ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Topotecan Hospira 4 mg/4 ml concentrate for solution for infusion
1 ml of concentrate for solution for infusion contains 1 mg topotecan (as hydrochloride).
Each 4 ml vial of concentrate contains 4 mg topotecan (as hydrochloride).
For a full list of excipients see section 6.1.
3.
Concentrate for solution for infusion (sterile concentrate).
A clear yellow to yellow-green solution.
4.
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).
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).
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 10
9
/l, a platelet count of ≥ 100 x 10
9
/l and a haemoglobin level of ≥ 9g/dl (after transfusion if
necessary).
Topotecan must be further diluted before use (see section 6.6).
Small Cell Lung Carcinoma
Initial dose
The recommended dose of topotecan is 1.5 mg/m
2
body surface area/day, administered by intravenous
infusion over 30 minutes for 5 consecutive days, with a 3 week interval between the start of each
course. If well tolerated, treatment may continue until disease progression (see sections 4.8 and 5.1).
2
Subsequent doses
Topotecan should not be re-administered unless the neutrophil count is ≥ 1 x 10
9
/l, the platelet count is
≥ 100 x 10
9
/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
10
9
/l) for 7 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/m
2
/day to
1.25 mg/m
2
/day (or subsequently down to 1.0 mg/m
2
/day if necessary).
Doses should be similarly reduced if the platelet count falls below 25 x 10
9
/l. In clinical trials,
topotecan was discontinued if the dose had been reduced to 1.0 mg/m
2
and a further dose reduction
was required to manage adverse effects.
Cervical Carcinoma
Initial dose
The recommended dose of topotecan is 0.75 mg/m
2
/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/m
2
/day and following the topotecan dose. This treatment schedule is repeated every 21
days for 6 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 10
9
/l, the platelet count is more than or equal to 100 x 10
9
/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 10
9
/l) for 7 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/m
2
/day for
subsequent courses (or subsequently down to 0.45 mg/m
2
/day if necessary).
Doses should be similarly reduced if the platelet count falls below 25 x 10
9
/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/m
2
/day for 5 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 132 μmol/l. If, during
topotecan/cisplatin combination therapy serum creatinine exceeds 132 μmol/l, it is recommended that
the full prescribing information be consulted for any advice on cisplatin dose reduction/continuation.
If cisplatin is discontinued, there are insufficient data regarding continuing monotherapy with
topotecan in patients with cervical cancer.
3
Paediatric population
The experience in children is limited, therefore no recommendation for treatment of paediatric patients
with topotecan can be given (see sections 5.1 and 5.2).
Topotecan is contraindicated in patients who
− have a history of severe hypersensitivity to the active substance or to any of the excipients
− are breast feeding (see section 4.6)
− already have severe bone marrow depression prior to starting first course, as evidenced by baseline
neutrophils < 1.5 x 10
9
/l and/or a platelet count of < 100 x 10
9
/l.
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, 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 interstitial lung disease (e.g.
cough, fever, dyspnoea and/or hypoxia), and topotecan should be discontinued if a new diagnosis of
ILD is confirmed.
Topotecan and topotecan in combination with cisplatin are commonly associated with clinically
relevant thrombocytopenia. This should be taken into account, e.g. in case patients at increased risk of
tumour bleeds are considered for therapy.
As expected, patients with poor performance status (PS>1) have a lower response rate and an
increased incidence of complications such as fever, infection and sepsis (see section 4.8). 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 1.5 mg/m
2
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.
No
in vivo
human pharmacokinetic interaction studies have been performed.
Topotecan does not inhibit human P450 enzymes (see section 5.2). In a population study, 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).
4
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/m
2
day for 5 consecutive days) and cisplatin (60 mg/m
2
/day on Day 1) were
administered in 13 patients with ovarian cancer, a slight increase in AUC (12%, n=9) and C
max
(23%, n=11) was noted on day 5. This increase is considered unlikely to be of clinical relevance.
As with all cytotoxic chemotherapy, effective contraceptive methods must be advised when either
partner is treated with topotecan.
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. 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.
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.
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.
No studies on the effects of 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.
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 were 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
5
(≥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:
sepsis
Blood and lymphatic system
disorders
Very common:
febrile neutropenia, neutropenia
(see gastrointestinal disorders),
thrombocytopenia, anaemia, leucopenia
Immune system disorders
Common:
hypersensitivity reaction including rash
Rare:
anaphylactic reaction, angioedema,
Metabolism and nutrition
disorders
Very common:
anorexia (which may be severe)
Respiratory, thoracic and
mediastinal disorders
Rare
:
interstitial lung disease
Gastrointestinal disorders
Very common:
nausea, vomiting and diarrhoea (all of
which may be severe), constipation,
abdominal pain* and mucositis
*Neutropenic colitis, including fatal neutropenic colitis, has
been reported to occur as a complication of topotecan-induced
neutropenia (see section 4.4).
Hepato-biliary 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:
extravasation
†
†
Extravasation has been reported very rarely. Reactions have
been mild and have not generally required specific therapy.
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).
6
urticaria
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 10
9
/l) during course 1 was seen in 55 % of the patients
and with duration ≥7 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 9 days and the
median duration was 7 days. Severe neutropenia lasted beyond 7 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 10
9
/l) in 25 % of patients (8 % of courses);
moderate (platelets between 25.0 and 50.0 x 10
9
/l) in 25 % of patients (15 % of courses). Median time
to onset of severe thrombocytopenia was Day 15 and the median duration was 5 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 (15 %). 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.
There is no known antidote for topotecan overdose. The primary complications of overdose are
anticipated to be bone marrow suppression and mucositis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX17.
7
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 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 i.v 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.
Table 1. Summary of survival, response rate, and time to progression in SCLC patients treated
with oral topotecan or intravenous topotecan
Study 065
Study 396
Oral
topotecan
Intravenous
topotecan
Oral
topotecan
Intravenous
topotecan
(N = 52)
(N = 54)
(N = 153)
(N = 151)
Median survival
(weeks)
(95% CI)
32.3
(26.3, 40.9)
25.1
(21.1, 33.0)
33.0
(29.1, 42.4)
35.0
(31.0, 37.1)
Hazard ratio
(95% CI)
0.88 (0.59, 1.31)
0.88 (0.7, 1.11)
Response rate (%)
(95% CI)
23.1
(11.6, 34.5)
14.8
(5.3, 24.3)
18.3
(12.2, 24.4)
21.9
(15.3, 28.5)
Difference in response
rate
(95% CI)
8.3 (-6.6, 23.1)
-3.6 (-12.6, 5.5)
Median time to
progression (weeks)
(95% CI)
14.9
(8.3, 21.3)
13.1
(11.6, 18.3)
11.9
(9.7, 14.1)
14.6
(13.3, 18.9)
Hazard ratio
(95% CI)
0.90 (0.60, 1.35)
1.21 (0.96, 1.53)
N = total number of patients treated.
CI = Confidence interval.
8
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).
Study results Study GOG-0179
ITT population
Cisplatin
50 mg/m
2
d. 1
q2l d.
Cisplatin
50 mg/m
2
d. 1 +
Topotecan
0.75 mg/m
2
dx3
q21
Survival (months)
(n = 146)
(n = 147)
Median (95% C.I.)
6.5 (5.8, 8.8)
9.4 (7.9, 11.9)
Hazard ratio (95% C.I.)
0.76 (0.59-0.98)
Log rank p-value
0.033
Patients without Prior Cisplatin Chemoradiotherapy
Cisplatin
Topotecan/Cisplatin
Survival (months)
(n = 46)
(n = 44)
Median (95% C.I.)
8.8 (6.4, 11.5)
15.7 (11.9, 17.7)
Hazard ratio (95% C.I.)
0.51 (0.31, 0.82)
Patients with Prior Cisplatin Chemoradiotherapy
Cisplatin
Topotecan/Cisplatin
Survival (months)
(n = 72)
(n = 69)
Median (95% C.I.)
5.9 (4.7, 8.8)
7.9 (5.5, 10.9)
Hazard ratio (95% C.I.)
0.85 (0.59, 1.21)
In patients (n=39) with recurrence within 180 days after chemoradiotherapy with cisplatin, the median
survival in the topotecan plus cisplatin arm was 4.6 months (95% C.I.: 2.6, 6.1) versus 4.5 months
(95% C.I.: 2.9, 9.6) for the cisplatin arm with an hazard ratio of 1.15 (0.59, 2.23). In those (n=102)
with recurrence after 180 days, the median survival in the topotecan plus cisplatin arm was 9.9 months
(95% C.I.: 7, 12.6) versus 6.3 months (95%C.I.: 4.9, 9.5) for the cisplatin arm with an hazard ratio of
0.75 (0.49, 1.16).
9
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/m
2
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/m
2
day with G-CSF and 1.4 mg/m
2
/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/m
2
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 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 Ndemethylated
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/m
2
compared to 21.3 L/h/m
2
[n=9]) (see
section 4.5).
10
Plasma clearance in patients with hepatic impairment (serum bilirubin between 1.5 and 10 mg/dl)
decreased to about 67 % when compared with a control group of patients. Topotecan half-life was
increased by about 30 % but no clear change in volume of distribution was observed. Plasma clearance
of total topotecan (active and inactive form) in patients with hepatic impairment only decreased by
about 10 % compared with the control group of patients.
Plasma clearance in patients with renal impairment (creatinine clearance 41-60 ml/min.) decreased to
about 67 % compared with control patients. Volume of distribution was slightly decreased and thus
half-life only increased by 14 %. In patients with moderate renal impairment topotecan plasma
clearance was reduced to 34 % of the value in control patients. Mean half-life increased from
1.9 hours to 4.9 hours.
In a population study, a number of factors including age, weight and ascites had no significant effect
on clearance of total topotecan (active and inactive form).
Paediatric population
The pharmacokinetics of topotecan given as a 30 minute infusion for 5 days were evaluated in two
studies. One study included a dose range of 1.4 mg/m
2
to 2.4 mg/m
2
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/m
2
to 5.2 mg/m
2
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.
6.
6.1 List of excipients
Tartaric acid (E334)
Hydrochloric acid (E507) (for pH adjustment)
Sodium hydroxide (for pH adjustment)
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
Unopened vial
18 months.
11
After first opening
Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C under normal light
conditions and at 2-8°C when protected from light. 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 to 8°C, unless
reconstitution/dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2°C-8°C). Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Topotecan Hospira 4 mg/4 ml is supplied in Type I clear glass vials, each sealed with a chlorobutyl
rubber stopper, aluminium seal and plastic flip-off closure.
Each vial contains 4 ml of concentrate.
Topotecan Hospira is available in pack sizes of 1 vial and 5 vials. Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Topotecan Hospira is provided as a sterile concentrate containing 4 mg topotecan in 4 ml solution (1
mg/ml).
Parenteral products should be visually inspected for particulate matter and discolouration prior to
administration. Topotecan Hospira is a yellow/yellow green solution. If visible particles are
observed,
the product should not be administered.
Further dilution with either sodium chloride 9 mg/ml (0.9%) solution for injection or glucose
50 mg/ml (5%) solution for injection is required, to obtain a final concentration of between 25 and
50 micrograms/ml prior to administration to the patient.
The normal procedures for proper handling and disposal of anticancer medicinal products should be
adopted, namely:
− Personnel should be trained to prepare and administer the medicinal product.
− Pregnant staff should be excluded from working with this medicinal product.
− Personnel handling this medicinal product should wear protective clothing including mask, goggles
and gloves.
− All items for administration or cleaning, including gloves, should be placed in high-risk, waste
disposal bags for high-temperature incineration. Liquid waste may be flushed with large amounts of
water.
− Accidental contact with the skin or eyes should be treated immediately with copious amounts of
water. If there is lasting irritation, a doctor should be consulted.
-
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Hospira UK Limited
Queensway
Royal Leamington Spa
Warwickshire
CV31 3RW
12
United Kingdom
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu.
13
ANNEX II
A.
THE MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
14
A. THE MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Hospira UK Limited
Queensway
Royal Leamington Spa
Warwickshire
CV31 3RW
United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, Section 4.2).
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of Pharmacovigilance, as presented in version 5.3 (dated 17
November 2009) in Module 1.8.1 of the Marketing Authorisation Application, is in place and
functioning before and whilst the product is on the market.
PSUR
The PSUR submission schedule should follow the PSUR schedule for the reference product.
15
ANNEX III
LABELLING AND PACKAGE LEAFLET
16
A. LABELLING
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Topotecan Hospira 4 mg/4 ml concentrate for solution for infusion
topotecan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml of sterile concentrate contains 1 mg topotecan (as hydrochloride).
Each 4 ml vial contains 4 mg topotecan (as hydrochloride).
3.
LIST OF EXCIPIENTS
Also contains: tartaric acid (E334), water for injections, and hydrochloric acid
(E507) or sodium hydroxide (for pH adjustment).
4.
Concentrate for solution for infusion
4 mg/4 ml
1 vial
5 vials
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use.
Dilute before use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED
OUT OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP:
Use immediately after opening.
18
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator
.
Do not freeze.
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
WARNING: This is a cytotoxic agent. Special handling and disposal instructions apply (see package
leaflet).
Hospira UK Limited
Queensway
Royal Leamington Spa
Warwickshire
CV31 3RW
United Kingdom
13. BATCH NUMBER
BN:
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.
19
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
Topotecan Hospira 4 mg/4 ml sterile concentrate
Intravenous use
2.
METHOD OF ADMINISTRATION
Dilute before use.
3.
EXPIRY DATE
EXP:
4.
BATCH NUMBER
BN:
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
4 mg/ 4ml
6.
OTHER
Hospira UK Limited
20
B. PACKAGE LEAFLET
21
PACKAGE LEAFLET: INFORMATION FOR THE USER
Topotecan Hospira 4 mg/4 ml concentrate for solution for infusion
topotecan
Read all of this leaflet carefully before you are given this medicine.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor.
• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
In this leaflet:
1. What Topotecan Hospira is and what it is used for
2. Before you are given Topotecan Hospira
3. How Topotecan Hospira is given
4. Possible side effects
5. How to store Topotecan Hospira
6. Further information
1.
WHAT TOPOTECAN HOSPIRA IS AND WHAT IT IS USED FOR
Topotecan Hospira is an anti-cancer medicine, which will be given to you through a drip, as an
infusion into a vein.
Topotecan Hospira is used to treat:
•
small cell lung cancer
that has come back after chemotherapy
•
advanced cervical cancer
if surgery or radiotherapy treatment is not possible. When treating
cervical cancer, Topotecan Hospira is combined with another drug called
cisplatin
.
Your doctor will decide with you whether Topotecan Hospira therapy is better than further treatment
with your initial chemotherapy.
2.
BEFORE YOU ARE GIVEN TOPOTECAN HOSPIRA
You should not receive Topotecan Hospira:
• if you are allergic (hypersensitive
)
to topotecan or any of the other ingredients of Topotecan Hospira
• if you are breast-feeding
• if your blood cell counts are too low. Your doctor will tell if this applies to you based on the results
of your last blood test.
If you think any of these things may apply to you, please tell your doctor.
Take special care with Topotecan Hospira
Your doctor needs to know before you are given this medicine if:
• you have a problem with your kidneys
• you have a problem with your liver
If either of these applies to you, your doctor will need to know before treatment begins, as he or she
may need to adjust your dose
• you are pregnant or plan to become pregnant
• you plan to father a child
If either of these applies to you, your doctor will need to know before treatment begins, as topotecan
may harm a baby which is conceived before, during or soon after treatment. You should therefore use
an effective method of contraception. Ask your doctor for further advice.
22
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription and herbal medicines. It is also important that you check
with your doctor before you start taking any other medicines or herbal products while you are treated
with Topotecan Hospira
.
Using Topotecan Hospira with food and drink
Alcohol: There is no known interaction between topotecan and alcohol; however, you should check
with your doctor whether drinking alcohol is advisable for you.
Pregnancy and breast-feeding
Topotecan is not recommended for use by pregnant women
.
Topotecan may harm a baby which is
conceived before, during or soon after treatment. You should tell your doctor if you are pregnant
before your treatment starts.
An effective method of contraception should be used during treatment, to avoid becoming pregnant or
fathering a child. Do not try to become pregnant or father a child until a doctor advises you that it is
safe to do so. You can ask your doctor for family planning advice. If a baby is conceived/you fall
pregnant during treatment, you should tell their doctor immediately.
Do not
breast-feed if you are being treated with topotecan. Do not restart breastfeeding until the
doctor tells you it is safe to do so.
Driving and using machines
Topotecan can make you feel tired. If you feel tired or weak, do not drive and do not use machines.
3.
HOW TOPOTECAN HOSPIRA IS GIVEN
The dose of topotecan you receive is calculated by your doctor, based on:
• your body size (your surface area, measured in square metres (m
2
))
• the results of your blood tests (these will be carried out before your treatment starts)
• the disease you are being treated for
The usual dose
Your doctor will calculate what dose you need to be given, based on your own circumstances. Typical
doses are given below.
•
For small cell lung cancer:
1.5 milligrams per m
2
of body surface area per day.
•
For cervical cancer:
0.75 milligrams per m
2
of body surface area per day. When treating cervical
cancer, topotecan will be given to you with another medicine, called cisplatin. Your doctor will advise
you about the correct dose of cisplatin.
How topotecan is given
Topotecan Hospira is a concentrated solution which will be diluted before use. A doctor or nurse will
give you your dose of topotecan as an infusion (a drip). It is usually given into a vein in your arm, over
a period of about 30 minutes.
Duration of treatment
Your treatment may vary and will depend on the results of your regular blood tests. Typical courses of
treatment are given below.
•
For small cell lung cancer:
treatment will usually be given once a day for 5 days.
•
For cervical cancer:
treatment will usually be given once a day for 3 days.
23
This course of treatment will normally be repeated every three weeks, for all types of cancer. Your
doctor will decide when to stop your treatment.
If you are concerned about your dose or the duration of your treatment, talk to your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Topotecan Hospira can cause side effects, although not everybody gets them.
The frequency of possible side effects listed below is defined using the following convention:
Very common affects more than 1 user in 10
Common
affects 1 to 10 users in 100
Uncommon
affects 1 to 10 users in 1,000
Rare
affects 1 to 10 users in 10,000
Very rare
affects less than 1 user in 10,000
Not known
frequency cannot be estimated from the available data
Serious side effects: tell your doctor
The following very common side effects may be serious. Tell your doctor immediately if you notice
any of these symptoms, as hospitalisation may be necessary.
•
Signs of infection.
Topotecan may reduce the number of white blood cells in your body and make
you more likely to get an infection. This can be life threatening. A blood test will be taken to check for
a reduction in the amount of your white blood cells. Signs of infection should be monitored and
include:
fever
serious deterioration in your general condition/health
local symptoms, such as a sore throat or urinary problems (for example, a burning
sensation when urinating, which may be a sign of a urinary tract infection)
•
Severe stomach pain, fever and possibly diarrhoea (rarely with blood).
Occasionally, these symptoms can be a sign of bowel inflammation (
colitis
)
The following rare side effects may be serious. Tell your doctor immediately if you notice any of the
symptoms.
•
Lung inflammation (interstitial lung disease).
You are most at risk of this side effect if you have
an existing lung disease, if you have had radiation treatment on your lungs, or have previously taken
medicines that caused lung damage. Signs of lung inflammation include:
difficulty in breathing
cough
fever
Very common side effects
The following side effects are very common. Tell a doctor if any of these become troublesome.
• Feeling generally weak and tired (temporary
anaemia
). In some cases you may need a blood
transfusion
• Unusual bruising or bleeding, caused by a decrease in the number of clotting cells in the blood. This
can lead to severe bleeding from relatively minor injuries such as a small cut. Rarely, it can lead to
more severe bleeding (
haemorrhage
). Talk to your doctor for advice on how to minimise the risk of
bleeding
• Weight loss and loss of appetite (
anorexia
), tiredness, weakness, feeling unwell
• Feeling sick
(nausea
), being sick (
vomiting
), diarrhoea, stomach pain, constipation
24
• Inflammation and ulcers of the mouth, tongue, or gums
• High body temperature (
fever
)
• Hair loss
Common side effects
The following side effects are common. Tell a doctor if any of these become troublesome.
• Allergic or hypersensitivity reactions (including rash)
• Yellow skin (jaundice)
• Itching sensation
• Muscle pain
Rare side effects
The following side effects are rare. Tell a doctor if any of these become troublesome.
• Severe allergic or anaphylactic reactions
• Swelling caused by fluid build up
(
angioedema
)
• Mild pain and inflammation at the site of injection
• Itchy rash (or hives)
Note for patients treated for cervical cancer
: If you are being treated for cervical cancer, you will
usually receive another medicine called cisplatin, alongside your topotecan treatment. You may also
get side effects from the cisplatin medication. These side effects will be described in the cisplatin
patient information leaflet.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, tell your
doctor.
5.
HOW TO STORE TOPOTECAN HOSPIRA
Keep out of the reach and sight of children.
Do not use Topotecan Hospira after the expiry date stated on the vial and carton after EXP.
Store in a refrigerator (2°C-8°C). Do not freeze.
Keep the vial in the outer carton to protect from light.
This medicine is for single use only. After opening, the product should be used immediately. If not
used immediately, Topotecan Hospira can be used for up to 24 hours when stored in the fridge
(protected from light) or at room temperature (in normal daylight conditions).
Any unused product or waste material should be disposed of in accordance with local requirements for
cytotoxic material.
6.
FURTHER INFORMATION
What Topotecan Hospira contains
The active substance in Topotecan Hospira is topotecan (as hydrochloride). 1 ml of concentrate for
solution for infusion contains 1 mg topotecan (as hydrochloride). Each 4 ml vial of concentrate
contains 4 mg topotecan (as hydrochloride).
The other ingredients are: tartaric acid (E334), water for injections and hydrochloric acid (E507) or
sodium hydroxide (to adjust the pH of the solution).
25
What Topotecan Hospira looks like and the contents of the pack
Topotecan Hospira is a clear, yellow or yellow-green concentrate for solution for infusion, supplied in
clear glass vials, each containing 4 ml concentrate. Topotecan Hospira is available in two pack sizes,
containing either 1 vial or 5 vials. Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Hospira UK Limited
Queensway
Royal Leamington Spa
Warwickshire
CV31 3RW
United Kingdom
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
AT / DE
Hospira Deutschland GmbH
Tel: + 49 (0) 89 43 77 77 0
BE / LX / NL
Hospira Benelux BVBA
Tél/Tel: + 32 2 332 03 15
CY
Name: N.Karoullas
Pharmaceutical Trading Co Ltd
33, Artemidos avenue, 6025 Larnaca
Tel: 24656165/ Mob.: 99403969
Email:
n.karoullas@ptc-ltd.com
CZ / EE / EL / IE / LT / LV /
MT / PL / RO / SI / SK / UK
Hospira UK Limited
Tel: + 44 (0) 1926 820820
DK / FI / IS / NO / SE
Hospira Nordic AB
Tel: + 46 (0) 8 672 85 00
ES
Hospira Productos Farmacéuticos y Hospitalarios S.L.
Tel: + 34 914847100
FR
Hospira France
Tél: + 33 (0) 826 30 03 02
HU
Pharmacenter Hungary Ltd
Tel.: +36-1-209-5927
IT
Hospira Italia Srl
Tel: + 39 0812405912
PT
Hospira Portugal Lda
Tel: + 351 214857434
This leaflet was last approved in
Detailed information on this medicine is available on the website of the European Medicines Agency
The following information is intended for medical or health care professionals only.
Storage, Use, Handling & Disposal of Topotecan Hospira
Storage
Unopened vial: Store in a refrigerator (2°C-8°C). Do not freeze. Keep the vial in the outer carton in
order to protect from light.
26
Use
Refer to the SPC for full details.
Topotecan Hospira 4 mg/4 ml concentrate for solution for infusion requires dilution to a final
concentration of 25-50 micrograms/ml, prior to administration to the patient. The approved diluents
for the concentrate are sodium chloride 9 mg/ml (0.9%) solution for injection and glucose 50 mg/ml
(5%) solution for injection. Use the aseptic technique during any further dilution of the solution for
infusion.
Parenteral products should be visually inspected for particulate matter and discolouration prior to
administration. Topotecan Hospira is a yellow/yellow green solution. If visible particles are
observed,
the product should not be administered.
Prior to administration of the first course of topotecan, patients must have a baseline neutrophil count
of ≥1.5 x 10
9
/l, a platelet count of ≥ 100 x 10
9
/l and a haemoglobin level of ≥ 9g/dl (after transfusion if
necessary). Neutropenia and thrombocytopenia should be managed. For further details, refer to the
SPC.
Dosage: Small Cell Lung Carcinoma
Initial dose: 1.5 mg/ m
2
body surface area/day, administered by intravenous infusion over 30 minutes
for 5 consecutive days, with a 3 week interval between the start of each course.
Subsequent doses: Topotecan should not be re-administered unless the neutrophil count is ≥ 1 x 109/l,
the platelet count is ≥ 100 x 10
9
/l, and the haemoglobin level is ≥ 9 g/dl (after transfusion if
necessary).
Dosage: Cervical Carcinoma
Initial dose: 0.75 mg/m
2
/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/m
2
/day and following
the topotecan dose. This treatment schedule is repeated every 21 days for 6 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 10
9
/l, the platelet count is more than or equal to 100 x 10
9
/l, and the haemoglobin
level is more than or equal to 9g/dl (after transfusion if necessary).
Dosage: Renally impaired patients
Limited data indicate that the dose should be reduced in patients with moderate renal impairment.
Please refer to the SPC for further details.
Dosage: Paediatric population
Limited data available. Use not recommended.
Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C under normal light
conditions and at 2-8°C when protected from light. 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 to 8°C, unless
reconstitution/dilution has taken place in controlled and validated aseptic conditions.
Handling and disposal
The normal procedures for proper handling and disposal of anti-tumour medicinal products should be
adopted:
• Staff should be adequately trained in the preparation, administration and disposal of cytotoxics
• Pregnant staff should be excluded from working with this medicinal product.
• Staff handling this medicinal product should wear adequate protective clothing including mask,
goggles and gloves.
27
• All items for used in the preparation, administration, and cleaning of the medicinal product,
including gloves, should be placed in high-risk, waste disposal bags for high-temperature incineration.
Liquid waste may be flushed with large amounts of water.
• Accidental contact with the skin or eyes should be treated immediately with copious amounts of
water. If there is lasting irritation, a doctor should be consulted.
• Any unused product or waste material should be disposed of in accordance with local requirements.
28
Source: European Medicines Agency
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