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TOPOTECAN FAIR-MED HEALTHCARE 1 MG/ML POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance(s): TOPOTECAN HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Topotecan Fair-Med Healthcare 1 mg/ml powder for concentrate for solution for
infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
1ml of concentrate for infusion contains 1 mg topotecan (as hydrochloride).
1 mg vial: Each vial contains 1 mg topotecan for reconstitution in 1ml of solvent
4 mg vial: Each vial contains 4 mg topotecan for reconstitution in 4 ml of solvent
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion.
Light yellow to greenish powder.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Topotecan monotherapy is indicated for the treatment of:



patients with metastatic carcinoma of the ovary after failure of first-line or
subsequent therapy.
patients with relapsed small cell lung cancer (SCLC) for whom re-treatment
with the first-line regimen is not considered appropriate (see section 5.1).

Topotecan in combination with cisplatin is indicated for patients with carcinoma of
the cervix recurrent after radiotherapy and for patients with Stage IVB disease.
Patients with prior exposure to cisplatin require a sustained treatment free interval to
justify treatment with the combination (see section 5.1)

1

4.2

Posology and method of administration
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).
Topotecan must be reconstituted and further diluted before use (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).

Ovarian and Small Cell Lung Carcinoma
Initial dose
The recommended dose of topotecan is 1.5 mg/m2 body surface area/day administered
by intravenous infusion over 30 minutes daily for five consecutive days with a three
week interval between the start of each course. If well tolerated, treatment may
continue until disease progression (see sections 4.8 and 5.1).
Subsequent doses
Topotecan should not be re-administered unless the neutrophil count is ≥ 1 x 109/l, the
platelet count is ≥ 100 x 109/l, and the haemoglobin level is ≥ 9 g/dl (after transfusion
if necessary). Standard oncology practice for the management of neutropenia is either
to administer topotecan with other medications (e.g. G-CSF) or to dose reduce to
maintain neutrophil counts.
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil
count < 0.5 x 109/l) for seven days or more, or severe neutropenia associated with
fever or infection, or who have had treatment delayed due to neutropenia, the dose
should be reduced by 0.25 mg/m2/day to 1.25 mg/m2/day (or subsequently down to
1.0 mg/m2/day if necessary). Doses should be similarly reduced if the platelet count
falls below 25 x 109/l. In clinical trials, topotecan was discontinued if the dose had

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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 9g/dl (after transfusion if necessary).
Standard oncology practice for the management of neutropenia is either to administer
topotecan with other medications (e.g. G-CSF) or to dose reduce to maintain
neutrophil counts.
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil
count less than 0.5 x 109/l) for seven days or more, or severe neutropenia associated
with fever or infection or who have had treatment delayed due to neutropenia, the
dose should be reduced by 20 % to 0.60 mg/m2/day for subsequent courses (or
subsequently down to 0.45 mg/m2/day if necessary).
Doses should be similarly reduced if the platelet count falls below 25 x 109/l.
Dosage in renally impaired patients
Monotherapy (Ovarian and 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 ovarian or small cell lung carcinoma and a
creatinine clearance between 20 and 39 ml/min is 0.75 mg/m2 /day for five
consecutive days.
Combination therapy (Cervical carcinoma)
In clinical studies with topotecan in combination with cisplatin for the treatment of
cervical cancer, therapy was only initiated in patients with serum creatinine less than
or equal to 1.5 mg/dl. If, during topotecan/cisplatin combination therapy serum
creatinine exceeds 1.5 mg/dl, it is recommended that the full prescribing information

3

be consulted for any advice on cisplatin dose reduction/continuation. If cisplatin is
discontinued, there are insufficient data regarding continuing monotherapy with
topotecan in patients with cervical cancer.
Paediatric population
The experience in children is limited, therefore no recommendation for treatment of
paediatric patients with Topotecan 1 mg/ml powder for concentrate for infusion can
be given (see sections 5.1 and 5.2).

4.3

Contraindications
Topotecan 1 mg/ml powder for concentrate for infusion is contraindicated in patients
who:
− have a history of severe hypersensitivity to the active substance or to any of the
excipients
− are breast feeding (see section 4.6)
− already have severe bone marrow depression prior to starting first course, as
evidenced by baseline neutrophils < 1.5 x 109/l and/or a platelet count of < 100 x
109/l.

4.4

Special warnings and precautions for use
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 drugs and/or colony stimulating factors.
Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough,
fever, dyspnoea and/or hypoxia), and topotecan should be discontinued if a new
diagnosis of ILD is confirmed.
Topotecan monotherapy and topotecan in combination with cisplatin are commonly
associated with clinically relevant thrombocytopenia. This should be taken into
account when prescribing Topotecan, e.g. in case patients at increased risk of tumour
bleeds are considered for therapy.
As expected, patients with poor performance status (PS>1) have a lower response rate
and an increased incidence of complications such as fever, infection and sepsis (see
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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.

4.5

Interaction with other medicinal products and other forms of interaction
No in vivo human pharmacokinetic interaction studies have been performed.
Topotecan does not inhibit human P450 enzymes (see section 5.2). In an intravenous
population study, the co-administration of granisetron, ondansetron, morphine or
corticosteroids did not appear to have a significant effect on the pharmacokinetics of
total topotecan (active and inactive form).
In combining topotecan with other chemotherapy agents, reduction of the doses of
each medicinal product may be required to improve tolerability. However, in
combining with platinum agents, there is a distinct sequence-dependent interaction
depending on whether the platinum agent is given on day 1 or 5 of the topotecan
dosing. If either cisplatin or carboplatin is given on day 1 of the topotecan dosing, a
lower dose of each agent must be given to improve tolerability compared to the dose
of each agent which can be given if the platinum agent is given on day 5 of the
topotecan dosing.
When topotecan (0.75 mg/m2/day for 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 contra-indicated during breast-feeding (see section 4.3). Although it is
not known whether topotecan is excreted in human breast milk, breast-feeding should
be discontinued at the start of therapy.
Fertility
No effects on male or female fertility have been observed in reproductive toxicity
studies in rats (see section 5.3). However, as with other cytotoxic medicinal products
topotecan is genotoxic and effects on fertility, including male fertility, cannot be
excluded.

4.7

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

4.8

Undesirable effects
In dose-finding trials involving 523 patients with relapsed ovarian cancer and 631
patients with relapsed small cell lung cancer, the dose limiting toxicity of topotecan
monotherapy was found to be haematological. Toxicity was predictable and
reversible. There were no signs of cumulative haematological or non-haematological
toxicity.
The adverse event profile for topotecan when given in combination with cisplatin in
the cervical cancer clinical trials is consistent with that seen with topotecan
monotherapy. The overall haematological toxicity is lower in patients treated with
topotecan in combination with cisplatin compared to topotecan monotherapy, but
higher than with cisplatin alone.
Additional adverse events were seen when topotecan was given in combination with
cisplatin, however, these events were seen with cisplatin monotherapy and not
attributable to topotecan. The prescribing information for cisplatin should be
consulted for a full list of adverse events associated cisplatin use.
The integrated safety data for topotecan monotherapy are presented below.
Adverse reactions are listed below, by system organ class and absolute frequency (all
reported events).
Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10);
uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (<
1/10,000), including isolated reports and not known (cannot be estimated from the
available data).
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
Blood and lymphatic system disorders
Very common: febrile neutropenia, neutropenia (see Gastrointestinal disorders),
thrombocytopenia, anaemia, leucopenia

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Common: pancytopenia
Not known: severe bleeding (associated with thrombocytopenia)
Respiratory, thoracic and mediastinal disorders
Rare: interstitial lung disease (some cases have been fatal)
Gastrointestinal disorders
Very common: nausea, vomiting and diarrhoea (all of which may be severe),
constipation, abdominal pain1, mucositis
1

Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as
a complication of topotecan-induced neutropenia (see section 4.4)
Skin and subcutaneous tissue disorders
Very common: alopecia
Common: pruritus
Metabolism and nutrition disorders
Very common: anorexia (which may be severe)
Infections and infestations
Very common: infection
Common: sepsis2

2

Fatalities due to sepsis have been reported in patients treated with topotecan (see
section 4.4)
General disorders and administration site conditions
Very common: pyrexia, asthenia, fatigue
Common: malaise
Very rare: extravasation3

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Extravasation has been reported very rarely. Reactions have been mild and have not
generally required specific therapy.
Immune system disorders
Common: hypersensitivity reaction including rash
Rare: anaphylactic reaction, angioedema, urticaria
Hepato-biliary disorders
Common: hyperbilirubinaemia
The incidence of adverse events listed above have the potential to occur with a higher
frequency in patients who have a poor performance status (see section 4.4).
The frequencies associated with the haematological and non-haematological adverse
events listed below represent the adverse event reports considered to be
related/possibly related to topotecan therapy.
Haematological

Neutropenia: Severe (neutrophil count <0.5 x 109/l) during course 1 was seen in 55 %
of the patients and with duration ≥ seven days in 20 % and overall in 77 % of patients
(39 % of courses). In association with severe neutropenia, fever or infection occurred
in 16 % of patients during course 1 and overall in 23 % of patients (6 % of courses).
Median time to onset of severe neutropenia was nine days and the median duration
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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.

4.9

Overdose
There is no known antidote for topotecan overdose. The primary complications of
overdose are anticipated to be bone marrow suppression and mucositis.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Other antineoplastic agents : ATC code: L01XX17.

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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 singlestrand breaks.
Relapsed Ovarian Cancer
In a comparative study of topotecan and paclitaxel in patients previously treated for
ovarian carcinoma with platinum based chemotherapy (n = 112 and 114,
respectively), the response rate (95 % CI) was 20.5 % (13 %, 28 %) versus 14 %
(8 %, 20 %) and median time to progression 19 weeks versus 15 weeks (hazard ratio
0.7 [0.6, 1.0]), for topotecan and paclitaxel, respectively. Median overall survival was
62 weeks for topotecan versus 53 weeks for paclitaxel (hazard ratio 0.9 [0.6, 1.3]).
The response rate in the whole ovarian carcinoma programme (n = 392, all previously
treated with cisplatin or cisplatin and paclitaxel) was 16 %. The median time to
response in clinical trials was 7.6- 11.6 weeks. In patients refractory to, or relapsing
within 3 months after cisplatin therapy (n = 186), the response rate was 10 %.
These data should be evaluated in the context of the overall safety profile of the
medicinal product, in particular to the important haematological toxicity (see section
4.8).
A supplementary retrospective analysis was conducted on data from 523 patients with
relapsed ovarian cancer. Altogether, 87 complete and partial responses were
observed, with 13 of these occurring during cycles 5 and 6 and 3 occurring thereafter.
For patients administered more than 6 cycles of therapy, 91 % completed the study as
planned or were treated until disease progression with only 3 % withdrawn for
adverse events.
Relapsed SCLC
A phase III 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 (Logrank 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 selfreports on an
unblinded symptom scale assessment in each of these two studies.
Table 1. Summary of survival, response rate, and time to progression in SCLC
patients treated with oral topotecan or intravenous topotecan

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Study 065

Median
survival
(weeks)
(95 % CI)
Hazard
(95 % CI)

ratio

Study 396

Oral
topotecan

Intravenous
topotecan

Oral
topotecan

Intravenous
topotecan

(N = 52)

(N = 54)

(N = 153)

(N = 151)

32.3

25.1

33.0

35.0

(26.3, 40.9)

(21.1, 33.0)

(29.1, 42.4)

(31.0, 37.1)

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
response
(95 % CI)

in
rate

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

to

ratio

8.3 (-6.6, 23.1)

-3.6 (-12.6, 5.5)

14.9

13.1

11.9

14.6

(8.3, 21.3)

(11.6, 18.3)

(9.7, 14.1)

(13.3, 18.9)

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, Adriamycin (doxorubicin) and vincristine (CAV) in patients with
relapsed, sensitive SCLC, the overall response rate was 24.3 % for topotecan
compared to 18.3 % for the CAV group. Median time to progression was similar in
the two groups (13.3 weeks and 12.3 weeks respectively). Median survivals for the
two groups were 25.0 and 24.7 weeks respectively. The hazard ratio for survival of IV
topotecan relative to CAV was 1.04 (95 % CI 0.78 – 1.40).
The response rate to topotecan in the combined small cell lung cancer programme (n
= 480) for patients with relapsed disease sensitive to first-line therapy, was 20.2 %.
The median survival was 30.3 weeks (95 % CI: 27.6, 33.4).
In a population of patients with refractory SCLC (those not responding to first line
therapy), the response rate to topotecan was 4.0 %.
Cervical Carcinoma
In a randomised, comparative phase III trial conducted by the Gynaecological
Oncology Group (GOG 0179), topotecan plus cisplatin (n=147) was compared with
cisplatin alone (n=146) for the treatment of histologically confirmed persistent,
recurrent or Stage IVB carcinoma of the cervix where curative treatment with surgery
and/or radiation was not considered appropriate. Topotecan plus cisplatin had a
statistically significant benefit in overall survival relative to cisplatin monotherapy
after adjusting for interim analyses (Log-rank p =0.033).

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Table 2. Study results Study GOG-0179
ITT population
Cisplatin

Cisplatin

2

50 mg/m d. 1

50 mg/m2 d. 1 +

q21 d.

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 % 0.76 (0.59-0.98)
C.I.)
Log rank p-value

0.033

Patients without Prior Cisplatin Chemoradiotherapy
Cisplatin

Topotecan/Cisplatin

Survival (months)

(n= 46)

(n = 44)

Median (95 % C.I.)

8.8 (6.4, 11.5)

15.7 (11.9, 17.7)

Hazard ratio (95 % 0.51 (0.31, 0.82)
C.I.)

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 % 0.85 (0.59, 1.21)
C.I.)

In patients (n=39) with recurrence within 180 days after chemoradiotherapy with
cisplatin, the median survival in the topotecan plus cisplatin arm was 4.6 months (95
% C.I.: 2.6, 6.1) versus 4.5 months (95 %C.I.: 2.9, 9.6) for the cisplatin arm with an
hazard ratio of 1.15 (0.59, 2.23). In those (n=102) with recurrence after 180 days, the
median survival in the topotecan plus cisplatin arm was 9.9 months (95 % C.I.: 7,
12.6) versus 6.3 months (95 %C.I.: 4.9, 9.5) for the cisplatin arm with an hazard ratio
of 0.75 (0.49, 1.16).
Paediatrics
Topotecan was also evaluated in the paediatric population; however, only limited data
on efficacy and safety are available.

11

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; sixtyfive (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 GCSF 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 ringopened 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 cellbased assay, was found in urine, plasma, and faeces. The mean metabolite:parent
AUC ratio was less than 10 % for both total topotecan and topotecan lactone. An Oglucuronidation 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-Oglucuronide 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

12

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 12 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 preimplantation loss were observed.
The carcinogenic potential of topotecan has not been studied.

6

PHARMACEUTICAL PARTICULARS

13

6.1

List of excipients
Tartaric acid (E334)
Mannitol (E421)
Hydrochloric acid (E507) (for pH adjustment)
Sodium hydroxide (for pH adjustment)

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
30 months.
Reconstituted and diluted solutions
The product should be used immediately after reconstitution as it contains no
antibacterial preservative. If reconstitution and dilution is performed under strict
aseptic conditions (e.g. an LAF bench) the product should be used (infusion
completed) within 12 hours at room temperature or 24 hours if stored at 2-8 0C after
the first puncture of the vial.

6.4

Special precautions for storage
Keep the vial in the outer carton in order to protect from light.

6.5

Nature and contents of container
Topotecan Fair-Med Healthcare 1 mg/ml powder for concentrate for solution for
infusion is supplied in type I clear glass vials, together with grey bromobutyl stoppers
and aluminium seals with polypropylene caps.
Pack sizes:
1 or 5 x 1 mg vial
1 or 5 x 4 mg vial
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Topotecan vials must be reconstituted with water for injections to a concentration of
1mg/ml. Further dilution of the reconstituted solution with either 0.9 % w/v sodium

14

chloride intravenous infusion or 5 % w/v glucose intravenous infusion is required to a
final concentration of between 25 and 50 microgram/ml.
The normal procedures for proper handling and disposal of anticancer medicinal
products should be adopted, namely:
− Personnel should be trained to reconstitute the medicinal product.
− Pregnant staff should be excluded from working with this medicinal product.
− Personnel handling this medicinal product during reconstitution should wear
protective clothing including mask, goggles and gloves.
− All items for administration or cleaning, including gloves, should be placed in highrisk, waste disposal bags for high-temperature incineration. Any unused product or
waste material should be disposed of in accordance with local requirements.
− Accidental contact with the skin or eyes should be treated immediately with
copious amounts of water.

7

MARKETING AUTHORISATION HOLDER
Fair-Med Healthcare GmbH
Planckstrasse 13,
22765 Hamburg
Germany

8

MARKETING AUTHORISATION NUMBER(S)
PL 20242/0013

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
22/08/2011

10

DATE OF REVISION OF THE TEXT
01/10/2013

15

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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