CI = Confidence interval. 
 
In another randomised phase III trial which compared intravenous topotecan to cyclophosphamide, 
Adriamycin (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 of 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 %. The 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 trial conducted by the Gynaecological 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). 
 

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24 

Table 2. Study results Study GOG-0179 
ITT population 

 Cisplatin  
50mg/m2 d.1 

q21 d. 

Cisplatin  
50mg/m2 d.1 +  

Topotecan 0.75mg/m2 dx3  
q21 

Survival (months) (n = 146) (n = 147) 
Median (95 % C.I.) 6.5 (5.8, 8.8) 9.4 (7.9, 11.9) 
Hazard ratio (95 % C.I.) 0.76 (0.59-0.98) 
Log rank p-value 0.033 

   
Patients without prior Cisplatin chemoradiotherapy 

 Cisplatin Topotecan/Cisplatin 
Survival (months) (n = 46) (n = 44) 
Median (95 % C.I.) 8.8 (6.4, 11.5) 15.7 (11.9, 17.7) 
Hazard ratio (95 % C.I.) 0.51 (0.31, 0.82) 

   
Patients with prior Cisplatin chemoradiotherapy 

 Cisplatin Topotecan/Cisplatin 
Survival (months) (n = 72) (n = 69) 
Median (95 % C.I) 5.9 (4.7, 8.8) 7.9 (5.5, 10.9) 
Hazard ratio (95 % C.I.) 0.85 (0.59, 1.21) 

 
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 % C.I.: 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 
(n = 102) with recurrence after 180 days, the median survival in the topotecan plus cisplatin arm was 
9.9 months (95 % C.I.: 7, 12.6) versus 6.3 months (95 % C.I.: 4.9, 9.5) for the cisplatin arm with an 
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 trial 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. Antitumour 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/m2/day with G-CSF and 1.4 mg/m2/day 
without G-CSF in a pharmacokinetic study in paediatric patients with refractory solid tumours (see 
section 5.2). 
 
5.2 Pharmacokinetic properties 
 
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 132 l, (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 

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25 

in the PK after multiple doses. Preclinical studies indicate plasma protein binding of topotecan is low 
(35 %) and distribution between blood cells and plasma was fairly homogeneous. 
 
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 less than 10 % for both total topotecan 
and topotecan lactone. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has 
been identified in the urine. 
 
Overall recovery of medicinal product-related material following five daily doses of topotecan was 
71 to 76 % of the administered intravenous 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 less than 7 % (range 4-9 %) of the total medicinal 
product related material accounted for in the urine and faeces. The topotecan-O-glucuronide and 
N-desmethyl topotecan-O-glucuronide in the urine were less than 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]) (see 
section 4.5). 
 
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. 
 
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. 
 
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 mg/m2 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 mg/m2 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. 
 

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26 

5.3 Preclinical safety data 
 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Hydrochloric acid (E507) (for pH adjustment) 
Water for injections 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Vial before opening 
3 years. 
 
Vial after first opening 
Chemical and physical in-use stability has been demonstrated for 14 days at 20°C - 25°C when stored 
in the outer carton to protect from light. 
From a microbiological point of view, once opened, the product may be stored for a maximum of 
14 days at 20°C - 25°C. Other in-use storage times and conditions are the responsibility of the user. 
 
Diluted solution 
From a microbiological point of view, the solution should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 20°C - 25°C and ambient lighting conditions. 
 
6.4 Special precautions for storage 
 
Do not store above 25°C. 
 
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions of once-opened and diluted medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
5 ml concentrate in type 1 clear glass vial, together with grey butyl rubber stopper and aluminium seal 
with yellow polypropylene flip-off cap, and with yellow vial ring collar. 
Each pack contains 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
General precautions 

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The normal procedures for proper handling and disposal of anticancer medicinal products should be 
adopted, namely: 
− Personnel should be trained to dilute the medicinal product. 
− Pregnant staff should be excluded from working with this medicinal product. 
− Personnel handling this medicinal product during dilution 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. 

 
Instructions for dilution 
 
Concentration must be noticed or life-threatening overdose may occur. 
 
Topotecan Eagle concentrate is clear yellow to orange in colour and contains 3 mg/ml of topotecan, 
which is a higher concentration than found in other topotecan products for intravenous infusion. 
 
The user is requested to report any medication errors. 
 
The following dosing tables should be used as reference: 
 
Instructions for Preparation for Intravenous Administration for Small Cell Lung Cancer 

For recommended dose 
'1.5 mg/m2' 

For reduced dose 
'1.25 mg/m2' 

For reduced dose 
'1.0 mg/m2' Body  

surface area 
(m2) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

1 0.50 1.50 0.42 1.26 0.33 0.99 

1.1 0.55 1.65 0.46 1.38 0.37 1.11 

1.2 0.60 1.80 0.50 1.50 0.40 1.20 

1.3 0.65 1.95 0.54 1.62 0.43 1.29 

1.4 0.70 2.10 0.58 1.74 0.47 1.41 

1.5 0.75 2.25 0.63 1.89 0.50 1.50 

1.6 0.80 2.40 0.67 2.01 0.53 1.59 

1.7 0.85 2.55 0.71 2.13 0.57 1.71 

1.8 0.90 2.70 0.75 2.25 0.60 1.80 

1.9 0.95 2.85 0.79 2.37 0.63 1.89 

2 1.00 3.00 0.83 2.49 0.67 2.01 

2.1 1.05 3.15 0.88 2.64 0.70 2.10 

2.2 1.10 3.30 0.92 2.76 0.73 2.19 

2.3 1.15 3.45 0.96 2.88 0.77 2.31 

2.4 1.20 3.60 1.00 3.00 0.80 2.40 

2.5 1.25 3.75 1.04 3.12 0.83 2.49 
 

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28 

Instructions for Preparation for Intravenous Administration for Cervical Cancer 
For recommended dose  

'0.75 mg/m2' 
For reduced dose  

'0.60 mg/m2' 
For reduced dose  

'0.45 mg/m2' Body 
surface area 

(m2) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

1 0.25 0.75 0.20 0.60 0.15 0.45 

1.1 0.28 0.84 0.22 0.66 0.17 0.51 

1.2 0.30 0.90 0.24 0.72 0.18 0.54 

1.3 0.33 0.99 0.26 0.78 0.20 0.60 

1.4 0.35 1.05 0.28 0.84 0.21 0.63 

1.5 0.38 1.14 0.30 0.90 0.23 0.69 

1.6 0.40 1.20 0.32 0.96 0.24 0.72 

1.7 0.43 1.29 0.34 1.02 0.26 0.78 

1.8 0.45 1.35 0.36 1.08 0.27 0.81 

1.9 0.48 1.44 0.38 1.14 0.29 0.87 

2 0.50 1.50 0.40 1.20 0.30 0.90 

2.1 0.53 1.59 0.42 1.26 0.32 0.96 

2.2 0.55 1.65 0.44 1.32 0.33 0.99 

2.3 0.58 1.74 0.46 1.38 0.35 1.05 

2.4 0.60 1.80 0.48 1.44 0.36 1.08 

2.5 0.63 1.89 0.50 1.50 0.38 1.14 
 
Further dilution of Topotecan Eagle is required with either sodium chloride 9 mg/ml (0.9 % w/v) 
solution for injection or glucose 50 mg/ml (5 % w/v) solution for injection in order to reach a final 
topotecan concentration of between 25 µg/ml and 50 µg/ml in the solution for infusion to the patient. 
Dilution should be performed under strict aseptic conditions (e.g. an LAF bench). 
 
Disposal 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Eagle Laboratories Limited 
The Clock House 
Station Approach 
Marlow, Bucks, SL7 1NT 
United Kingdom 
Tel: +1 (201) 326-5324 
Fax: +1 (201) 391-2430 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/11/744/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

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Date of first authorisation: 
22/12/2011 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/. 
 

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http://www.emea.europa.eu/�


30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
 AUTHORISATION 
 
 
 

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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
MAWDSLEY-BROOKS & COMPANY LIMITED 
Unit 22, Quest Park 
Wheatley Hall Road 
Doncaster, DN2 4LT 
United Kingdom 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
Pharmacovigilance system 
The MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1. of the 
Marketing Authorisation is in place and functioning before and whilst the medicinal product is on the 
market. 
 
Risk Management Plan 
The MAH shall perform the pharmacovigilance activities detailed in the Pharmacovigilance Plan, as 
agreed in the Risk Management Plan (RMP) presented in Module 1.8.2. of the Marketing 
Authorisation and any subsequent updates of the RMP agreed by the Committee for Medicinal 
Products for Human Use (CHMP). 
 
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the 
updated RMP should be submitted at the same time as the next Periodic Safety Update Report 
(PSUR). 
 
In addition, an updated RMP should be submitted 

 When new information is received that may impact on the current Safety Specification, 
Pharmacovigilance Plan or risk minimisation activities 

 Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being 
reached 

 At the request of the European Medicines Agency. 
 
PSURs 
The PSUR cycle for the medicinal product should follow a half-yearly cycle until otherwise agreed by 
the CHMP. 
 
 
 CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 

USE OF THE MEDICINAL PRODUCT 
 
Prior to launch of the product in each Member State, the Marketing Authorisation Holder shall agree 
the content and format of a Safety Information Communication with the national competent authority, 
including the need and the timing of any follow-up Safety Communication Information, as well as the 
distribution list of such information. 
 

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The Marketing Authorisation Holder (MAH) should ensure that, at launch, all Healthcare 
Professionals who are expected to use and/or prescribe Topotecan Eagle are provided with a Safety 
Information Communication. 
 
The Safety Information Communication should contain the following: 
 The risk of medication error due to the higher concentration than the dilution concentration of 

the originator, with potentially life-threatening consequences. 
 Reference to the vial collar as visual reminder of this difference and the instruction that it must 

not be removed at any time. 
 The anticipated effects of overdose (e.g. bone marrow suppression). 
 An encouragement of reporting of actual medication errors and any safety events that might be a 

consequence of a medication error. 
 A form to report medication errors. 

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33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

 

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34 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 

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35 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 1 ml vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Topotecan Eagle 3 mg/1 ml concentrate for solution for infusion 
topotecan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One ml of concentrate for solution for infusion contains 3 mg topotecan (as hydrochloride). 
Each vial contains 3 mg topotecan (as hydrochloride) in 1 ml concentrate. 
 
 
3. LIST OF EXCIPIENTS 
 
Hydrochloric acid (E507) 
Water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intravenous use. Must be diluted before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
CYTOTOXIC 
Read the package leaflet before use. 
 
Notice concentration or life-threatening overdose may occur. 
 
 
8. EXPIRY DATE 
 
EXP 
 
Read the leaflet for the shelf life of the diluted product. 

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36 

 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25ºC. 
Keep the vial in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Eagle Laboratories Limited 
The Clock House 
Station Approach 
Marlow, Bucks, SL7 1NT 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/744/001 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille acceptedMe

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37 

 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 1 ml 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Topotecan Eagle 3 mg/1 ml concentrate for solution for infusion 
Topotecan 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
To be diluted before use. 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 ml 
 
 
6. OTHER 
 
Cytotoxic 
 
Notice concentration or life-threatening overdose may occur. 
 

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39 

 
 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 5 ml multidose vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Topotecan Eagle 15 mg/5 ml concentrate for solution for infusion 
topotecan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One ml of concentrate for solution for infusion contains 3 mg topotecan (as hydrochloride). 
Each vial contains 15 mg topotecan (as hydrochloride) in 5 ml concentrate. 
 
 
3. LIST OF EXCIPIENTS 
 
Hydrochloric acid (E507) 
Water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
(3 mg/ml) 
1 vial 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intravenous use. Must be diluted before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
CYTOTOXIC 
Read the package leaflet before use. 
 
Notice concentration or life-threatening overdose may occur. 
 
 
8. EXPIRY DATE 
 
EXP 
 

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Multidose vial: once opened, store for a maximum of 14 days at 20°C-25°C. 
Opened on: DD/MM/YY 
 
Read the leaflet for the shelf life of the diluted product. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25ºC. 
Keep the vial in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Eagle Laboratories Limited 
The Clock House 
Station Approach 
Marlow, Buck, SL7 1NT 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/744/002 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 5 ml 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Topotecan Eagle 15 mg/5 ml concentrate for solution for infusion 
Topotecan 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
To be diluted before use. 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
Multidose vial: once opened, store for a maximum of 14 days at 20°C-25°C. 
Opened on: DD/MM/YY 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 ml 
3 mg/ml 
 
6. OTHER 
 
Cytotoxic 
 
Notice concentration or life-threatening overdose may occur. 
 

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42 

 
 
 

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43 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 

  

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44 

PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Topotecan Eagle 3 mg/1 ml concentrate for solution for infusion 
topotecan 

 
Read all of this leaflet carefully before you start using this medicine. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or nurse. 
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours. 
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or nurse. 
 
In this leaflet: 
 
1. What Topotecan Eagle is and what it is used for 
2. Before you are given Topotecan Eagle 
3. How to use Topotecan Eagle 
4. Possible side effects 
5. How to store Topotecan Eagle 
6. Further information 
 
 
1. WHAT TOPOTECAN EAGLE IS AND WHAT IT IS USED FOR 
 
The name of your medicine is Topotecan Eagle 3 mg/1 ml concentrate for solution for infusion (called 
Topotecan Eagle in this leaflet). 
 
Topotecan Eagle helps to kill tumour cells. It is a type of chemotherapy. 
 
Topotecan Eagle is used to treat: 
- small cell lung cancer that has come back after chemotherapy 
- advanced cervical cancer when surgery or radiotherapy are not possible. In this case, it is used 

with another medicine called cisplatin. 
 
 
2. BEFORE YOU ARE GIVEN TOPOTECAN EAGLE 
 
You should not receive Topotecan Eagle: 
- if you are allergic (hypersensitive) to topotecan or to any of the other ingredients of this 

medicine listed in Section 6 
- if you are breast-feeding. You should stop breast-feeding before starting treatment with 

Topotecan Eagle 
- if your blood cell count is too low. Your doctor will check this. 
 
Do not use Topotecan Eagle if any of the above apply to you. If you are not sure, talk to your doctor 
or nurse before using this medicine. 
 
Take special care with Topotecan Eagle 
Check with your doctor or nurse before using your medicine: 
- if you have any kidney problems. Your dose of Topotecan Eagle may need to be adjusted.  

This medicine is not recommended if you have severe kidney problems; 
- if you have liver problems. Your dose of Topotecan Eagle may need to be adjusted.  

This medicine is not recommended if you have severe liver problems; 
- if you have lung problems, or if you have had lung problems before from using other medicines 

or radiation. This is because you are more likely to get severe lung problems (interstitial lung 
disease) when using Topotecan Eagle; 

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45 

- if you have unusual bruising or bleeding; 
- if you are feeling very ill. 
 
If any of the above apply to you (or you are not sure), talk to your doctor or nurse before using 
Topotecan Eagle. 
 
Using other medicines 
Please tell your doctor if you are taking or have recently taken any other medicines, including 
medicines obtained without a prescription and herbal medicines. This is because Topotecan Eagle can 
affect the way some other medicines work. Also some other medicines can affect the way Topotecan 
Eagle works. 
 
Pregnancy and breast-feeding 
- Topotecan Eagle should not be used during pregnancy, unless clearly necessary. If you are 

pregnant or think you might be pregnant, tell your doctor immediately. 
- Women who could get pregnant should use contraception to stop them getting pregnant during 

treatment. 
- Men having Topotecan Eagle who wish to father a child should ask their doctor for family 

planning advice. 
- Do not breast-feed while using Topotecan Eagle. 
 
Driving and using machines 
Topotecan Eagle can make you feel tired or weak. If this happens, do not drive or use any tools or 
machines.  
 
 
3. HOW TO USE TOPOTECAN EAGLE 
 
How much you will be given 
Your dose of Topotecan Eagle will depend on: 
- the disease being treated 
- the size of your body (measured in ‘square meters’ or ‘m2’) 
- the results of blood tests before and during treatment 
- how well your body responds to the medicine. 
 
Small cell lung cancer 
- The usual dose is 1.5 mg of the medicine for each square meter of your body. 
- It is given once each day for 5 days. 
- This treatment cycle will normally be repeated every 3 weeks. 
 
Cervical cancer 
- The usual dose is 0.75 mg of the medicine for each square meter of your body. 
- It is given once each day for 3 days. 
- This treatment cycle will normally be repeated every 3 weeks. 
 
For cervical cancer Topotecan Eagle will be used with another medicine called cisplatin. For more 
information about cisplatin, please read its Package Leaflet. 

The experience of using Topotecan Eagle in children is limited. This means that treatment is not 
recommended. 

If you have any further questions on the use of this medicine, ask your doctor or nurse. 

 

How Topotecan Eagle is prepared 
Topotecan Eagle is supplied as a concentrate for solution for infusion. The concentration of topotecan 
is higher (3 mg/ml) than with other topotecan products. The concentrate must be diluted before 
administration. 

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46 

 

How Topotecan Eagle is given 
Topotecan Eagle is normally given by a doctor or nurse: 
- as a drip (infusion) for about 30 minutes 
- usually into your arm. 
 
 
4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Topotecan Eagle can cause side effects, although not everybody gets them. 
 
How likely these side effects may happen, is as follows: 
- very common affects more than 1 user in 10 
- common affects 1 to 10 users in 100 
- uncommon affects 1 to 10 users in 1,000 
- rare affects 1 to 10 users in 10,000 
- very rare affects less than 1 user in 10,000 
- not known frequency cannot be estimated from the available data. 
 
Serious side effects 
Tell your doctor immediately if you notice any of the following serious side effects. You may need 
urgent medical treatment: 

• Infections (very common) – because Topotecan Eagle may reduce your ability to fight infections. 
The signs include:  

- fever 
- sudden decline of your general health 
- sore throat or burning sensation when passing water 
- severe stomach pain, fever and possibly diarrhoea (rarely with blood in it) - these can be signs 

of bowel inflammation (neutropenic colitis). 

• Lung inflammation (rare), with signs such as: 
- difficulty in breathing 
- cough 
- fever. 
You are more likely to get severe lung problems (interstitial lung disease) if you already have lung 
problems or have had lung problems before from using other medicines or radiation. 
 
Other side effects may include: 
Very common 
- feeling generally weak and tired. These may be signs of a drop in the number of your red blood 

cells (anaemia). In some cases you may need a blood transfusion. 
- unusual bruising or bleeding, sometimes severe. This is caused by a drop in the number of blood 

clotting cells (platelets). 
- abnormally low white blood cell count (neutropenia) which may be accompanied with fever and 

signs of infection (febrile neutropenia) 
- weight loss and loss of appetite, feeling tired or weak 
- feeling or being sick, diarrhoea, stomach pain, constipation 
- inflammation and ulcers of the mouth, throat, tongue or gums (mucositis) 
- high body temperature (fever) 
- infections 
- hair loss. 
 
Common 
- mild allergic reactions (including rash) 
- yellow skin (jaundice) caused by liver problems 
- itching (pruritus) 

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- severe infection (sepsis) 
- feeling unwell (malaise). 
 
Rare 
- severe allergic (anaphylactic) reactions causing swelling of the lips, face or neck leading to 

severe difficulty in breathing, skin rash or hives, anaphylactic shock (a severe reduction in 
blood pressure, paleness, agitation, weak pulse, decreased consciousness) 

- sudden swelling of the skin and mucosa (e.g. throat or tongue) caused by fluid build up 
(angioedema) 

- itchy rash (or hives). 
 
Very rare 
- Mild pain and inflammation at the site of injection due to accidental administration of the 

medicinal product into the surrounding tissue (extravasation) e.g. by leakage. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or nurse. 
 
If you are being treated for cervical cancer, you may get side effects from the other medicine 
(cisplatin) that you will be given along with Topotecan Eagle. 
 
 
5. HOW TO STORE TOPOTECAN EAGLE 
 
Keep out of the sight and reach of children. 
 
Do not use Topotecan Eagle after the expiry date which is stated on the carton and vial after EXP. The 
expiry date refers to the last day of that month. 
 
Do not store above 25°C. 
 
Keep the vial in the outer carton in order to protect from light. 
 
Diluted solution 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 20°C - 25°C and ambient lighting conditions. 
 
Do not use Topotecan Eagle if you notice any visible particles or if the solution is unclear. 
 
Medicines should not be disposed of via wastewater or household waste. Your doctor should dispose 
of medicines that are no longer required. These measures will help to protect the environment. 
 
 
6. FURTHER INFORMATION 
 
What Topotecan Eagle contains 
- The active substance is topotecan. 
- One ml of concentrate for solution for infusion contains 3 mg topotecan (as hydrochloride). 
 Each 1 ml single dose vial contains 3 mg of topotecan. 
- The other ingredients are: hydrochloric acid (E507) (for pH adjustment) and water for 
 injections. 
 

What Topotecan Eagle looks like and contents of the pack 
- Topotecan Eagle is a clear yellow to orange liquid in a colourless glass vial with a butyl rubber 

stopper, aluminium seal and blue snap-cap and with yellow vial ring collar. 

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- Topotecan Eagle is supplied in cartons containing 1 vial. 
 
Marketing Authorisation Holder 
Eagle Laboratories Limited 
The Clock House 
Station Approach 
Marlow, Bucks, SL7 1NT 
United Kingdom 
 
Manufacturer 
MAWDSLEY-BROOKS & COMPANY LIMITED 
Unit 22, Quest Park 
Wheatley Hall Road 
Doncaster, DN2 4LT 
United Kingdom 
 
This leaflet was last approved in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 
__________________________________________________________________________________ 

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http://www.ema.europa.eu/�


49 

The following information is intended for medical or healthcare professionals only: 
 
Instructions on how to dilute, store and dispose of Topotecan Eagle 
 
General precautions 
The concentration of topotecan in Topotecan Eagle differs from other topotecan products and care 
should be taken to ensure appropriate dilution occurs to achieve the intended dose, which should be 
checked prior to administration to the patient. 
 
The normal procedures for proper handling and disposal of anticancer medicinal products should be 
adopted: 
- Staff should be trained to dilute the medicinal product. 
- Pregnant staff should be excluded from working with this medicinal product. 
- Staff handling this medicinal product during dilution 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. 
 
Instructions for dilution 
 
Concentration must be noticed or life-threatening overdose may occur. 
 
Topotecan Eagle concentrate is clear yellow to orange in colour and contains 3 mg/ml of topotecan, 
which is a higher concentration than found in other topotecan products for intravenous infusion. 
 
The user is requested to report any medication errors. 
 
The following dosing tables should be used as reference: 

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Instructions for Preparation for Intravenous Administration for Small Cell Lung Cancer 

For recommended dose 
'1.5 mg/m2' 

For reduced dose 
'1.25 mg/m2' 

For reduced dose 
'1.0 mg/m2' Body  

surface area 
(m2) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required  

(ml) 

Total dose 
(mg) 

1 0.50 1.50 0.42 1.26 0.33 0.99 

1.1 0.55 1.65 0.46 1.38 0.37 1.11 

1.2 0.60 1.80 0.50 1.50 0.40 1.20 

1.3 0.65 1.95 0.54 1.62 0.43 1.29 

1.4 0.70 2.10 0.58 1.74 0.47 1.41 

1.5 0.75 2.25 0.63 1.89 0.50 1.50 

1.6 0.80 2.40 0.67 2.01 0.53 1.59 

1.7 0.85 2.55 0.71 2.13 0.57 1.71 

1.8 0.90 2.70 0.75 2.25 0.60 1.80 

1.9 0.95 2.85 0.79 2.37 0.63 1.89 

2 1.00 3.00 0.83 2.49 0.67 2.01 

2.1 1.05 3.15 0.88 2.64 0.70 2.10 

2.2 1.10 3.30 0.92 2.76 0.73 2.19 

2.3 1.15 3.45 0.96 2.88 0.77 2.31 

2.4 1.20 3.60 1.00 3.00 0.80 2.40 

2.5 1.25 3.75 1.04 3.12 0.83 2.49 
 

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Instructions for Preparation for Intravenous Administration for Cervical Cancer 
For recommended dose  

'0.75 mg/m2' 
For reduced dose  

'0.60 mg/m2' 
For reduced dose  

'0.45 mg/m2' Body 
surface area 

(m2) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

1 0.25 0.75 0.20 0.60 0.15 0.45 

1.1 0.28 0.84 0.22 0.66 0.17 0.51 

1.2 0.30 0.90 0.24 0.72 0.18 0.54 

1.3 0.33 0.99 0.26 0.78 0.20 0.60 

1.4 0.35 1.05 0.28 0.84 0.21 0.63 

1.5 0.38 1.14 0.30 0.90 0.23 0.69 

1.6 0.40 1.20 0.32 0.96 0.24 0.72 

1.7 0.43 1.29 0.34 1.02 0.26 0.78 

1.8 0.45 1.35 0.36 1.08 0.27 0.81 

1.9 0.48 1.44 0.38 1.14 0.29 0.87 

2 0.50 1.50 0.40 1.20 0.30 0.90 

2.1 0.53 1.59 0.42 1.26 0.32 0.96 

2.2 0.55 1.65 0.44 1.32 0.33 0.99 

2.3 0.58 1.74 0.46 1.38 0.35 1.05 

2.4 0.60 1.80 0.48 1.44 0.36 1.08 

2.5 0.63 1.89 0.50 1.50 0.38 1.14 
 
Further dilution of Topotecan Eagle is required with either sodium chloride 9 mg/ml (0.9 % w/v) 
solution for injection or glucose 50 mg/ml (5 % w/v) solution for injection in order to reach a final 
topotecan concentration of between 25 µg/ml and 50 µg/ml in the solution for infusion to the patient. 
Dilution should be performed under strict aseptic conditions (e.g. an LAF bench). 
 
Storage of the diluted solution 
From a microbiological point of view, the solution should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 20°C - 25°C and ambient lighting conditions. 
 
Disposal 
Topotecan Eagle 3 mg/1 ml is for single use only. Any unused product or waste material should be 
disposed of in accordance with local requirements. 
 

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PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Topotecan Eagle 15 mg/5 ml concentrate for solution for infusion 
topotecan 

 
Read all of this leaflet carefully before you start using this medicine. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or nurse. 
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours. 
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or nurse. 
 
In this leaflet: 
 
1. What Topotecan Eagle is and what it is used for 
2. Before you are given Topotecan Eagle 
3. How to use Topotecan Eagle 
4. Possible side effects 
5. How to store Topotecan Eagle 
6. Further information 
 
 
1. WHAT TOPOTECAN EAGLE IS AND WHAT IT IS USED FOR 
 
The name of your medicine is Topotecan Eagle 15 mg/5 ml concentrate for solution for infusion 
(called Topotecan Eagle in this leaflet). 
 
Topotecan Eagle helps to kill tumour cells. It is a type of chemotherapy. 
 
Topotecan Eagle is used to treat: 
- small cell lung cancer that has come back after chemotherapy 
- advanced cervical cancer when surgery or radiotherapy are not possible. In this case, it is used 

with another medicine called cisplatin. 
 
 
2. BEFORE YOU ARE GIVEN TOPOTECAN EAGLE 
 
You should not receive Topotecan Eagle: 
- if you are allergic (hypersensitive) to topotecan or to any of the other ingredients of this 

medicine listed in Section 6 
- if you are breast-feeding. You should stop breast-feeding before starting treatment with 

Topotecan Eagle 
- if your blood cell count is too low. Your doctor will check this. 
 
Do not use Topotecan Eagle if any of the above apply to you. If you are not sure, talk to your doctor 
or nurse before using this medicine. 
 
Take special care with Topotecan Eagle 
Check with your doctor or nurse before using your medicine: 
- if you have any kidney problems. Your dose of Topotecan Eagle may need to be adjusted.  

This medicine is not recommended if you have severe kidney problems; 
- if you have liver problems. Your dose of Topotecan Eagle may need to be adjusted.  

This medicine is not recommended if you have severe liver problems; 
- if you have lung problems, or if you have had lung problems before from using other medicines 

or radiation. This is because you are more likely to get severe lung problems (interstitial lung 
disease) when using Topotecan Eagle; 

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- if you have unusual bruising or bleeding; 
- if you are feeling very ill. 
 
If any of the above apply to you (or you are not sure), talk to your doctor or nurse before using 
Topotecan Eagle. 
 
Using other medicines 
Please tell your doctor if you are taking or have recently taken any other medicines, including 
medicines obtained without a prescription and herbal medicines. This is because Topotecan Eagle can 
affect the way some other medicines work. Also some other medicines can affect the way Topotecan 
Eagle works. 
 
Pregnancy and breast-feeding 
- Topotecan Eagle should not be used during pregnancy, unless clearly necessary. If you are 

pregnant or think you might be pregnant, tell your doctor immediately. 
- Women who could get pregnant should use contraception to stop them getting pregnant during 

treatment. 
- Men having Topotecan Eagle who wish to father a child should ask their doctor for family 

planning advice. 
- Do not breast-feed while using Topotecan Eagle. 
 
Driving and using machines 
Topotecan Eagle can make you feel tired or weak. If this happens, do not drive or use any tools or 
machines. 
 
 
3. HOW TO USE TOPOTECAN EAGLE 
 
How much you will be given 
Your dose of Topotecan Eagle will depend on: 
- the disease being treated 
- the size of your body (measured in ‘square meters’ or ‘m2’) 
- the results of blood tests before and during treatment 
- how well your body responds to the medicine. 
 
Small cell lung cancer 
- The usual dose is 1.5 mg of the medicine for each square meter of your body. 
- It is given once each day for 5 days. 
- This treatment cycle will normally be repeated every 3 weeks. 
 
Cervical cancer 
- The usual dose is 0.75 mg of the medicine for each square meter of your body. 
- It is given once each day for 3 days. 
- This treatment cycle will normally be repeated every 3 weeks. 
 
For cervical cancer Topotecan Eagle will be used with another medicine called cisplatin. For more 
information about cisplatin, please read its Package Leaflet. 

The experience of using Topotecan Eagle in children is limited. This means that treatment is not 
recommended.  

If you have any further questions on the use of this medicine, ask your doctor or nurse. 

 

How Topotecan Eagle is prepared 
Topotecan Eagle is supplied as a concentrate for solution for infusion. The concentration of topotecan 
is higher (3 mg/ml) than with other topotecan products. The concentrate must be diluted before 
administration. 

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How Topotecan Eagle is given 
Topotecan Eagle is normally given by a doctor or nurse: 
- as a drip (infusion) for about 30 minutes 
- usually into your arm. 
 
 
4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Topotecan Eagle can cause side effects, although not everybody gets them. 
 
How likely these side effects may happen, is as follows: 
- very common affects more than 1 user in 10 
- common affects 1 to 10 users in 100 
- uncommon affects 1 to 10 users in 1,000 
- rare affects 1 to 10 users in 10,000 
- very rare affects less than 1 user in 10,000 
- not known frequency cannot be estimated from the available data. 
 
Serious side effects 
Tell your doctor immediately if you notice any of the following serious side effects. You may need 
urgent medical treatment: 

• Infections (very common) – because Topotecan Eagle may reduce your ability to fight infections. 
The signs include:  

- fever 
- sudden decline of your general health 
- sore throat or burning sensation when passing water 
- severe stomach pain, fever and possibly diarrhoea (rarely with blood in it) - these can be signs 

of bowel inflammation (neutropenic colitis). 

• Lung inflammation (rare), with signs such as: 
- difficulty in breathing 
- cough 
- fever. 
You are more likely to get severe lung problems (interstitial lung disease) if you already have lung 
problems or have had lung problems before from using other medicines or radiation. 
 
Other side effects may include: 
Very common 
- feeling generally weak and tired. These may be signs of a drop in the number of your red blood 

cells (anaemia). In some cases you may need a blood transfusion. 
- unusual bruising or bleeding, sometimes severe. This is caused by a drop in the number of blood 

clotting cells (platelets). 
- abnormally low white blood cell count (neutropenia) which may be accompanied with fever and 

signs of infection (febrile neutropenia) 
- weight loss and loss of appetite, feeling tired or weak 
- feeling or being sick, diarrhoea, stomach pain, constipation 
- inflammation and ulcers of the mouth, throat, tongue or gums (mucositis) 
- high body temperature (fever) 
- infections 
- hair loss. 
 
Common 
- mild allergic reactions (including rash) 
- yellow skin (jaundice) caused by liver problems 
- itching (pruritus) 

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- severe infection (sepsis) 
- feeling unwell (malaise). 
 
Rare 
- severe allergic (anaphylactic) reactions causing swelling of the lips, face or neck leading to 

severe difficulty in breathing, skin rash or hives, anaphylactic shock (a severe reduction in 
blood pressure, paleness, agitation, weak pulse, decreased consciousness) 

- sudden swelling of the skin and mucosa (e.g. throat or tongue) caused by fluid build up 
(angioedema) 

- itchy rash (or hives). 
 
Very rare 
- Mild pain and inflammation at the site of injection due to accidental administration of the 

medicinal product into the surrounding tissue (extravasation) e.g. by leakage. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or nurse. 
 
If you are being treated for cervical cancer, you may get side effects from the other medicine 
(cisplatin) that you will be given along with Topotecan Eagle. 
 
 
5. HOW TO STORE TOPOTECAN EAGLE 
 
Keep out of the sight and reach of children. 
 
Do not use Topotecan Eagle after the expiry date which is stated on the carton and vial after EXP. The 
expiry date refers to the last day of that month. 
 
Do not store above 25°C. 
 
Keep the vial in the outer carton in order to protect from light. 
 
Vials after first opening 
Chemical and physical in-use stability has been demonstrated for 14 days at 20°C - 25°C when stored 
in the outer carton to protect from light. 
From a microbiological point of view, once opened, the product may be stored for a maximum of 
14 days at 20°C - 25°C. Other in-use storage times and conditions are the responsibility of the user. 
 
Diluted solution 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 20°C - 25°C and ambient lighting conditions. 
 
Do not use Topotecan Eagle if you notice any visible particles or if the solution is unclear. 
 
Medicines should not be disposed of via wastewater or household waste. Your doctor should dispose 
of medicines that are no longer required. These measures will help to protect the environment. 
 
 
6. FURTHER INFORMATION 
 
What Topotecan Eagle contains 
- The active substance is topotecan. 
- One ml of concentrate for solution for infusion contains 3 mg topotecan (as hydrochloride). 
 Each 5 ml multi dose vial contains 15 mg of topotecan. 

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56 

- The other ingredients are: hydrochloric acid (E507) (for pH adjustment) and water for 
 injections. 
 

What Topotecan Eagle looks like and contents of the pack 
- Topotecan Eagle is a clear yellow to orange liquid in a colourless glass vial with a butyl rubber 

stopper, aluminium seal and yellow snap-cap and with yellow vial ring collar. 
- Topotecan Eagle is supplied in cartons containing 1 vial. 
 
Marketing Authorisation Holder 
Eagle Laboratories Limited 
The Clock House 
Station Approach 
Marlow, Bucks, SL7 1NT 
United Kingdom 
 
Manufacturer 
MAWDSLEY-BROOKS & COMPANY LIMITED 
Unit 22, Quest Park 
Wheatley Hall Road 
Doncaster, DN2 4LT 
United Kingdom 
 
This leaflet was last approved in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 
__________________________________________________________________________________ 

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http://www.ema.europa.eu/�


57 

The following information is intended for medical or healthcare professionals only: 
 
Instructions on how to dilute, store and dispose of Topotecan Eagle 
 
General precautions 
The concentration of topotecan in Topotecan Eagle differs from other topotecan products and care 
should be taken to ensure appropriate dilution occurs to achieve the intended dose, which should be 
checked prior to administration to the patient. 
 
The normal procedures for proper handling and disposal of anticancer medicinal products should be 
adopted: 
- Staff should be trained to dilute the medicinal product. 
- Pregnant staff should be excluded from working with this medicinal product. 
- Staff handling this medicinal product during dilution 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. 
 
Instructions for dilution 
 
Concentration must be noticed or life-threatening overdose may occur. 
 
Topotecan Eagle concentrate is clear yellow to orange in colour and contains 3 mg/ml of topotecan, 
which is a higher concentration than found in other topotecan products for intravenous infusion. 
 
The user is requested to report any medication errors. 
 
The following dosing tables should be used as reference: 

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58 

 
Instructions for Preparation for Intravenous Administration for Small Cell Lung Cancer 

For recommended dose 
'1.5 mg/m2' 

For reduced dose 
'1.25 mg/m2' 

For reduced dose 
'1.0 mg/m2' Body  

surface area 
(m2) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required  

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required  

(ml) 

Total dose 
(mg) 

1 0.50 1.50 0.42 1.26 0.33 0.99 

1.1 0.55 1.65 0.46 1.38 0.37 1.11 

1.2 0.60 1.80 0.50 1.50 0.40 1.20 

1.3 0.65 1.95 0.54 1.62 0.43 1.29 

1.4 0.70 2.10 0.58 1.74 0.47 1.41 

1.5 0.75 2.25 0.63 1.89 0.50 1.50 

1.6 0.80 2.40 0.67 2.01 0.53 1.59 

1.7 0.85 2.55 0.71 2.13 0.57 1.71 

1.8 0.90 2.70 0.75 2.25 0.60 1.80 

1.9 0.95 2.85 0.79 2.37 0.63 1.89 

2 1.00 3.00 0.83 2.49 0.67 2.01 

2.1 1.05 3.15 0.88 2.64 0.70 2.10 

2.2 1.10 3.30 0.92 2.76 0.73 2.19 

2.3 1.15 3.45 0.96 2.88 0.77 2.31 

2.4 1.20 3.60 1.00 3.00 0.80 2.40 

2.5 1.25 3.75 1.04 3.12 0.83 2.49 
 

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59 

Instructions for Preparation for Intravenous Administration for Cervical Cancer 
For recommended dose  

'0.75 mg/m2' 
For reduced dose  

'0.60 mg/m2' 
For reduced dose  

'0.45 mg/m2' Body 
surface area 

(m2) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

Volume of 
solution 
required 

(ml) 

Total dose 
(mg) 

1 0.25 0.75 0.20 0.60 0.15 0.45 

1.1 0.28 0.84 0.22 0.66 0.17 0.51 

1.2 0.30 0.90 0.24 0.72 0.18 0.54 

1.3 0.33 0.99 0.26 0.78 0.20 0.60 

1.4 0.35 1.05 0.28 0.84 0.21 0.63 

1.5 0.38 1.14 0.30 0.90 0.23 0.69 

1.6 0.40 1.20 0.32 0.96 0.24 0.72 

1.7 0.43 1.29 0.34 1.02 0.26 0.78 

1.8 0.45 1.35 0.36 1.08 0.27 0.81 

1.9 0.48 1.44 0.38 1.14 0.29 0.87 

2 0.50 1.50 0.40 1.20 0.30 0.90 

2.1 0.53 1.59 0.42 1.26 0.32 0.96 

2.2 0.55 1.65 0.44 1.32 0.33 0.99 

2.3 0.58 1.74 0.46 1.38 0.35 1.05 

2.4 0.60 1.80 0.48 1.44 0.36 1.08 

2.5 0.63 1.89 0.50 1.50 0.38 1.14 
 
Further dilution of Topotecan Eagle is required with either sodium chloride 9 mg/ml (0.9 % w/v) 
solution for injection or glucose 50 mg/ml (5 % w/v) solution for injection in order to reach a final 
topotecan concentration of between 25 µg/ml and 50 µg/ml in the solution for infusion to the patient. 
Dilution should be performed under strict aseptic conditions (e.g. an LAF bench). 
 
Storage of the diluted solution 
From a microbiological point of view, the solution should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 20°C - 25°C and ambient lighting conditions. 
 
Vials after first opening 
Chemical and physical in-use stability has been demonstrated for 14 days at 20°C - 25°C when stored 
in the outer carton to protect from light. 
From a microbiological point of view, once opened, the product may be stored for a maximum of 
14 days at 20°C - 25°C. Other in-use storage times and conditions are the responsibility of the user. 
 
Disposal 
Any unused product or waste material should be disposed of in accordance with local requirements. 
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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET