ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Topotecan Teva 1 mg/1 ml concentrate for solution for infusion
2.
1 ml of concentrate for solution for infusion contains 1 mg topotecan (as hydrochloride).
For a full list of excipients, see section 6.1.
3.
Concentrate for solution for infusion.
Clear pale yellow liquid. pH = 2.0-2.6.
4.
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).
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 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 10
9
/l, a platelet count of ≥ 100 x 10
9
/l and a haemoglobin level of ≥ 9 g/dl (after
transfusion if necessary).
Ovarian and Small Cell Lung Carcinoma
Initial dose
2
The recommended dose of topotecan is 1.5 mg/m
2
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 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 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 10
9
/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/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 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 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 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 10
9
/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/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 (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/m
2
/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
3
1.5 mg/dl. If, during topotecan/cisplatin combination therapy serum creatinine exceeds
1.5 mg/dl, it is recommended that the full prescribing information be consulted for any advice
on cisplatin dose reduction/continuation. If cisplatin is discontinued, there are insufficient data
regarding continuing monotherapy with topotecan in patients with cervical cancer.
Paediatric population
The experience in children is limited, therefore no recommendation for treatment of paediatric patients
with topotecan can be given (see sections 5.1 and 5.2).
Topotecan Teva 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 < 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 (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 Teva, 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 intravenous topotecan at 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.
4
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/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.
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.
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.
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.
5
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), not
known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic system disorders
Very common: febrile neutropenia, neutropenia (see Gastrointestinal disorders),
thrombocytopenia, anaemia, leucopenia.
Common: pancytopeniaNot 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 pain
1
, 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:
sepsis
2
.
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: extravasation
3
3
Extravasation has been reported very rarely. Reactions have been mild and have not
generally required specific therapy.
6
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 10
9
/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 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
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.
7
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.
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 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 (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.
8
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.
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).
9
Table 2: Study results Study GOG-0179
ITT population
Cisplatin
50 mg/m
2
d. 1
q2l d.
Cisplatin
50 mg/m2 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).
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
10
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 1, (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
N-demethylated topotecan. In vitro, topotecan did not inhibit human P450 enzymes CYP1A2,
CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, of 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).
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
11
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
leukemia. 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 (E524) (for pH adjustment)
Water for injections
6.2
Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
Vial before opening
30 months.
Diluted solution
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 12 hours if stored below 25°C or 24 hours at 2-8°C, unless 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
12
Colourless, type I glass vial with bromobutyl rubber stopper, aluminium seal and polypropylene snap-
cap containing 1 ml of concentrate.
Topotecan Teva 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
General precautions
The normal procedures for proper handling and disposal of anticancer medicinal products
should be adopted, namely:
-
Personnel should be trained to dilute the medicinal product.
-
Pregnant staff should be excluded from working with this medicinal product.
-
Personnel handling this medicinal product during dilution should wear protective clothing
including mask, goggles and gloves.
-
All items for administration or cleaning, including gloves, should be placed in high-risk,
waste disposal bags for high-temperature incineration. Liquid waste may be flushed with
large amounts of water.
-
Accidental contact with the skin or eyes should be treated immediately with copious amounts of
water.
Instructions for dilution
The concentrate is pale yellow in colour and contains 1 mg per ml of topotecan. Futher dilution of the
appropriate volume of the concentrate with either sodium chloride 9 mg/ml (0.9%) solution for
injection or glucose 50 mg/ml (5%) solution for injection to reach a final topotecan concentration of
between 25 and 50 microgram/ml in the solution for infusion.
Disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
8.
EU/1/09/552/001- 1vial
EU/1/09/552/002- 5 vials
9.
21 September 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu/
.
13
14
1.
Topotecan Teva 4 mg/4 ml concentrate for solution for infusion
2.
1 ml of concentrate for solution for infusion contains 1 mg topotecan (as hydrochloride).
One vial of 4 ml of concentrate for solution for infusion contains 4 mg topotecan (as hydrochloride).
For a full list of excipients, see section 6.1.
3.
Concentrate for solution for infusion.
Clear pale yellow liquid. pH = 2.0-2.6.
4.
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).
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 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 10
9
/l, and a platelet count of ≥ 100 x 10
9
/l and a haemoglobin level of ≥ 9 g/dl
(after transfusion if necessary).
Ovarian and Small Cell Lung Carcinoma
Initial dose
15
The recommended dose of topotecan is 1.5 mg/m
2
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 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 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 10
9
/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/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 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 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 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 10
9
/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/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 (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/m
2
/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
16
1.5 mg/dl, it is recommended that the full prescribing information be consulted for any advice
on cisplatin dose reduction/continuation. If cisplatin is discontinued, there are insufficient data
regarding continuing monotherapy with topotecan in patients with cervical cancer.
Paediatric population
The experience in children is limited, therefore no recommendation for treatment of paediatric patients
with topotecan can be given (see sections 5.1 and 5.2).
Topotecan Teva 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 < 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 (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 Teva, 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 intravenous topotecan at 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.
17
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/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.
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.
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.
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
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
18
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), not
known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic system disorders
Very common: febrile neutropenia, neutropenia (see Gastrointestinal disorders),
thrombocytopenia, anaemia, leucopenia.
Common: pancytopenia
Not known: severe bleeding (associated with thrombocytopenia)
Respiratory, thoracic and mediastinal disorders
Rare: interstitial lung disease (some cases have been fatal).
Gastrointestinal disorders
Very common: nausea, vomiting and diarrhoea (all of which may be severe),
constipation, abdominal pain
1
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:
sepsis
2
.
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: extravasation
3
3
Extravasation has been reported very rarely. Reactions have been mild and have not
generally required specific therapy.
Immune system disorders
19
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 10
9
/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 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 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.
There is no known antidote for topotecan overdose. The primary complications of overdose are
anticipated to be bone marrow suppression and mucositis.
20
5.
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 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 (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
21
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.
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).
Table 2: Study results Study GOG-0179
ITT population
Cisplatin
50 mg/m
2
d. 1
q2l d.
Cisplatin
50 mg/m2 d. 1 +
Topotecan
0.75 mg/m
2
dx3
q21
22
Survival (months)
(n = 146)
(n = 147)
Median (95% C.I.)
6.5 (5.8, 8.8)
9.4 (7.9, 11.9)
Hazard ratio (95% C.I.)
0.76 (0.59-0.98)
Log rank p-value
0.033
Patients without Prior Cisplatin Chemoradiotherapy
Cisplatin
Topotecan/Cisplatin
Survival (months)
(n = 46)
(n = 44)
Median (95% C.I.)
8.8 (6.4, 11.5)
15.7 (11.9, 17.7)
Hazard ratio (95% C.I.)
0.51 (0.31, 0.82)
Patients with Prior Cisplatin Chemoradiotherapy
Cisplatin
Topotecan/Cisplatin
Survival (months)
(n = 72)
(n = 69)
Median (95% C.I.)
5.9 (4.7, 8.8)
7.9 (5.5, 10.9)
Hazard ratio (95% C.I.)
0.85 (0.59, 1.21)
In patients (n = 39) with recurrence within 180 days after chemoradiotherapy with cisplatin, the
median survival in the topotecan plus cisplatin arm was 4.6 months (95 % C.I.: 2,6, 6.1) versus
4.5 months (95 % C.I.: 2.9, 9.6) for the cisplatin arm with an hazard ratio of 1.15 (0.59, 2.23). In those
(n = 102) with recurrence after 180 days, the median survival in the topotecan plus cisplatin arm was
9.9 months (95 % C.I.: 7, 12.6) versus 6.3 months (95 % C.I.: 4.9, 9.5) for the cisplatin arm with an
hazard ratio of 0.75 (0.49, 1.16).
Paediatric population
Topotecan was also evaluated in the paediatric population; however, only limited data on
efficacy and safety are available.
In an open-label trial involving children (n = 108, age range: infant to 16 years) with recurrent
or progressive solid tumours, topotecan, was administered at a starting dose of 2.0 mg/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 1, (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.
23
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
N-demethylated topotecan. In vitro, topotecan did not inhibit human P450 enzymes CYP1A2,
CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, of 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).
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
leukemia. 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
24
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 (E524) (for pH adjustment)
Water for injections
6.2
Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
Vial before opening
30 months.
Diluted solution
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 12 hours if stored below 25°C or 24 hours at 2-8°C, unless 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
Colourless, type I glass vial with bromobutyl rubber stopper, aluminium seal and polypropylene snap-
cap containing 4 ml of concentrate.
Topotecan Teva 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
General precautions
The normal procedures for proper handling and disposal of anticancer medicinal products
should be adopted, namely:
25
-
Personnel should be trained to dilute the medicinal product.
-
Pregnant staff should be excluded from working with this medicinal product.
-
Personnel handling this medicinal product during dilution should wear protective clothing
including mask, goggles and gloves.
-
All items for administration or cleaning, including gloves, should be placed in high-risk,
waste disposal bags for high-temperature incineration. Liquid waste may be flushed with
large amounts of water.
-
Accidental contact with the skin or eyes should be treated immediately with copious amounts of
water.
Instructions for dilution
The concentrate is pale yellow in colour and contains 1 mg per ml of topotecan. Futher dilution of the
appropriate volume of the concentrate with either sodium chloride 9 mg/ml (0.9%) solution for
injection or glucose 50 mg/ml (5%) solution for injection to reach a final topotecan concentration of
between 25 and 50 microgram/ml in the solution for infusion.
Disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
8.
EU/1/09/552/003- 1 vial
EU/1/09/552/004- 5 vials
9.
21 September 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu/
.
26
ANNEX II
A.
THE MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
27
A. THE MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR
BATCH RELEASE
Name and address of the manufacturers responsible for batch release
Pharmachemie B.V.
Swensweg 5
NL-2031 GA Haarlem
The Netherlands
TEVA Pharmaceutical Works Private Limited Company
Táncsics Mihály út 82
H-2100 Gödöllő
Hungary
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
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, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
Not applicable. The application is based on a reference medicinal product for which no safety
concerns requiring additional risk minimisation activities have been identified.
PSURs
The PSUR submission schedule should follow the PSUR schedule for the reference product.
28
ANNEX III
LABELLING AND PACKAGE LEAFLET
29
A. LABELLING
30
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON 1 mg/1 ml,
1.
Topotecan Teva 1 mg/1 ml concentrate for solution for infusion
topotecan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 ml of concentrate for solution for infusion contains 1 mg topotecan (as hydrochloride).
Each vial contains 1 mg topotecan (as hydrochloride) in 1 ml concentrate.
3.
LIST OF EXCIPIENTS
tartaric acid (E334), hydrochloric acid (E507) (for pH adjustment), sodium hydroxide (E524) (for pH
adjustment) and water for injections.
4.
Concentrate for solution for infusion
1 vial of 1 ml (1 mg topotecan)
5 vials of 1 ml (1 mg topotecan)
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use, after dilution.
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
CYTOTOXIC, special handling instructions (see package leaflet).
8.
EXPIRY DATE
EXP
Read the leaflet for the shelf life of the diluted product.
31
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
Any unused product or waste material should be disposed of in accordance with local requirements.
11.
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
12.
EU/1/09/552/001 – 1 vial
EU/1/09/552/002 – 5 vials
13.
BATCH NUMBER
Batch
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Justification for not including Braille accepted.
32
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Vial Label 1 mg/1 ml
1.
Topotecan Teva 1 mg/1 ml concentrate for solution for infusion
topotecan
IV use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1 ml
6.
OTHER
Cytotoxic
33
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON 4 mg/4 ml
1.
Topotecan Teva 4 mg/4 ml concentrate for solution for infusion
topotecan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 ml of concentrate for solution for infusion contains 1 mg topotecan (as hydrochloride).
Each vial contains 4 mg topotecan (as hydrochloride) in 4 ml concentrate.
3.
LIST OF EXCIPIENTS
tartaric acid (E334), hydrochloric acid (E507) (for pH adjustment), sodium hydroxide (E524) (for pH
adjustment) and water for injections.
4.
Concentrate for solution for infusion
1 vial of 4 ml (4 mg topotecan)
5 vials of 4 ml (4 mg topotecan)
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use, after dilution.
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
CYTOTOXIC, special handling instructions (see package leaflet).
8.
EXPIRY DATE
EXP
Read the leaflet for the shelf life of the diluted product.
34
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
Any unused product or waste material should be disposed of in accordance with local requirements.
11.
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
12.
EU/1/09/552/003 – 1 vial
EU/1/09/552/004 – 5 vials
13.
BATCH NUMBER
Batch
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Justification for not including Braille accepted.
35
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Vial Label 4 mg/4 ml
1.
Topotecan Teva 4 mg/4 ml concentrate for solution for infusion
topotecan
IV use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
4 ml
6.
OTHER
Cytotoxic
36
B. PACKAGE LEAFLET
37
PACKAGE LEAFLET: INFORMATION FOR THE USER
Topotecan Teva 1 mg/1 ml concentrate for solution for infusion
topotecan
Read all of this leaflet carefully before you start using this medicine.
-
If you have any further questions, ask your doctor or nurse.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or nurse.
In this leaflet:
1.
What Topotecan Teva is and what it is used for
3.
How to use Topotecan Teva
4.
Possible side effects
5.
How to store Topotecan Teva
6.
Further information
1.
WHAT TOPOTECAN TEVA IS AND WHAT IT IS USED FOR
Topotecan Teva helps to kill tumour cells.
Topotecan Teva is used to treat:
-
ovarian cancer or 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 Teva is combined with another medicine called cisplatin.
2.
BEFORE YOU USE TOPOTECAN TEVA
Do not use Topotecan Teva
-
if you are allergic (hypersensitive) to topotecan or any of the other ingredients of Topotecan
Teva (listed in section 6 under ‘What Topotecan Teva contains’);
-
if you are breast feeding. You should stop breast-feeding before starting treatment with
Topotecan Teva;
-
if your blood cells count is too low.
→
Tell your doctor
if you think any of these could apply to you.
Take special care with Topotecan Teva
Tell your doctor:
-
if you have any kidney problems. Your dose of Topotecan Teva may need to be adjusted. The
use of Topotecan Teva is not recommended in patients with severe renal impairment;
-
if you have liver problems. Your dose of Topotecan Teva may need to be adjusted. The use of
Topotecan Teva is not recommended in patients with liver problems;
-
if you currently have lung problems, or if you have received previous radiation treatment or
medicines that affected your lungs (also see section 4 ‘Possible side effects’);
-
if you suffer from unusual bruising or bleeding (also see section 4 ‘Possible side effects’);
-
if you are feeling very ill.
Taking other medicines
Please tell your doctor if you are taking
or have recently taken any other medicines, including
medicines obtained without a prescription.
Pregnancy and breast-feeding
38
-
Keep this leaflet. You may need to read it again.
2.
Before you use Toptecan Teva
Topotecan Teva should not be used in pregnant women, unless clearly necessary. If you are or think
you might be pregnant, tell your doctor immediately.
Women of child-bearing potential should use effective contraception to avoid becoming pregnant
while on treatment.
Male patients who may wish to father a child should ask their doctor for family planning advice or
treatment.
You must not breast-feed while on treatment with Topotecan Teva.
Driving and using machines
Topotecan Teva can make you feel tired or weak.
If you experience this, do not drive or use machines.
3.
HOW TO USE TOPOTECAN TEVA
Your dose of Topotecan Teva will depend on:
-
the disease being treated
-
your body surface area (m
2
)
-
the results of blood tests carried out before and during treatment
-
how well you tolerate treatment.
Ovarian and small cell lung cancer
The usual dose is
1.5 mg per m
2
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 m
2
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 medicine containing cisplatin. For
more information about cisplatin, please refer to the corresponding Package Leaflet.
The experience in children is limited and treatment is therefore not recommended.
How Topotecan Teva is prepared
Topotecan Teva is supplied as a concentrate for solution for infusion. The concentrate must be diluted
before administration.
How Topotecan Teva is given
A doctor or nurse will give you the diluted Topotecan Teva solution as an infusion (a drip) usually into
your arm over about 30 minutes.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Topotecan Teva can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, which are defined as follows:
-
very common: affects more than 1 user in 10
-
common: affects 1 to 10 users in 100
-
uncommon: affects 1 to 10 users in 1,000
-
rare: affects 1 to 10 users in 10,000
-
very rare: affects less than 1 user in 10,000
-
not known: frequency cannot be estimated from the available data.
39
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), 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 Teva may reduce your ability to fight infections.
•
Lung inflammation
(rare), 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 (also see section 2 ‘Before you use Topotecan Teva’).
Other side effects with Topotecan Teva include:
Very common side effects
-
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.
-
Unusual bruising or bleeding, sometimes severe, caused by a decrease in the number of blood
clotting cells (platelets).
-
Abnormally low white blood cell count (neutropenia) which may be accompanied with fever
and signs of infections (febrile neutropenia).
-
Weight loss and loss of appetite (anorexia), tiredness, weakness.
-
Feeling sick (nausea), vomiting, diarrhoea, stomach pain, constipation.
-
Inflammation and ulcers of the mouth, throat, tongue or gums (mucositis).
-
Fever.
-
Infections.
-
Hair loss.
Common side effects
-
Allergic or hypersensitivity reactions (including rash).
-
Yellow skin (jaundice) caused by abnormal liver function.
-
Itching (pruritus).
-
Severe infection (sepsis).
-
Feeling unwell (malaise).
Rare side effects
-
Severe allergic (anaphylactic) reactions causing swelling of the lips, face or neck leading to
severe difficulty in breathing, skin rash or hives, anaphylactic shock (a severe reduction in blood
pressure, paleness, agitation, weak pulse, decreased consciousness).
-
Sudden swelling of the skin and mucosa (e.g. throat or tongue) caused by fluid build up
(angioedema).
-
Itchy rash (or hives).
Very rare side effects
-
Discharge of blood into tissues (extravasation).
Tell a doctor if any of these becomes troublesome.
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 Teva.
40
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or nurse.
5.
HOW TO STORE TOPOTECAN TEVA
Keep out of the reach and sight of children.
Do not use Topotecan Teva after the expiry date which is stated on the carton and vial after EXP. The
expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C). Do not freeze.
Keep the vial in the outer carton in order to protect from light.
Diluted solution
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 12 hours if stored below 25°C or 24 hours at 2-8°C, unless dilution
has taken place in controlled and validated aseptic conditions.
Do not use Topotecan Teva if you notice any visible particles or if the solution is unclear.
Medicines should not be disposed of via wastewater or household waste. Your doctor should dispose
of medicines that are no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Topotecan Teva contains
-
The active substance is topotecan hydrochloride. One vial of 1 ml of concentrate contains 1 mg
topotecan (as hydrochloride).
-
The other ingredients are: tartaric acid (E334), hydrochloric acid (E507), sodium hydroxide
(E524) and water for injections.
What Topotecan Teva looks like and contents of the pack
Topotecan Teva is a clear pale yellow liquid in a colourless glass vial with bromobutyl rubber stopper,
aluminium seal and snap-cap.
Each vial contains 1 ml of the concentrate for solution for infusion. Topotecan Teva is supplied in
cartons containing 1 vial or 5 vials. Not all pack sizes may be marketed.
Marketing Authorisation Holder
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
Manufacturer
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
41
The Netherlands
TEVA Pharmaceutical Works Private Limited Company
Táncsics Mihály út 82
H-2100 Gödöllő
Hungary
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva Generics GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
España
Teva Genéricos Española, S.L.U.
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 212 08 90
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
42
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
Detailed information on this medicine is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu/
.
The following information is intended for medical or healthcare professionals only:
Instructions on how to dilute, store and dispose of Topotecan Teva
General precautions
The normal procedures for proper handling and disposal of anticancer medicinal products should be
adopted:
-
Staff should be trained to dilute the medicinal product.
-
Staff handling this medicinal product during dilution should wear protective clothing including
mask, goggles and gloves.
-
All items for administration or cleaning, including gloves, should be placed in high-risk, waste
disposal bags for high-temperature incineration.
-
Liquid waste may be flushed with large amounts of water.
-
Accidental contact with the skin or eyes should be treated immediately with copious amounts of
water.
Instructions for dilution
The concentrate is pale yellow in colour and contains 1 mg per ml of topotecan. Futher dilution of the
appropriate volume of the concentrate with either sodium chloride 9 mg/ml (0.9%) solution for
injection or glucose 50 mg/ml (5%) solution for injection to reach a final topotecan concentration of
between 25 and 50 microgram/ml in the solution for infusion.
Storage of the diluted solution
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 12 hours if stored below 25°C or 24 hours at 2-8°C, unless 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.
43
-
Pregnant staff should be excluded from working with this medicinal product.
PACKAGE LEAFLET: INFORMATION FOR THE USER
Topotecan Teva 4 mg/4 ml concentrate for solution for infusion
topotecan
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or nurse.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or nurse.
In this leaflet:
1.
What Topotecan Teva is and what it is used for
2.
Before you use Toptecan Teva
3.
How to use Topotecan Teva
5.
How to store Topotecan Teva
6.
Further information
1.
WHAT TOPOTECAN TEVA IS AND WHAT IT IS USED FOR
Topotecan Teva helps to kill tumour cells.
Topotecan Teva is used to treat:
-
ovarian cancer or 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 Teva is combined with another medicine called cisplatin.
2.
BEFORE YOU USE TOPOTECAN TEVA
Do not use Topotecan Teva
-
if you are allergic (hypersensitive) to topotecan or any of the other ingredients of Topotecan
Teva (listed in section 6 under ‘What Topotecan Teva contains’);
-
if you are breast feeding. You should stop breast-feeding before starting treatment with
Topotecan Teva;
-
if your blood cells count is too low.
→
Tell your doctor
if you think any of these could apply to you.
Take special care with Topotecan Teva
Tell your doctor:
-
if you have any kidney problems. Your dose of Topotecan Teva may need to be adjusted. The
use of Topotecan Teva is not recommended in patients with severe renal impairment;
-
if you have liver problems. Your dose of Topotecan Teva may need to be adjusted. The use of
Topotecan Teva is not recommended in patients with liver problems;
-
if you currently have lung problems, or if you have received previous radiation treatment or
medicines that affected your lungs (also see section 4 ‘Possible side effects’);
-
if you suffer from unusual bruising or bleeding (also see section 4 ‘Possible side effects’);
-
if you are feeling very ill.
Taking other medicines
Please tell your doctor if you are taking
or have recently taken any other medicines, including
medicines obtained without a prescription.
Pregnancy and breast-feeding
44
4.
Possible side effects
Topotecan Teva should not be used in pregnant women, unless clearly necessary. If you are or think
you might be pregnant, tell your doctor immediately.
Women of child-bearing potential should use effective contraception to avoid becoming pregnant
while on treatment.
Male patients who may wish to father a child should ask their doctor for family planning advice or
treatment.
You must not breast-feed while on treatment with Topotecan Teva.
Driving and using machines
Topotecan Teva can make you feel tired or weak.
If you experience this, do not drive or use machines.
3.
HOW TO USE TOPOTECAN TEVA
Your dose of Topotecan Teva will depend on:
-
the disease being treated
-
your body surface area (m
2
)
-
the results of blood tests carried out before and during treatment
-
how well you tolerate treatment.
Ovarian and small cell lung cancer
The usual dose is
1.5 mg per m
2
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 m
2
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 medicine containing cisplatin. For
more information about cisplatin, please refer to the corresponding Package Leaflet.
The experience in children is limited and treatment is therefore not recommended.
How Topotecan Teva is prepared
Topotecan Teva is supplied as a concentrate for solution for infusion. The concentrate must be diluted
before administration.
How Topotecan Teva is given
A doctor or nurse will give you the diluted Topotecan Teva solution as an infusion (a drip) usually into
your arm over about 30 minutes.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Topotecan Teva can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, which are defined as follows:
-
very common: affects more than 1 user in 10
-
common: affects 1 to 10 users in 100
-
uncommon: affects 1 to 10 users in 1,000
-
rare: affects 1 to 10 users in 10,000
-
very rare: affects less than 1 user in 10,000
-
not known: frequency cannot be estimated from the available data.
45
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), 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 Teva may reduce your ability to fight infections.
•
Lung inflammation
(rare), 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 (also see section 2 ‘Before you use Topotecan Teva’).
Other side effects with Topotecan Teva include:
Very common side effects
-
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.
-
Unusual bruising or bleeding, sometimes severe, caused by a decrease in the number of blood
clotting cells (platelets).
-
Abnormally low white blood cell count (neutropenia) which may be accompanied with fever
and signs of infections (febrile neutropenia).
-
Weight loss and loss of appetite (anorexia), tiredness, weakness.
-
Feeling sick (nausea), vomiting, diarrhoea, stomach pain, constipation.
-
Inflammation and ulcers of the mouth, throat, tongue or gums (mucositis).
-
Fever.
-
Infections.
-
Hair loss.
Common side effects
-
Allergic or hypersensitivity reactions (including rash).
-
Yellow skin (jaundice) caused by abnormal liver function.
-
Itching (pruritus).
-
Severe infection (sepsis).
-
Feeling unwell (malaise).
Rare side effects
-
Severe allergic (anaphylactic) reactions causing swelling of the lips, face or neck leading to
severe difficulty in breathing, skin rash or hives, anaphylactic shock (a severe reduction in
blood pressure, paleness, agitation, weak pulse, decreased consciousness).
-
Sudden swelling of the skin and mucosa (e.g. throat or tongue) caused by fluid build up
(angioedema).
-
Itchy rash (or hives).
Very rare side effects
-
Discharge of blood into tissues (extravasation).
Tell a doctor if any of these becomes troublesome.
46
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 Teva.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or nurse.
5.
HOW TO STORE TOPOTECAN TEVA
Keep out of the reach and sight of children.
Do not use Topotecan Teva after the expiry date which is stated on the carton and vial after EXP. The
expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C). Do not freeze.
Keep the vial in the outer carton in order to protect from light.
Diluted solution
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 12 hours if stored below 25°C or 24 hours at 2-8°C, unless dilution
has taken place in controlled and validated aseptic conditions.
Do not use Topotecan Teva if you notice any visible particles or if the solution is unclear.
Medicines should not be disposed of via wastewater or household waste. Your doctor should dispose
of medicines that are no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Topotecan Teva contains
-
The active substance is topotecan hydrochloride. One vial of 4 ml of concentrate contains 4 mg
topotecan (as hydrochloride).
-
The other ingredients are: tartaric acid (E334), hydrochloric acid (E507), sodium hydroxide
(E524) and water for injections.
What Topotecan Teva looks like and contents of the pack
Topotecan Teva is a clear pale yellow liquid in a colourless glass vial with bromobutyl rubber stopper,
aluminium seal and snap-cap.
Each vial contains 4 ml of the concentrate for solution for infusion. Topotecan Teva is supplied in
cartons containing 1 vial or 5 vials. Not all pack sizes may be marketed.
Marketing Authorisation Holder
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
Manufacturer
Pharmachemie B.V.
Swensweg 5
47
2031 GA Haarlem
The Netherlands
TEVA Pharmaceutical Works Private Limited Company
Táncsics Mihály út 82
H-2100 Gödöllő
Hungary
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva Generics GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
España
Teva Genéricos Española, S.L.U.
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 212 08 90
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
48
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
Detailed information on this medicine is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu/
.
The following information is intended for medical or healthcare professionals only:
Instructions on how to dilute, store and dispose of Topotecan Teva
General precautions
The normal procedures for proper handling and disposal of anticancer medicinal products should be
adopted:
-
Staff should be trained to dilute the medicinal product.
-
Staff handling this medicinal product during dilution should wear protective clothing including
mask, goggles and gloves.
-
All items for administration or cleaning, including gloves, should be placed in high-risk, waste
disposal bags for high-temperature incineration.
-
Liquid waste may be flushed with large amounts of water.
-
Accidental contact with the skin or eyes should be treated immediately with copious amounts of
water.
Instructions for dilution
The concentrate is pale yellow in colour and contains 1 mg per ml of topotecan. Futher dilution of the
appropriate volume of the concentrate with either sodium chloride 9 mg/ml (0.9%) solution for
injection or glucose 50 mg/ml (5%) solution for injection to reach a final topotecan concentration of
between 25 and 50 microgram/ml in the solution for infusion.
Storage of the diluted solution
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 12 hours if stored below 25°C or 24 hours at 2-8°C, unless 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.
49
-
Pregnant staff should be excluded from working with this medicinal product.
Source: European Medicines Agency
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