Topotecan Actavis

1 

ANNEX I 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Topotecan Actavis 1 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 1 mg topotecan (as hydrochloride).  
After reconstitution, 1 ml concentrate contains 1 mg topotecan. 
 
Excipient with known effect:  
Each vial contains 0.52 mg (0.0225 mmol) sodium. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
 
Yellow lyophilisate. 
 
 
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 
 
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). 
 
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 

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of each course. If well tolerated, treatment may continue until disease progression (see sections 4.8 
and 5.1).  
 
Subsequent doses 

Topotecan should not be re-administered unless the neutrophil count is ≥ 1 x 109/l, the platelet count 
is ≥ 100 x 109/l, and the haemoglobin level is ≥ 9 g/dl (after transfusion if necessary). 
 
Standard oncology practice for the management of neutropenia is either to administer topotecan with 
other medicinal products (e.g. G-CSF) or to 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. 

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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 Actavis can be given (see sections 5.1 and 5.2). 
 
Method of administration 
 
Topotecan Actavis is for intravenous infusion after reconstitution and dilution. It must be 
reconstituted and further diluted before use (see section 6.6). 
 
Precautions to be taken before handling or administering the medicinal product 
Reconstitution and dilution of the medicinal product must be performed by trained personnel. The 
preparation should be performed in a designated area under aseptic conditions.  
Adequate protective disposable gloves, goggles, gown and mask should be worn. Precautions should 
be taken to avoid the medicinal product accidentally coming into contact with the eyes. In the event of 
contact with the eyes, irrigate with large amounts of water. Then seek medical evaluation by a 
physician. In case of skin contact, thoroughly wash the affected area with large amount of water. 
Always wash hands after removing gloves. See section 6.6. 
 
Pregnant staff should not handle the cytotoxic preparation. 
 
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 

listed in section 6.1 
- 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 
 
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. 

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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). 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. 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-
free’. 
 
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 coadministration 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 5 consecutive days) and cisplatin (60 mg/m2/day on Day 1) were 
administered in 13 patients with ovarian cancer, a slight increase in AUC (12 %, n=9) and 
Cmax (23 %, n=11) was noted on day 5. This increase is considered unlikely to be of clinical relevance. 
 
4.6 Fertility, pregnancy and lactation 
 
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 child bearing 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. 
 

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Breastfeeding 
Topotecan is contraindicated during breast-feeding (see section 4.3). Although it is not known 
whether topotecan is excreted in human breast milk, breast-feeding should be discontinued at the start 
of therapy. 
 
Fertility 
No effects on male or female fertility have been observed in reproductive toxicity studies in rats (see 
section 5.3). However, as with other cytotoxic medicinal products topotecan is genotoxic and effects 
on fertility, including male fertility, cannot be excluded. 
 
4.7 Effects on ability to drive and use machines 
 
No studies 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 
 
Summary of the safety profile 
 
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. 
 
Tabulated list of adverse reactions 
 
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. 
 
Infections and infestations 

Very common: infection 
Common: sepsis1 

 

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

 
Blood and lymphatic system disorders  

Very common:  

 
febrile neutropenia 
neutropenia (see Gastrointestinal disorders below) 
thrombocytopenia 

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anaemia 
leukopenia 
 

Common:  

 

pancytopenia 
 

Not known: severe bleeding (associated with thrombocytopenia) 
 
Immune system disorders 

Common:  

 

hypersensitivity reaction including rash 

Rare: anaphylactic reaction 
angioedema 
urticaria 

 
Metabolism and nutrition disorders 

Very common:  anorexia (which may be severe) 
 
Respiratory, thoracic and mediastinal disorders 

Rare: interstitial lung disease (some cases have been fatal) 
 
Gastrointestinal disorders 

Very common:  

 
nausea, vomiting and diarrhoea (all of which may be severe) 
constipation 
abdominal pain2 
mucositis 
 
2Neutropenic colitis, including fatal neutropenic colitis, has 
been reported to occur as a complication of topotecan-
induced neutropenia (see section 4.4). 

 
Hepatobiliary disorders 

Common:  hyperbilirubinaemia 
 
Skin and subcutaneous tissue disorders 

Very common:  

 
alopecia 
 

Common:  pruritus 
 
General disorders and administration site conditions 

Very common:  

 
pyrexia 
asthenia 
fatigue 
 

Common:  malaise 
 

Very rare:  extravasation3 
 
3Extravasation has been reported very rarely. Reactions have 
been mild and have not generally required specific therapy 

 
The incidence of adverse reactions 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. 

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Description of selected adverse reactions 
 
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. 
 
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. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Overdoses have been reported in patients being treated with intravenous topotecan (up to 10 fold of 
the recommended dose) and topotecan capsules (up to 5 fold of the recommended dose).  The 
observed signs and symptoms for overdose were consistent with the known undesirable events 
associated with topotecan (see section 4.8). The primary complications of overdose are bone marrow 
suppression and mucositis. In addition, elevated hepatic enzymes have been reported with intravenous 
topotecan overdose. 

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There is no known antidote for topotecan overdose. Further management should be as clinically 
indicated or as recommended by the national poisons centre, where available. 
 
 
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)  32.3 25.1 33.0 35.0 
 (95 % CI)  (26.3, 40.9) (21.1, 33.0) (29.1, 42.4) (31.0, 37.1) 
 Hazard ratio (95 % CI) 0.88 (0.59, 1.31) 0.88 (0.7, 1.11) 
Response rate (%) 23.1 14.8 18.3 21.9 
 (95 % CI)  (11.6, 34.5) (5.3, 24.3) (12.2, 24.4) (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)  

14.9 13.1 11.9 14.6 

 (95 % CI)  (8.3, 21.3) (11.6, 18.3) (9.7, 14.1) (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 IV topotecan to cyclophosphamide, doxorubicin 
and vincristine (CAV) in patients with relapsed, sensitive SCLC, the overall response rate was 24.3 % 
for topotecan compared to 18.3 % for the CAV group. Median time to progression was similar in the 
two groups (13.3 weeks and 12.3 weeks respectively). Median survivals for the two groups were 25.0 
and 24.7 weeks respectively. The hazard ratio for survival 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). 
 
Table 2 Study results Study GOG-0179 

 
ITT population 

 Cisplatin 50 mg/m2 d.1 q21 d. Cisplatin 50 mg/m2 d.1 + 
Topotecan 0,75 mg/ 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 

   

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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 a 
hazard ratio of 0.75 (0.49, 1.16). 
 
Paediatric population 

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

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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 IV dose. Approximately 51 % was excreted as total topotecan and 3 % 
was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted 
for 18 % while faecal elimination of N-desmethyl topotecan was 1.7 %. Overall, the N-desmethyl 
metabolite contributed a mean of 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). 
 
Paediatrics 

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. 
 
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. 
 

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6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol (E421) 
Tartaric acid (E334) 
Sodium hydroxide 
Hydrochloric acid (E507) 
 
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 
 
Vials 

3 years. 
 
Reconstituted and diluted solutions 

Chemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C, in 
normal light conditions and 24 hours at 2°C to 8°C, protected from light. 
 
Chemical and physical stability of the solution obtained after dilution of the concentrate in sodium 
chloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %) glucose solution for infusion has 
been demonstrated for 4 hours at 25 ± 2°C, in normal lighting conditions. The concentrates tested  
were stored at 25 ± 2°C  for 12 hours and 24 hours respectively after reconstitution, and then diluted.  
 
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 2°C to 8°C, unless reconstitution/dilution has taken 
place in controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Type I colourless glass vial (5 ml) with grey bromobutylic stopper and aluminium seal with plastic 
flip-off cap containing 1 mg topotecan. Each vial is sheathed in a protective sleeve. 
 
Topotecan Actavis is available in cartons containing 1 vial and 5 vials. Not all pack sizes may be 
marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Topotecan Actavis 1 mg vials must be reconstituted with 1.1 ml water for injections. The clear 
concentrate is pale yellow in colour and provides 1 mg per ml of topotecan, as Topotecan Actavis 
1 mg contains a 10 % overage of fill. Further dilution of the appropriate volume of the reconstituted 
solution with either sodium chloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %) glucose 
solution for infusion is required to a final concentration of between 25 and 50 microgram/ml. 
 

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The normal procedures for proper handling and disposal of anticancer medicinal products should be 
adopted, namely: 
1. Reconstitution and dilution of the medicinal product must be performed by trained personnel. 
2. The preparation should be performed in a designated area under aseptic conditions. 
3. Adequate protective disposable gloves, goggles, gown and mask should be worn. 
4. Precautions should be taken to avoid the medicinal product accidentally coming into contact 

with the eyes. In the event of contact with the eyes, irrigate with large amounts of water. Then 
seek medical evaluation by a physician. 

5. In case of skin contact, thoroughly wash the affected area with large amount of water. Always 
wash hands after removing gloves. 

6. Pregnant staff should not handle the cytotoxic preparation. 
7. Adequate care and precautions should be taken in the disposal of items (syringes, needles etc) 

used to reconstitute and/or dilute cytotoxic medicinal products. Any unused product or waste 
material should be disposed of in accordance with local requirements. 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.  

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. 
Reykjavíkurvegi 76-78 
IS-220 Hafnarfjörður 
Iceland 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/536/001 
EU/1/09/536/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 24 July 2009 
Date of latest renewal: 6 June 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/. 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Topotecan Actavis 4 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 4 mg topotecan (as hydrochloride). 
After reconstitution, 1 ml concentrate contains 1 mg topotecan. 
 
Excipient with known effect:  
Each vial contains 2.07 mg (0.09 mmol) sodium. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
 
Yellow lyophilisate. 
 
 
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 
 
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). 
 
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 

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of each course. If well tolerated, treatment may continue until disease progression (see sections 4.8 
and 5.1).  
 
Subsequent doses 

Topotecan should not be re-administered unless the neutrophil count is ≥ 1 x 109/l, the platelet count 
is ≥ 100 x 109/l, and the haemoglobin level is ≥ 9 g/dl (after transfusion if necessary). 
 
Standard oncology practice for the management of neutropenia is either to administer topotecan with 
other medicinal products (e.g. G-CSF) or to 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. 

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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 Actavis can be given (see sections 5.1 and 5.2). 
 
Method of administration 
 
Topotecan Actavis is for intravenous infusion after reconstitution and dilution. It must be 
reconstituted and further diluted before use (see section 6.6). 
 
Precautions to be taken before handling or administering the medicinal product 
Reconstitution and dilution of the medicinal product must be performed by trained personnel. The 
preparation should be performed in a designated area under aseptic conditions.  
Adequate protective disposable gloves, goggles, gown and mask should be worn. Precautions should 
be taken to avoid the medicinal product accidentally coming into contact with the eyes. In the event of 
contact with the eyes, irrigate with large amounts of water. Then seek medical evaluation by a 
physician. In case of skin contact, thoroughly wash the affected area with large amount of water. 
Always wash hands after removing gloves. See section 6.6. 
 
Pregnant staff should not handle the cytotoxic preparation. 
 
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 

listed in section 6.1 
- 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 
 
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. 

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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). 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. 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-
free’. 
 
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 coadministration 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 5 consecutive days) and cisplatin (60 mg/m2/day on Day 1) were 
administered in 13 patients with ovarian cancer, a slight increase in AUC (12 %, n=9) and 
Cmax (23 %, n=11) was noted on day 5. This increase is considered unlikely to be of clinical relevance. 
 
4.6 Fertility, pregnancy and lactation 
 
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 child bearing 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. 
 

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Breastfeeding 
Topotecan is contraindicated during breast-feeding (see section 4.3). Although it is not known 
whether topotecan is excreted in human breast milk, breast-feeding should be discontinued at the start 
of therapy. 
 
Fertility 
No effects on male or female fertility have been observed in reproductive toxicity studies in rats (see 
section 5.3). However, as with other cytotoxic medicinal products topotecan is genotoxic and effects 
on fertility, including male fertility, cannot be excluded. 
 
4.7 Effects on ability to drive and use machines 
 
No studies 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 
 
Summary of the safety profile 
 
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. 
 
Tabulated list of adverse reactions 
 
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. 
 
Infections and infestations 

Very common: infection 
Common: sepsis1 

 

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

 
Blood and lymphatic system disorders  

Very common:  

 
febrile neutropenia 
neutropenia (see Gastrointestinal disorders below) 
thrombocytopenia 

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anaemia 
leukopenia 
 

Common:  

 
pancytopenia 
 

Not known:  severe bleeding (associated with thrombocytopenia) 
 
Immune system disorders 

Common:  

 

hypersensitivity reaction including rash 

Rare: anaphylactic reaction 
angioedema 
urticaria 

 
Metabolism and nutrition disorders 

Very common:  anorexia (which may be severe) 
 
Respiratory, thoracic and mediastinal disorders 

Rare: interstitial lung disease (some cases have been fatal) 
 
Gastrointestinal disorders 

Very common:  

 
nausea, vomiting and diarrhoea (all of which may be severe), 
constipation 
abdominal pain2 
mucositis 
 
2Neutropenic colitis, including fatal neutropenic colitis, has 
been reported to occur as a complication of topotecan-
induced neutropenia (see section 4.4). 

 
Hepatobiliary disorders 

Common:  hyperbilirubinaemia 
 
Skin and subcutaneous tissue disorders 

Very common:  

 
alopecia 
 

Common:  pruritus 
 
General disorders and administration site conditions 

Very common:  

 
pyrexia 
asthenia 
fatigue 
 

Common:  malaise 
 

Very rare:  extravasation3 
 
3Extravasation has been reported very rarely. Reactions have 
been mild and have not generally required specific therapy 

 
The incidence of adverse reactions 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. 

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Description of selected adverse reactions 
 
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. 
 
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. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Overdoses have been reported in patients being treated with intravenous topotecan (up to 10 fold of 
the recommended dose) and topotecan capsules (up to 5 fold of the recommended dose).   The 
observed signs and symptoms for overdose were consistent with the known undesirable events 
associated with topotecan (see section 4.8). The primary complications of overdose are bone marrow 
suppression and mucositis. In addition, elevated hepatic enzymes have been reported with intravenous 
topotecan overdose. 

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There is no known antidote for topotecan overdose. Further management should be as clinically 
indicated or as recommended by the national poisons centre, where available. 
 
 
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)  32.3 25.1 33.0 35.0 
 (95 % CI)  (26.3, 40.9) (21.1, 33.0) (29.1, 42.4) (31.0, 37.1) 
 Hazard ratio (95 % CI) 0.88 (0.59, 1.31) 0.88 (0.7, 1.11) 
Response rate (%) 23.1 14.8 18.3 21.9 
 (95 % CI)  (11.6, 34.5) (5.3, 24.3) (12.2, 24.4) (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)  

14.9 13.1 11.9 14.6 

 (95 % CI)  (8.3, 21.3) (11.6, 18.3) (9.7, 14.1) (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 IV topotecan to cyclophosphamide, doxorubicin 
and vincristine (CAV) in patients with relapsed, sensitive SCLC, the overall response rate was 24.3 % 
for topotecan compared to 18.3 % for the CAV group. Median time to progression was similar in the 
two groups (13.3 weeks and 12.3 weeks respectively). Median survivals for the two groups were 25.0 
and 24.7 weeks respectively. The hazard ratio for survival 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). 
 
Table 2 Study results Study GOG-0179 

 
ITT population 

 Cisplatin 50 mg/m2 d.1 q21 d. Cisplatin 50 mg/m2 d.1 + 
Topotecan 0,75 mg/ 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 

   

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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 a 
hazard ratio of 0.75 (0.49, 1.16). 
 
Paediatric population 

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

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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 IV dose. Approximately 51 % was excreted as total topotecan and 3 % 
was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted 
for 18 % while faecal elimination of N-desmethyl topotecan was 1.7 %. Overall, the N-desmethyl 
metabolite contributed a mean of 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). 
 
Paediatrics 

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. 
 
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. 
 

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6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol (E421) 
Tartaric acid (E334) 
Sodium hydroxide 
Hydrochloric acid (E507) 
 
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 
 
Vials 

3 years. 
 
Reconstituted and diluted solutions 

Chemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C, in 
normal light conditions and 24 hours at 2°C to 8°C, protected from light. 
 
Chemical and physical stability of the solution obtained after dilution of the concentrate in sodium 
chloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %) glucose solution for infusion has 
been demonstrated for 4 hours at 25 ± 2°C, in normal lighting conditions. The concentrates tested  
were stored at 25 ± 2°C  for 12 hours and 24 hours respectively after reconstitution, and then diluted.  
 
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 2°C to 8°C, unless reconstitution/dilution has taken 
place in controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Type I colourless glass vial (8 ml), with grey bromobutylic stopper and aluminium seal with plastic 
flip-off cap containing 4 mg topotecan. Each vial is sheathed in a protective sleeve. 
 
Topotecan Actavis is available in cartons containing 1 vial and 5 vials. Not all pack sizes may be 
marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Topotecan Actavis 4 mg vials must be reconstituted with 4 ml water for injections. The clear 
concentrate is pale yellow in colour and provides 1 mg per ml of topotecan. Further dilution of the 
appropriate volume of the reconstituted solution with either sodium chloride 9 mg/ml (0.9 %) solution 
for injection or 50 mg/ml (5 %) glucose solution for infusion is required to a final concentration of 
between 25 and 50 microgram/ml. 
 

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The normal procedures for proper handling and disposal of anticancer medicinal products should be 
adopted, namely: 
1. Reconstitution and dilution of the medicinal product must be performed by trained personnel. 
2. The preparation should be performed in a designated area under aseptic conditions. 
3. Adequate protective disposable gloves, goggles, gown and mask should be worn. 
4. Precautions should be taken to avoid the medicinal product accidentally coming into contact 

with the eyes. In the event of contact with the eyes, irrigate with large amounts of water. Then 
seek medical evaluation by a physician. 

5. In case of skin contact, thoroughly wash the affected area with large amount of water. Always 
wash hands after removing gloves. 

6. Pregnant staff should not handle the cytotoxic preparation. 
7. Adequate care and precautions should be taken in the disposal of items (syringes, needles etc) 

used to reconstitute and/or dilute cytotoxic medicinal products. Any unused product or waste 
material should be disposed of in accordance with local requirements. 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.  

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. 
Reykjavíkurvegi 76-78 
IS-220 Hafnarfjörður 
Iceland 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/536/002 
EU/1/09/536/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 24 July 2009 
Date of latest renewal: 6 June 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/. 
 

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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 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 
SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 

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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
S.C. Sindan-Pharma S.R.L. 
11 Ion Mihalache Blvd. 
011171 Bucharest 
Romania 
 
 
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 
 
 Periodic Safety Update Reports 
 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
 Risk Management Plan (RMP) 

 
Not applicable.

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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Topotecan Actavis 1 mg powder for concentrate for solution for infusion 
topotecan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 1 mg topotecan (as hydrochloride). 
After reconstitution, 1 ml concentrate contains 1 mg topotecan. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains mannitol (E421), tartaric acid (E334), hydrochloric acid (E507) and sodium hydroxide. See 
leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion. 
1 x 1 mg vial 
5 x 1 mg vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous use as infusion, after reconstitution and dilution. 
 
 
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, special handling instructions (see package leaflet). 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 

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9. SPECIAL STORAGE CONDITIONS 
 
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 
 
Actavis Group PTC ehf. 
Hafnarfjörður 
Iceland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/536/001 
EU/1/09/536/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
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 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Topotecan Actavis 1 mg powder for concentrate for solution for infusion 
topotecan 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use.  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 mg 
 
 
6. OTHER 
 
Cytotoxic 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Topotecan Actavis 4 mg powder for concentrate for solution for infusion 
topotecan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 4 mg topotecan (as hydrochloride). 
After reconstitution, 1 ml concentrate contains 1 mg topotecan. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains mannitol (E421), tartaric acid (E334), hydrochloric acid (E507) and sodium hydroxide. See 
leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion. 
1 x 4 mg vial 
5 x 4 mg vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 

Read the package leaflet before use. 
For intravenous use as infusion, after reconstitution and dilution. 
 
 
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, special handling instructions (see package leaflet). 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 

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9. SPECIAL STORAGE CONDITIONS 
 
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 
 
Actavis Group PTC ehf. 
Hafnarfjörður 
Iceland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/536/002 
EU/1/09/536/004 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
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 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Topotecan Actavis 4 mg powder for concentrate for solution for infusion 
topotecan 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use.  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
4 mg 
 
 
6. OTHER 
 
Cytotoxic 

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B. PACKAGE LEAFLET 
 

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Package leaflet: Information for the user 
 

Topotecan Actavis 1 mg powder for concentrate for solution for infusion 
Topotecan Actavis 4 mg powder for concentrate for solution for infusion 

topotecan 
 

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or nurse. 
- If  you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet:  
1. What Topotecan Actavis is and what it is used for 
2. What you need to know before you use Topotecan Actavis 
3. How to use Topotecan Actavis 
4. Possible side effects 
5. How to store Topotecan Actavis 
6. Contents of the pack and other information 
 
 
1. What Topotecan Actavis is and what it is used for 
 
Topotecan Actavis contains the active substance topotecan which helps to kill tumour cells.  
 
Topotecan Actavis is used to treat: 
- small cell lung cancer that has come back after chemotherapy, or 
- advanced cervical cancer if surgery or radiotherapy is not possible. In this case Topotecan 

Actavis treatment is combined with medicines containing cisplatin.  
 
 
2. What you need to know before you use Topotecan Actavis 
 
Do not use Topotecan Actavis 
- if you are allergic to topotecan or 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 Actavis; 
- if your blood cell counts are too low.  
Tell you doctor if you think any of these could apply to you. 
 
Warnings and precautions 
Talk to your doctor before using Topotecan Actavis:  
- if you have any kidney problems. Your dose of Topotecan Actavis may need to be adjusted. 

Topotecan Actavis is not recommended in case of severe kidney impairment; 
- if you have liver problems. Topotecan Actavis is not recommended in case of severe liver 

impairment; 
- if you suffer from lung inflammation with signs such as cough, fever and difficulties in 

breathing, see also section 4 “Possible side effects”. 
 
Topotecan Actavis may cause a decrease in the number of blood clotting cells (platelets). This can 
lead to severe bleeding from relatively small injuries such as a small cut. Rarely, it can lead to more 
severe bleeding (haemorrhage). Talk to your doctor for advice on how to minimize the risk of 
bleeding. 
 

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The incidence of side effects is more frequent in patients who are in poor general health. The doctor 
will evaluate your general health during the treatment and you should tell him/her in case you have 
fever, infection or are in some ways feeling unwell. 
 
Use in children and adolescents 
The experience in children and adolescents is limited and treatment is therefore not recommended. 
 
Other medicines and Topotecan Actavis 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
Pregnancy and breast-feeding 
Topotecan Actavis should not be used in pregnant women, unless clearly necessary. If you are or 
think you might be pregnant, tell your doctor immediately. 
 
Effective contraception methods should be used to avoid becoming pregnant/fathering a child while 
on treatment. Ask your doctor for advice. 
 
Patients who are concerned about their fertility should ask their doctor for counselling on fertility and 
family planning options prior to starting treatment. 
 
You must not breast-feed while on treatment with Topotecan Actavis.  
 
Driving and using machines 
Topotecan Actavis can make you feel tired or weak. If you experience this, do not drive or use 
machines. 
 
Topotecan Actavis contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-free’. 
 
 
3. How to use Topotecan Actavis 
 
Your dose of Topotecan Actavis will depend on: 
- the disease being treated, 
- your body surface area (m2), 
- the results of blood tests carried out before and during treatment, 
- how well you tolerate treatment. 
 
Adults 

Small cell lung cancer 

The usual dose is 1.5 mg per m2 of body surface area once daily for 5 days. This treatment cycle will 
normally be repeated every three weeks. 
 
Cervical cancer 

The usual dose is 0.75 mg per m2 of body surface area once daily for 3 days. This treatment cycle will 
normally be repeated every three weeks. 
For cervical cancer, it will be used together with another anticancer medicines containing cisplatin. 
For more information about cisplatin, please refer to the corresponding package leaflet. 
 
Patients with impaired kidney function 

Your doctor might need to reduce your dose based on your kidney function. 
 
How Topotecan Actavis is prepared 
Topotecan is supplied as a powder for concentrate for solution for infusion. The powder must be 
dissolved, and the resulting concentrate further diluted before administration. 
 

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How Topotecan Actavis is given 
A doctor or nurse will give you the reconstituted and diluted Topotecan Actavis solution as an 
infusion (drip), usually into your arm, over about 30 minutes. 
 
If you are given too much Topotecan Actavis 
As this medicine is being given by your doctor or nurse, it is unlikely that you will be given too much. 
In the unlikely event of an overdose, your doctor will monitor you for side effects. Tell your doctor or 
nurse if you have any concerns about the amount of medicine that you receive. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
You must tell your doctor immediately if you experience any of the following serious side effects. 
They may require hospitalisation and could even be life-threatening. 
 
- Infections (very common; may affect more than 1 in 10 people), with signs such as: 

- fever 
- serious decline of your general condition 
- local symptoms, such as sore throat or burning sensation when urinating 
- severe stomach pain, fever and possibly diarrhoea (rarely with blood) can be signs of bowel 

inflammation (neutropenic colitis) 
Topotecan Actavis may reduce your ability to fight infections. 
 
- Lung inflammation (rare; may affect up to 1 in 1,000 people), with signs such as: 

- difficulty in breathing 
- cough 
- fever 

The risk of developing this severe condition (interstitial lung disease) is higher if you currently have 
lung problems, or if you have received previous radiation treatment or medicines that affected your 
lungs, see also section 2 “Warnings and precautions”.This condition can be fatal. 
 
- Severe allergic (anaphylactic) reactions (rare; may affect up to 1 in 1,000 people), with signs 

such as: 
- swelling of the face, lips, tongue or throat, difficulty breathing, low blood pressure, 

dizziness and itchy rash. 
 
Other side effects with Topotecan Actavis include: 
 
Very common side effects (may affect more than 1 in 10 people) 
- Feeling generally weak and tired, which can be symptoms of a decrease in the number of red 

blood cells (anaemia). In some cases you may need a blood transfusion. 
- Decrese in number of circulating white blood cells (leucotyes) in the blood. Abnormal low 

number of neutrophil granulocytes (a type of white blood cell) in the blood, with or without 
fever. 

- Unusual bruising or bleeding, sometimes severe, caused by a decrease in the number of blood 
clotting cells (platelets). 

- Weight loss and loss of appetite (anorexia); tiredness; weakness. 
- Feeling sick (nausea), vomiting; diarrhoea; stomach pain; constipation. 
- Inflammation of the lining of the mouth and digestive tract. 
- Fever. 
- Infections. 
- Hair loss. 
 

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Common side effects (may affect up to 1 in 10 people) 
- Allergic (hypersensitivity) reactions (including rash). 
- Abnormal high level of bilirubin, a waste product produced by the liver during breakdown of 

red blood cells. Symptoms may include yellow skin (jaundice). 
- Decrease in the number of all blood cells (pancytopenia) 
- Feeling unwell. 
- Serious blood infection, which can be fatal. 
- Itching (pruritus). 
 
Rare side effects (may affect up to 1 in 1,000 people) 
- Swelling caused by fluid build-up (angioedema) e.g. around the eyes and lips as well as hands, 

feet and throat. If severe it may cause breathing difficulties. 
- Itchy rash (or hives). 
 
Very rare side effects (may affect up to 1 in 10,000 people) 
- 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 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 Actavis.  
 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Topotecan Actavis  
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the vial and carton. 
 
Keep the vial in the outer carton in order to protect from light. 
 
Storage after reconstitution and dilution 
Chemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C, in 
normal light conditions and 24 hours at 2°C to 8°C, protected from light. 
 
The physico-chemical stability of the drug product solution obtained after dilution in solutions for 
infusion (NaCl 0.9 % and Glucose 5 %) has been demonstrated for 4 hours at room temperature, in 
normal lighting conditions, on samples reconstituted and stored for 12 hours and respectively 
24 hours at 25oC ± 2oC and then diluted. 
 
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 2°C to 8°C, unless reconstitution/dilution has taken 
place in controlled and validated aseptic conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 

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What Topotecan Actavis contains 
- The active substance is topotecan. Each vial contains 1 mg or 4 mg topotecan (as 

hydrochloride). After reconstitution 1 ml concentrate contains 1 mg topotecan.  
- The other ingredients are: mannitol (E421), tartaric acid (E334), hydrochloric acid (E507) and 

sodium hydroxide. 
 
What Topotecan Actavis looks like and contents of the pack 
Topotecan Actavis is supplied in type I colourless glass vials with grey bromobutylic stopper and 
aluminium seals with plastic flip-off caps. Each vial is sheathed in a protective sleeve. 
 
Packs:  

1 x 1 mg vial; 5 x 1 mg vial 
1 x 4 mg vial; 5 x 4 mg vial 
 
Marketing Authorisation Holder  
Actavis Group PTC ehf. 
Reykjavíkurvegi 76-78 
Hafnarfjörður 
Iceland 
 
Manufacturer 
S.C. Sindan-Pharma S.R.L. 
11 Ion Mihalache Blvd 
Bucharest 
Romania 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
ALL-in-1 bvba 
Tél/Tel: +32 3 451 26 88 

Lietuva 
UAB “Actavis Baltics” 
Tel: +370 5 260 9615 
 

България 
Актавис ЕАД 
Teл.: +359 2 9321 680 

Luxembourg/Luxemburg 
ALL-in-1 bvba 
Belgique/Belgien 
Tél/Tel: +32 3 451 26 88 
 

Česká republika 
Actavis CZ a.s. 
Tel: +420 251 113 002 
 

Magyarország 
Actavis Hungary Kft. 
Tel.: +36 1 501 7001 

Danmark 
Actavis A/S 
Tlf: +45 72 22 30 00 
 

Malta 
Actavis Ltd. 
Tel: +35621693533 

Deutschland 
Actavis Deutschland GmbH & Co. KG 
Telefon: +49 (0)89 558909 0 

Nederland 
Actavis B.V. 
Tel: +31 35 54 299 33 
 

Eesti 
UAB “Actavis Baltics” Eesti Filiaal 
Tel: +372 6100 565 
 

Norge 
Actavis Norway AS 
Tlf: +47 815 22 099 
 

Ελλάδα 
Specifar ABEE 

Österreich 
Actavis GmbH 

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Τηλ: +30 210 5401500 
 

Tel: +43 (0)662 435 235 00 
 

España 
Actavis Spain, S.A. 
Tfno.: +34 91 630 86 45 
 

Polska 
Actavis Export Int. Ltd., Malta.  
Kontakt w Polsce: 
Tel.: (+48 22) 512 29 00 
 

France 
Actavis France 
Tél: +33 4 72 72 60 72 
 

Portugal 
Aurovitas, Unipessoal, Lda 
Tel: +351 214 185 104 
 

Hrvatska 
Agmar d.o.o.  
Tel: +385(1)6610-333 
 

România 
Actavis SRL 
Tel: +40 21 318 17 77 
 

Ireland 
Actavis Ireland Limited 
Tel: +353 (0)21 4619040 
 

Slovenija 
Apta Medica Internacional d.o.o. 
Tel: +386 51 615 015 
 

Ísland 
Actavis Group PTC ehf. 
Sími: +354 550 3300 
 

Slovenská republika 
Actavis s.r.o. 
Tel: +421 2 3255 3800 
 

Italia 
Aurobindo Pharma (Italia) s.r.l. 
Tel: +39 0296392601 
 

Suomi/Finland 
Actavis Oy 
Puh/Tel: +358 (0)9 348 233 
 

Κύπρος 
A. Potamitis Medicare Ltd 
Τηλ: +357 22583333 
 

Sverige 
Actavis AB 
Tel: +46 8 13 63 70 
 

Latvija 
Actavis Baltics pārstāvniecība Latvijā 
Tel: +371 67067873 
 

United Kingdom 
Actavis UK Limited 
Tel: +44 1271 385257 
 

 
 
This leaflet was last revised in {MM/YYYY}. 
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. 
 
-------------------------------------------------------------------------------------------------------------------------- 
The following information is intended for healthcare professionals only: 
 
 

Topotecan Actavis 
 

INSTRUCTIONS ON USE 
 

 
Guidelines for the safe handling and disposal of antineoplastic agents 
 
1. Reconstitution and dilution of the medicinal product must be performed by trained personnel. 
2. The preparation should be performed in a designated area under aseptic conditions. 

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3. Adequate protective disposable gloves, goggles, gown and mask should be worn. 
4. Precautions should be taken to avoid the medicinal product accidentally coming into contact 

with the eyes. In the event of contact with the eyes, irrigate with large amounts of water. Then 
seek medical evaluation by a physician. 

5. In case of skin contact, thoroughly wash the affected area with large amount of water. Always 
wash hands after removing gloves. 

6. Pregnant staff should not handle the cytotoxic preparation. 
7. Adequate care and precautions should be taken in the disposal of items (syringes, needles etc) 

used to reconstitute and/or dilute cytotoxic medicinal products. Any unused product or waste 
material should be disposed of in accordance with local requirements. 

 
 
Reconstitution and dilution prior to administration 
 
Before infusion, Topotecan Actavis powder for concentrate for solution for infusion must be 
reconstituted with an appropriate volume of water for injections, as follows: 
 
- Topotecan Actavis 1 mg with 1.1 ml water for injections (as it contains 10 % overage of fill) 
- Topotecan Actavis 4 mg with 4 ml water for injections 
 
Reconstitution will result in a concentrate containing 1 mg topotecan per ml.  
This concentrate (1 mg/ml) must be diluted prior to administration. 
 
The volume of reconstituted concentrate corresponding to the calculated individual dose, should be 
further diluted with either sodium chloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %) 
glucose solution for infusion, to a final concentration of between 25 and 50 microgram per ml in the 
solution for infusion, for example: 
 
 Volume for 

25 microgram/ml solution 
Volume for  
50 microgram/ml solution 

1 ml of 1 mg/ml topotecan solution Add 39 ml to give 40 ml Add 19 ml to give 20 ml 
4 ml of 1 mg/ml topotecan solution Add 156 ml to give 160 ml Add 76 ml to give 80 ml 

 
 
Storage after reconstitution and dilution  
Chemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C, in 
normal light conditions and 24 hours at 2°C to 8°C, protected from light. 
 
Chemical and physical stability of the solution obtained after dilution of the concentrate in sodium 
chloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %) glucose solution for infusion has 
been demonstrated for 4 hours at 25 ± 2°C, in normal lighting conditions .The concentrates tested 
were reconstituted and stored at 25 ± 2°C for 12 hours and 24 hours respectively after reconstitution, 
and then diluted.  
 
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 2°C to 8°C, unless reconstitution/dilution has taken 
place in controlled and validated aseptic conditions. 
 
 
Disposal  
Any unused product or waste material should be disposed of in accordance with local requirements. 
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.  
 

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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
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET