ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Potactasol 1 mg powder for concentrate for solution for infusion
2.
Each vial contains 1 mg topotecan (as hydrochloride), with a 10 % overage of fill.
After reconstitution, 1 ml concentrate contains 1 mg topotecan.
Excipient: Each vial contains 0.52 mg (0.0225 mmol) sodium, with a 10 % overage of fill.
For a full list of excipients, see section 6.1.
3.
Powder for concentrate for solution for infusion.
Yellow lyophilisate.
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 thefirst-
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 reconstituted and further diluted before use (see section 6.6).
Posology
When used in combination with cisplatin, the full prescribing information for cisplatin should
be consulted.
Prior to administration of the first course of topotecan, patients must have a baseline neutrophil
count of ≥ 1.5 x 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
2
Initial dose
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)
3
In clinical studies with topotecan in combination with cisplatin for the treatment of cervical
cancer, therapy was only initiated in patients with serum creatinine less than or equal to
1.5 mg/dl. If, during topotecan/cisplatin combination therapy serum creatinine exceeds
1.5 mg/dl, it is recommended that the full prescribing information be consulted for any advice
on cisplatin dose reduction/continuation.
If cisplatin is discontinued, there are insufficient data regarding continuing monotherapy with
topotecan in patients with cervical cancer.
Paediatric population
The experience in children is limited, therefore no recommendation for treatment of paediatric
patients with Potactasol can be given (see sections 5.1 and 5.2).
Topotecan is contraindicated in patients who
-
have a history of severe hypersensitivity to the active substance or to any of the
excipients
-
already have severe bone marrow depression prior to starting first course, as evidenced by
baseline neutrophils < 1.5 x 10
9
/l and/or a platelet count of < 100 x 10
9
/l.
Haematological toxicity is dose-related and full blood count including platelets should be
monitored regularly (see section 4.2)
.
As with other cytotoxic medicinal products, topotecan can cause severe myelosuppression.
Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients
treated with topotecan (see section 4.8).
Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic
colitis have been reported in clinical trials with topotecan. In patients presenting with fever,
neutropenia, and a compatible pattern of abdominal pain, the possibility of neutropenic colitis
should be considered.
Topotecan has been associated with reports of interstitial lung disease (ILD), some of which
have been fatal (see section 4.8). Underlying risk factors include history of ILD, pulmonary
fibrosis, lung cancer, thoracic exposure to radiation and use of pneumotoxic substances and/or
colony stimulating factors. Patients should be monitored for pulmonary symptoms indicative of
ILD (e.g. cough, fever, dyspnoea and/or hypoxia), and topotecan should be discontinued if a
new diagnosis of ILD is confirmed.
Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated
with clinically relevant thrombocytopenia. This should be taken into account when prescribing
topotecan, e.g. in case patients at increased risk of tumour bleeds are considered for therapy.
As expected, patients with poor performance status (PS > 1) have a lower response rate and an
increased incidence of complications such as fever, infection and sepsis (see section 4.8).
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.
4
-
are breast feeding (see section 4.6)
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.
This medicinal product contains
less than 1 mmol sodium (23 mg) per vial, i.e. essentially
‘sodium-free’.
No
in vivo
human pharmacokinetic interaction studies have been performed.
Topotecan does not inhibit human P450 enzymes (see section 5.2). In an intravenous population
study, the coadministration of granisetron, ondansetron, morphine or corticosteroids did not
appear to have a significant effect on the pharmacokinetics of total topotecan (active and
inactive form).
In combining topotecan with other chemotherapy agents, reduction of the doses of each
medicinal product is 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 contraindicated during breast-feeding (see section 4.3). Although it is not known
whether topotecan is excreted in human breast milk, breast-feeding should be discontinued at
the start of therapy.
5
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.
In dose-finding trials involving 523 patients with relapsed ovarian cancer and 631 patients with
relapsed small cell lung cancer, the dose limiting toxicity of topotecan monotherapy was found
to be haematological. Toxicity was predictable and reversible. There were no signs of
cumulative haematological or non-haematological toxicity.
The adverse event profile for topotecan when given in combination with cisplatin in the cervical
cancer clinical trials is consistent with that seen with topotecan monotherapy. The overall
haematological toxicity is lower in patients treated with topotecan in combination with cisplatin
compared to topotecan monotherapy, but higher than with cisplatin alone.
Additional adverse events were seen when topotecan was given in combination with cisplatin,
however, these events were seen with cisplatin monotherapy and not attributable to topotecan.
The prescribing information for cisplatin should be consulted for a full list of adverse events
associated cisplatin use.
The integrated safety data for topotecan monotherapy are presented below.
Adverse reactions are listed below, by system organ class and absolute frequency (all reported
events). Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10);
uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000),
including isolated reports and not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Blood and lymphatic system disorders
Very common:
febrile neutropenia
neutropenia (see Gastrointestinal disorders below)
thrombocytopenia
anaemia
leukopenia
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
6
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
Common:
hypersensitivity reaction including rash
Rare:
anaphylactic reaction
angioedema
urticaria
Hepatobiliary 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
7
(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.
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
8
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
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 or intravenous topotecan
9
Study 065
Study 396
Oral
topotecan
Intravenous
topotecan
Oral topotecan Intravenous
topotecan
(N = 52)
(N = 54)
(N = 153)
(N = 151)
Median survival (weeks)
32.3
25.1
33.0
35.0
(95 % CI)
(26.3, 40.9)
(21.1, 33.0)
(29.1, 42.4)
(31.0, 37.1)
Hazard ratio (95 % CI)
0.88 (0.59, 1.31)
0.88 (0.7, 1.11)
Response rate (%)
23.1
14.8
18.3
21.9
(95 % CI)
(11.6, 34.5)
(5.3, 24.3)
(12.2, 24.4)
(15.3, 28.5)
Difference in response rate
(95 % CI)
8.3 (-6.6, 23.1)
-3.6 (-12.6, 5.5)
Median time to
progression (weeks)
14.9
13.1
11.9
14.6
(95 % CI)
(8.3, 21.3)
(11.6, 18.3)
(9.7, 14.1)
(13.3, 18.9)
Hazard ratio (95 % CI)
0.90 (0.60, 1.35)
1.21 (0.96, 1.53)
N = total number of patients treated.
CI = Confidence interval.
In another randomised phase III trial which compared IV topotecan to cyclophosphamide,
doxorubicin and vincristine (CAV) in patients with relapsed, sensitive SCLC, the overall
response rate was 24.3 % for topotecan compared to 18.3 % for the CAV group. Median time to
progression was similar in the two groups (13.3 weeks and 12.3 weeks respectively). Median
survivals for the two groups were 25.0 and 24.7 weeks respectively. The hazard ratio for
survival of IV topotecan relative to CAV was 1.04 (95 % CI 0.78 -1.40).
The response rate to topotecan in the combined small cell lung cancer programme (n = 480) for
patients with relapsed disease sensitive to first-line therapy, was 20.2 %. The median survival
was 30.3 weeks (95 % CI: 27.6, 33.4).
In a population of patients with refractory SCLC (those not responding to first line therapy), the
response rate to topotecan was 4.0 %.
Cervical carcinoma
In a randomised, comparative phase III trial conducted by the Gynaecological Oncology Group
(GOG 0179), topotecan plus cisplatin (n = 147) was compared with cisplatin alone (n = 146) for
the treatment of histologically confirmed persistent, recurrent or Stage IVB carcinoma of the
cervix where curative treatment with surgery and/or radiation was not considered appropriate.
Topotecan plus cisplatin had a statistically significant benefit in overall survival relative to
cisplatin monotherapy after adjusting for interim analyses (Log-rank p = 0.033).
Table 2. Study results Study GOG-0179
Cisplatin 50 mg/m
2
d.1
q21 d.
ITT population
Cisplatin 50 mg/m
2
d.1 +
Topotecan 0,75 mg/m
2
dx3 q21
Survival (months)
(n = 146)
(n = 147)
Median (95 % C.I.)
6.5 (5.8, 8.8)
9.4 (7.9, 11.9)
Hazard ratio (95 % C.I.)
0.76 (0.59-0.98)
Log rank p-value
0.033
Patients without prior cisplatin chemoradiotherapy
Cisplatin
Topotecan/Cisplatin
Survival (months)
(n = 46)
(n = 44)
10
Median (95 % C.I.)
8.8 (6.4, 11.5)
15.7 (11.9, 17.7)
Hazard ratio (95 % C.I.)
0.51 (0.31, 0.82)
Patients with prior cisplatin chemoradiotherapy
Cisplatin
Topotecan/Cisplatin
Survival (months)
(n = 72)
(n = 69)
Median (95 % C.I)
5.9 (4.7, 8.8)
7.9 (5.5, 10.9)
Hazard ratio (95 % C.I.)
0.85 (0.59, 1.21)
In patients (n = 39) with recurrence within 180 days after chemoradiotherapy with cisplatin, the
median survival in the topotecan plus cisplatin arm was 4.6 months (95 % C.I.: 2.6, 6.1) versus
4.5 months (95 % C.I.: 2.9, 9.6) for the cisplatin arm with an hazard ratio of 1.15 (0.59, 2.23). In
those (n = 102) with recurrence after 180 days, the median survival in the topotecan plus
cisplatin arm was 9.9 months (95 % C.I.: 7, 12.6) versus 6.3 months (95 % C.I.: 4.9, 9.5) for the
cisplatin arm with a hazard ratio of 0.75 (0.49, 1.16).
Paediatrics
Topotecan was also evaluated in the paediatric population; however, only limited data on
efficacy and safety are available.
In an open-label trial involving children (n = 108, age range: infant to 16 years) with recurrent
or progressive solid tumours, topotecan was administered at a starting dose of 2.0 mg/m
2
given
as a 30 minute infusion for 5 days repeated every 3 weeks for up to one year depending on
response to therapy. Tumour types included were Ewing's Sarcoma/primitive neuroectodermal
tumour, neuroblastoma, osteoblastoma, and rhabdomyosarcoma. Antitumour activity was
demonstrated primarily in patients with neuroblastoma. Toxicities of topotecan in paediatric
patients with recurrent and refractory solid tumours were similar to those historically seen in
adult patients. In this study, forty-six (43 %) patients received G-CSF over 192 (42.1 %)
courses; sixty-five (60 %) received transfusions of Packed Red Blood Cells and fifty (46 %) of
platelets over 139 and 159 courses (30.5 % and 34.9 %) respectively. Based on the dose-
limiting toxicity of myelosuppression, the maximum tolerated dose (MTD) was established at
2.0 mg/m
2
/day with G-CSF and 1.4 mg/m
2
/day without G-CSF in a pharmacokinetic study in
paediatric patients with refractory solid tumours (see section 5.2).
5.2 Pharmacokinetic properties
Following intravenous administration of topotecan at doses of 0.5 to 1.5 mg/m
2
as a 30 minute
infusion daily for five days, topotecan demonstrated a high plasma clearance of 62 l/h (SD 22),
corresponding to approximately 2/3 of liver blood flow. Topotecan also had a high volume of
distribution, about 132 l, (SD 57) and a relatively short half-life of 2-3 hours. Comparison of
pharmacokinetic parameters did not suggest any change in pharmacokinetics over the 5 days of
dosing. Area under the curve increased approximately in proportion to the increase in dose. There is
little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change
in the PK after multiple doses. Preclinical studies indicate plasma protein binding of topotecan is low
(35 %) and distribution between blood cells and plasma was fairly homogeneous.
The elimination of topotecan has only been partly investigated in man. A major route of
clearance of topotecan was by hydrolysis of the lactone ring to form the ring-opened
carboxylate.
Metabolism accounts for < 10 % of the elimination of topotecan. An N-desmethyl metabolite,
which was shown to have similar or less activity than the parent in a cell-based assay, was
found in urine, plasma, and faeces. The mean metabolite:parent AUC ratio was less than 10 %
for both total topotecan and topotecan lactone. An O-glucuronidation metabolite of topotecan
and N-desmethyl topotecan has been identified in the urine.
11
Overall recovery of medicinal product-related material following five daily doses of topotecan
was 71 to 76 % of the administered IV dose. Approximately 51 % was excreted as total
topotecan and 3 % was excreted as N-desmethyl topotecan in the urine. Faecal elimination of
total topotecan accounted for 18 % while faecal elimination of N-desmethyl topotecan was
1.7 %. Overall, the N-desmethyl metabolite contributed a mean of less than 7 % (range 4-9 %)
of the total medicinal product related material accounted for in the urine and faeces. The
topotecan-O-glucuronide and N-desmethyl topotecan-O-glucuronide in the urine were less than
2.0 %.
In vitro
data using human liver microsomes indicate the formation of small amounts of
N-demethylated topotecan. In vitro, topotecan did not inhibit human P450 enzymes CYP1A2,
CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A or CYP4A nor did it inhibit the
human cytosolic enzymes dihydropyrimidine or xanthine oxidase.
When given in combination with cisplatin (cisplatin day 1, topotecan days 1 to 5), the clearance
of topotecan was reduced on day 5 compared to day 1 (19.1 l/h/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).
Paediatrics
The pharmacokinetics of topotecan given as a 30-minute infusion for 5 days were evaluated in
two studies. One study included a dose range of 1.4 mg/m
2
to 2.4 mg/m
2
in children (aged 2
up to 12 years, n = 18), adolescents (aged 12 up to 16 years, n = 9), and young adults (aged 16
to 21 years, n = 9) with refractory solid tumours. The second study included a dose range of
2.0 mg/m
2
to 5.2 mg/m
2
in children (n = 8), adolescents (n = 3), and young adults (n = 3) with
leukaemia. In these studies, there were no apparent differences in the pharmacokinetics of
topotecan among children, adolescents, and young adult patients with solid tumours or
leukaemia, but data are too limited to draw definite conclusions.
5.3 Preclinical safety data
Resulting from its mechanism of action, topotecan is genotoxic to mammalian cells (mouse
lymphoma cells and human lymphocytes)
in vitro
and mouse bone marrow cells
in vivo
.
Topotecan was also shown to cause embryo-foetal lethality when given to rats and rabbits.
In reproductive toxicity studies with topotecan in rats there was no effect on male or female fertility;
however, in females super-ovulation and slightly increased pre-implantation loss were observed.
The carcinogenic potential of topotecan has not been studied.
6.
12
6.1 List of excipients
Mannitol (E421)
Tartaric acid (E334)
Sodium hydroxide
Hydrochloric acid (E507)
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
Vials
3 years.
Reconstituted and diluted solutions
Chemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C, in
normal light conditions and 24 hours at 2 to 8°C, protected from light.
Chemical and physical stability of the solution obtained
after dilution
of the concentrate in sodium
chloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %) glucose solution for infusion has
been demonstrated for 4 hours at 25 ± 2°C, in normal lighting conditions. The concentrates tested
were stored at 25 ± 2°C for 12 hours and 24 hours respectively after reconstitution, and then diluted.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place
in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Keep the vial in the outer carton in order to protect from light.
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.
6.5
Nature and contents of container
Type I colourless glass vial (5 ml) with grey bromobutylic stopper and aluminium seal with
plastic flip-off cap.
Pack size:
1 vial containing 1 mg topotecan.
6.6 Special precautions for disposal and other handling
Potactasol 1 mg vials must be reconstituted with 1.1 ml water for injections. The clear
concentrate is pale yellow in colour and provides 1 mg per ml of topotecan, as Potactasol 1 mg
contains a 10 % overage of fill. Further dilution of the appropriate volume of the reconstituted
solution with either sodium chloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %)
glucose solution for infusion is required to a final concentration of between 25 and
50 microgram/ml.
The normal procedures for proper handling and disposal of anticancer medicinal products
should be adopted, namely:
13
1.
Reconstitution and dilution of the medicinal product must be performed by trained personnel.
2.
The preparation should be performed in a designated area under aseptic conditions.
3.
Adequate protective disposable gloves, goggles, gown and mask should be worn.
4.
Precautions should be taken to avoid the medicinal product accidentally coming into contact
with the eyes. In the event of contact with the eyes, irrigate with large amounts of water. Then
seek medical evaluation by a physician.
5.
In case of skin contact, thoroughly wash the affected area with large amount of water. Always
wash hands after removing gloves.
6.
Pregnant staff should not handle the cytotoxic preparation.
7.
Adequate care and precautions should be taken in the disposal of items (syringes, needles etc)
used to reconstitute and/or dilute cytotoxic medicinal products. Any unused product or waste
material should be disposed of in accordance with local requirements. All items for
administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags
for high-temperature incineration. Liquid waste may be flushed with large amounts of water.
7.
Actavis Group PTC ehf.
Reykjavíkurvegi 76-78
IS-220 Hafnarfjörður
Iceland
8.
9.
Detailed information on this medicinal product is available on the website of the European
Medicines Agency
http://www.ema.europa.eu/.
14
1.
Potactasol 4 mg powder for concentrate for solution for infusion
2.
Each vial contains 4 mg topotecan (as hydrochloride).
After reconstitution, 1 ml concentrate contains 1 mg topotecan.
Excipient: Each vial contains 2.07 mg sodium (0.09 mmol).
For a full list of excipients, see section 6.1.
3.
Powder for concentrate for solution for infusion.
Yellow lyophilisate.
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 reconstituted and further diluted before use (see section 6.6).
Posology
When used in combination with cisplatin, the full prescribing information for cisplatin should
be consulted.
Prior to administration of the first course of topotecan, patients must have a baseline neutrophil
count of ≥ 1.5 x 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
15
Initial dose
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)
16
In clinical studies with topotecan in combination with cisplatin for the treatment of cervical
cancer, therapy was only initiated in patients with serum creatinine less than or equal to
1.5 mg/dl. If, during topotecan/cisplatin combination therapy serum creatinine exceeds
1.5 mg/dl, it is recommended that the full prescribing information be consulted for any advice
on cisplatin dose reduction/continuation.
If cisplatin is discontinued, there are insufficient data regarding continuing monotherapy with
topotecan in patients with cervical cancer.
Paediatric population
The experience in children is limited, therefore no recommendation for treatment of paediatric
patients with Potactasol can be given (see sections 5.1 and 5.2).
Topotecan is contraindicated in patients who
-
have a history of severe hypersensitivity to the active substance or to any of the
excipients
-
already have severe bone marrow depression prior to starting first course, as evidenced by
baseline neutrophils < 1.5 x 10
9
/l and/or a platelet count of < 100 x 10
9
/l.
Haematological toxicity is dose-related and full blood count including platelets should be
monitored regularly (see section 4.2)
.
As with other cytotoxic medicinal products, topotecan can cause severe myelosuppression.
Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients
treated with topotecan (see section 4.8).
Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic
colitis have been reported in clinical trials with topotecan. In patients presenting with fever,
neutropenia, and a compatible pattern of abdominal pain, the possibility of neutropenic colitis
should be considered.
Topotecan has been associated with reports of interstitial lung disease (ILD), some of which
have been fatal (see section 4.8). Underlying risk factors include history of ILD, pulmonary
fibrosis, lung cancer, thoracic exposure to radiation and use of pneumotoxic substances and/or
colony stimulating factors. Patients should be monitored for pulmonary symptoms indicative of
ILD (e.g. cough, fever, dyspnoea and/or hypoxia), and topotecan should be discontinued if a
new diagnosis of ILD is confirmed.
Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated
with clinically relevant thrombocytopenia. This should be taken into account when prescribing
topotecan, e.g. in case patients at increased risk of tumour bleeds are considered for therapy.
As expected, patients with poor performance status (PS > 1) have a lower response rate and an
increased incidence of complications such as fever, infection and sepsis (see section 4.8).
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.
17
-
are breast feeding (see section 4.6)
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.
This medicinal product contains
less than 1 mmol sodium (23 mg) per vial, i.e. essentially
‘sodium-free’.
No
in vivo
human pharmacokinetic interaction studies have been performed.
Topotecan does not inhibit human P450 enzymes (see section 5.2). In an intravenous population
study, the coadministration of granisetron, ondansetron, morphine or corticosteroids did not
appear to have a significant effect on the pharmacokinetics of total topotecan (active and
inactive form).
In combining topotecan with other chemotherapy agents, reduction of the doses of each
medicinal product is 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 contraindicated during breast-feeding (see section 4.3). Although it is not known
whether topotecan is excreted in human breast milk, breast-feeding should be discontinued at
the start of therapy.
18
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.
In dose-finding trials involving 523 patients with relapsed ovarian cancer and 631 patients with
relapsed small cell lung cancer, the dose limiting toxicity of topotecan monotherapy was found
to be haematological. Toxicity was predictable and reversible. There were no signs of
cumulative haematological or non-haematological toxicity.
The adverse event profile for topotecan when given in combination with cisplatin in the cervical
cancer clinical trials is consistent with that seen with topotecan monotherapy. The overall
haematological toxicity is lower in patients treated with topotecan in combination with cisplatin
compared to topotecan monotherapy, but higher than with cisplatin alone.
Additional adverse events were seen when topotecan was given in combination with cisplatin,
however, these events were seen with cisplatin monotherapy and not attributable to topotecan.
The prescribing information for cisplatin should be consulted for a full list of adverse events
associated cisplatin use.
The integrated safety data for topotecan monotherapy are presented below.
Adverse reactions are listed below, by system organ class and absolute frequency (all reported
events). Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10);
uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000),
including isolated reports and not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Blood and lymphatic system disorders
Very common:
febrile neutropenia
neutropenia (see Gastrointestinal disorders below)
thrombocytopenia
anaemia
leukopenia
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
19
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
Common:
hypersensitivity reaction including rash
Rare:
anaphylactic reaction
angioedema
urticaria
Hepatobiliary 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
20
(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.
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
21
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
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 or intravenous topotecan
22
Study 065
Study 396
Oral
topotecan
Intravenous
topotecan
Oral topotecan Intravenous
topotecan
(N = 52)
(N = 54)
(N = 153)
(N = 151)
Median survival (weeks)
32.3
25.1
33.0
35.0
(95 % CI)
(26.3, 40.9)
(21.1, 33.0)
(29.1, 42.4)
(31.0, 37.1)
Hazard ratio (95 % CI)
0.88 (0.59, 1.31)
0.88 (0.7, 1.11)
Response rate (%)
23.1
14.8
18.3
21.9
(95 % CI)
(11.6, 34.5)
(5.3, 24.3)
(12.2, 24.4)
(15.3, 28.5)
Difference in response rate
(95 % CI)
8.3 (-6.6, 23.1)
-3.6 (-12.6, 5.5)
Median time to
progression (weeks)
14.9
13.1
11.9
14.6
(95 % CI)
(8.3, 21.3)
(11.6, 18.3)
(9.7, 14.1)
(13.3, 18.9)
Hazard ratio (95 % CI)
0.90 (0.60, 1.35)
1.21 (0.96, 1.53)
N = total number of patients treated.
CI = Confidence interval.
In another randomised phase III trial which compared IV topotecan to cyclophosphamide,
doxorubicin and vincristine (CAV) in patients with relapsed, sensitive SCLC, the overall
response rate was 24.3 % for topotecan compared to 18.3 % for the CAV group. Median time to
progression was similar in the two groups (13.3 weeks and 12.3 weeks respectively). Median
survivals for the two groups were 25.0 and 24.7 weeks respectively. The hazard ratio for
survival of IV topotecan relative to CAV was 1.04 (95 % CI 0.78 -1.40).
The response rate to topotecan in the combined small cell lung cancer programme (n = 480) for
patients with relapsed disease sensitive to first-line therapy, was 20.2 %. The median survival
was 30.3 weeks (95 % CI: 27.6, 33.4).
In a population of patients with refractory SCLC (those not responding to first line therapy), the
response rate to topotecan was 4.0 %.
Cervical carcinoma
In a randomised, comparative phase III trial conducted by the Gynaecological Oncology Group
(GOG 0179), topotecan plus cisplatin (n = 147) was compared with cisplatin alone (n = 146) for
the treatment of histologically confirmed persistent, recurrent or Stage IVB carcinoma of the
cervix where curative treatment with surgery and/or radiation was not considered appropriate.
Topotecan plus cisplatin had a statistically significant benefit in overall survival relative to
cisplatin monotherapy after adjusting for interim analyses (Log-rank p = 0.033).
Table 2. Study results Study GOG-0179
Cisplatin 50 mg/m
2
d.1
q21 d.
ITT population
Cisplatin 50 mg/m
2
d.1 +
Topotecan 0,75 mg/m
2
dx3 q21
Survival (months)
(n = 146)
(n = 147)
Median (95 % C.I.)
6.5 (5.8, 8.8)
9.4 (7.9, 11.9)
Hazard ratio (95 % C.I.)
0.76 (0.59-0.98)
Log rank p-value
0.033
Patients without prior cisplatin chemoradiotherapy
Cisplatin
Topotecan/Cisplatin
Survival (months)
(n = 46)
(n = 44)
23
Median (95 % C.I.)
8.8 (6.4, 11.5)
15.7 (11.9, 17.7)
Hazard ratio (95 % C.I.)
0.51 (0.31, 0.82)
Patients with prior cisplatin chemoradiotherapy
Cisplatin
Topotecan/Cisplatin
Survival (months)
(n = 72)
(n = 69)
Median (95 % C.I)
5.9 (4.7, 8.8)
7.9 (5.5, 10.9)
Hazard ratio (95 % C.I.)
0.85 (0.59, 1.21)
In patients (n = 39) with recurrence within 180 days after chemoradiotherapy with cisplatin, the
median survival in the topotecan plus cisplatin arm was 4.6 months (95 % C.I.: 2.6, 6.1) versus
4.5 months (95 % C.I.: 2.9, 9.6) for the cisplatin arm with an hazard ratio of 1.15 (0.59, 2.23). In
those (n = 102) with recurrence after 180 days, the median survival in the topotecan plus
cisplatin arm was 9.9 months (95 % C.I.: 7, 12.6) versus 6.3 months (95 % C.I.: 4.9, 9.5) for the
cisplatin arm with a hazard ratio of 0.75 (0.49, 1.16).
Paediatrics
Topotecan was also evaluated in the paediatric population; however, only limited data on
efficacy and safety are available.
In an open-label trial involving children (n = 108, age range: infant to 16 years) with recurrent
or progressive solid tumours, topotecan was administered at a starting dose of 2.0 mg/m
2
given
as a 30 minute infusion for 5 days repeated every 3 weeks for up to one year depending on
response to therapy. Tumour types included were Ewing's Sarcoma/primitive neuroectodermal
tumour, neuroblastoma, osteoblastoma, and rhabdomyosarcoma. Antitumour activity was
demonstrated primarily in patients with neuroblastoma. Toxicities of topotecan in paediatric
patients with recurrent and refractory solid tumours were similar to those historically seen in
adult patients. In this study, forty-six (43 %) patients received G-CSF over 192 (42.1 %)
courses; sixty-five (60 %) received transfusions of Packed Red Blood Cells and fifty (46 %) of
platelets over 139 and 159 courses (30.5 % and 34.9 %) respectively. Based on the dose-
limiting toxicity of myelosuppression, the maximum tolerated dose (MTD) was established at
2.0 mg/m
2
/day with G-CSF and 1.4 mg/m
2
/day without G-CSF in a pharmacokinetic study in
paediatric patients with refractory solid tumours (see section 5.2).
5.2 Pharmacokinetic properties
Following intravenous administration of topotecan at doses of 0.5 to 1.5 mg/m
2
as a 30 minute
infusion daily for five days, topotecan demonstrated a high plasma clearance of 62 l/h (SD 22),
corresponding to approximately 2/3 of liver blood flow. Topotecan also had a high volume of
distribution, about 132 l, (SD 57) and a relatively short half-life of 2-3 hours. Comparison of
pharmacokinetic parameters did not suggest any change in pharmacokinetics over the 5 days of
dosing. Area under the curve increased approximately in proportion to the increase in dose. There is
little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change
in the PK after multiple doses. Preclinical studies indicate plasma protein binding of topotecan is low
(35 %) and distribution between blood cells and plasma was fairly homogeneous.
The elimination of topotecan has only been partly investigated in man. A major route of
clearance of topotecan was by hydrolysis of the lactone ring to form the ring-opened
carboxylate.
Metabolism accounts for < 10 % of the elimination of topotecan. An N-desmethyl metabolite,
which was shown to have similar or less activity than the parent in a cell-based assay, was
found in urine, plasma, and faeces. The mean metabolite:parent AUC ratio was less than 10 %
for both total topotecan and topotecan lactone. An O-glucuronidation metabolite of topotecan
and N-desmethyl topotecan has been identified in the urine.
24
Overall recovery of medicinal product-related material following five daily doses of topotecan
was 71 to 76 % of the administered IV dose. Approximately 51 % was excreted as total
topotecan and 3 % was excreted as N-desmethyl topotecan in the urine. Faecal elimination of
total topotecan accounted for 18% while faecal elimination of N-desmethyl topotecan was
1.7 %. Overall, the N-desmethyl metabolite contributed a mean of less than 7 % (range 4-9 %)
of the total medicinal product related material accounted for in the urine and faeces. The
topotecan-O-glucuronide and N-desmethyl topotecan-O-glucuronide in the urine were less than
2.0 %.
In vitro
data using human liver microsomes indicate the formation of small amounts of
N-demethylated topotecan. In vitro, topotecan did not inhibit human P450 enzymes CYP1A2,
CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A or CYP4A nor did it inhibit the
human cytosolic enzymes dihydropyrimidine or xanthine oxidase.
When given in combination with cisplatin (cisplatin day 1, topotecan days 1 to 5), the clearance
of topotecan was reduced on day 5 compared to day 1 (19.1 l/h/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).
Paediatrics
The pharmacokinetics of topotecan given as a 30-minute infusion for 5 days were evaluated in
two studies. One study included a dose range of 1.4 mg/m
2
to 2.4 mg/m
2
in children (aged 2
up to 12 years, n = 18), adolescents (aged 12 up to 16 years, n = 9), and young adults (aged 16
to 21 years, n = 9) with refractory solid tumours. The second study included a dose range of
2.0 mg/m
2
to 5.2 mg/m
2
in children (n = 8), adolescents (n = 3), and young adults (n = 3) with
leukaemia. In these studies, there were no apparent differences in the pharmacokinetics of
topotecan among children, adolescents, and young adult patients with solid tumours or
leukaemia, but data are too limited to draw definite conclusions.
5.3 Preclinical safety data
Resulting from its mechanism of action, topotecan is genotoxic to mammalian cells (mouse
lymphoma cells and human lymphocytes)
in vitro
and mouse bone marrow cells
in vivo
.
Topotecan was also shown to cause embryo-foetal lethality when given to rats and rabbits.
In reproductive toxicity studies with topotecan in rats there was no effect on male or female fertility;
however, in females super-ovulation and slightly increased pre-implantation loss were observed.
The carcinogenic potential of topotecan has not been studied.
6.
25
6.1 List of excipients
Mannitol (E421)
Tartaric acid (E334)
Sodium hydroxide
Hydrochloric acid (E507)
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
Vials
3 years.
Reconstituted and diluted solutions
Chemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C, in
normal light conditions and 24 hours at 2 to 8°C, protected from light.
Chemical and physical stability of the solution obtained
after dilution
of the concentrate in sodium
chloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %) glucose solution for infusion has
been demonstrated for 4 hours at 25 ± 2°C, in normal lighting conditions. The concentrates tested
were stored at 25 ± 2°C for 12 hours and 24 hours respectively after reconstitution, and then diluted.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place
in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Keep the vial in the outer carton in order to protect from light.
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Type I colourless glass vials (8 ml), with grey bromobutylic stopper and aluminium seals with
plastic flip-off caps.
Pack size:
1 vial containing 4 mg topotecan.
6.6 Special precautions for disposal and other handling
Potactasol 4 mg vials must be reconstituted with 4 ml water for injections. The clear concentrate
is pale yellow in colour and provides 1 mg per ml of topotecan. Further dilution of the
appropriate volume of the reconstituted solution with either sodium chloride 9 mg/ml (0.9 %)
solution for injection 50 mg/ml (5 %) glucose solution for infusion is required to a final
concentration of between 25 and 50 microgram/ml.
The normal procedures for proper handling and disposal of anticancer medicinal products
should be adopted, namely:
1.
26
Reconstitution and dilution of the medicinal product must be performed by trained personnel.
2.
The preparation should be performed in a designated area under aseptic conditions.
3.
Adequate protective disposable gloves, goggles, gown and mask should be worn.
4.
Precautions should be taken to avoid the medicinal product accidentally coming into contact
with the eyes. In the event of contact with the eyes, irrigate with large amounts of water. Then
seek medical evaluation by a physician.
5.
In case of skin contact, thoroughly wash the affected area with large amount of water. Always
wash hands after removing gloves.
6.
Pregnant staff should not handle the cytotoxic preparation.
7.
Adequate care and precautions should be taken in the disposal of items (syringes, needles etc)
used to reconstitute and/or dilute cytotoxic medicinal products. Any unused product or waste
material should be disposed of in accordance with local requirements. All items for
administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags
for high-temperature incineration. Liquid waste may be flushed with large amounts of water.
7.
Actavis Group PTC ehf.
Reykjavíkurvegi 76-78
IS-220 Hafnarfjörður
Iceland
8.
9.
Detailed information on this medicinal product is available on the website of the European
Medicines Agency
http://www.ema.europa.eu/.
27
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
28
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
S.C. Sindan-Pharma S.R.L.
11 Ion Mihalache Blvd.
011171 Bucharest
Romania
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 5.03 of 12
October 2009, presented in Module 1.8.1. of the Marketing Authorisation Application, 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.
29
ANNEX III
LABELLING AND PACKAGE LEAFLET
30
A. LABELLING
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer Carton
1.
Potactasol 1 mg powder for concentrate for solution for infusion
topotecan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 1 mg topotecan (as hydrochloride), with a 10 % overage of fill.
After reconstitution, 1 ml concentrate contains 1 mg topotecan.
3.
LIST OF EXCIPIENTS
Contains mannitol (E421), tartaric acid (E334), hydrochloric acid (E507) and sodium
hydroxide. See leaflet for further information.
4.
Powder for concentrate for solution for infusion.
1 vial x 1 mg
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
For intravenous use as infusion, after reconstitution and dilution.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED
OUT OF THE 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).
Cytotoxic
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Keep the vial in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL
PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL
PRODUCTS, IF APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements.
32
Actavis Group PTC ehf.
Reykjavíkurvegi 76-78
Hafnarfjörður
Iceland
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
33
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING
UNITS
Vial
Potactasol 1 mg powder for concentrate for solution for infusion
topotecan
IV
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1 mg
6.
OTHER
Cytotoxic
34
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer Carton
1.
Potactasol 4 mg powder for concentrate for solution for infusion
topotecan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial cotnains 4 mg topotecan (as hydrochloride).
After reconstitution, 1 ml contains 1 mg topotecan.
3.
LIST OF EXCIPIENTS
Contains mannitol (E421), tartaric acid (E334), hydrochloric acid (E507) and sodium
hydroxide. See leaflet for further information.
4.
Powder for concentrate for solution for infusion.
1 vial x 4 mg
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
For intravenous use as infusion, after reconstitution and dilution.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED
OUT OF THE 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).
Cytotoxic
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Keep the vial in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL
PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL
PRODUCTS, IF APPROPRIATE
35
Any unused product or waste material should be disposed of in accordance with local
requirements.
Actavis Group PTC ehf.
Reykjavíkurvegi 76-78
Hafnarfjörður
Iceland
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
36
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING
UNITS
Vial
Potactasol 4 mg powder for concentrate for solution for infusion
topotecan
IV
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
4 mg
6.
OTHER
Cytotoxic
37
B. PACKAGE LEAFLET
38
PACKAGE LEAFLET: INFORMATION FOR THE USER
Potactasol 1 mg powder for concentrate for solution for infusion
Potactasol 4 mg powder for 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.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this
leaflet, please tell your doctor.
In this leaflet
:
1. What Potactasol is and what it is used for
2. Before you use Potactasol
3. How to use Potactasol
4. Possible side effects
5.
How to store Potactasol
6.
Further information
1.
WHAT POTACTASOL IS AND WHAT IT IS USED FOR
Potactasol helps to kill tumour cells.
Potactasol is used to treat:
-
ovarian cancer or small cell lung cancer that has come back after chemotherapy
-
advanced cervical cancer if surgery or radiotherapy is not possible. In this case Potactasol
treatment is combined with medicines containing cisplatin.
2.
BEFORE YOU USE POTACTASOL
Do not use Potactasol
- if you are allergic (hypersensitive) to topotecan or any of the other ingredients of
Potactasol (listed in section 6 under ‘What Potactasol contains’);
- if you are breast-feeding. You should stop breast-feeding before starting treatment with
Potactasol;
- if your blood cell counts are too low.
Tell you doctor
if you think any of these could apply to you.
Take special care with Potactasol
Tell your doctor:
-
if you have any kidney problems. Your dose of Potactasol may need to be adjusted. Potactasol
is not recommended in case of severe kidney impairment;
-
if you have liver problems. Potactasol is not recommended in case of severe liver impairment;
-
if you suffer from lung inflammation with signs such as cough, fever and difficulties in
breathing, see also section 4 “Possible side effects”.
Potactasol may cause a decrease in the number of blood clotting cells (platelets). This can lead to
severe bleeding from relatively small injuries such as a small cut. Rarely, it can lead to more severe
bleeding (haemorrhage). Talk to your doctor for advice on how to minimize the risk of bleeding.
39
-
Keep this leaflet. You may need to read it again.
The incidence of side effects is more frequent in patients who are in poor general health. The doctor
will evaluate your general health during the treatment and you should tell him/her in case you have
fever, infection or are in some ways feeling unwell.
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
Potactasol 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 Potactasol.
Driving and using machines
Potactasol can make you feel tired or weak. If you experience this, do not drive or use
machines.
Important information about some of the ingredients of Potactasol
This medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-free’.
3.
HOW POTACTASOL IS USED
Your dose of Potactasol 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.
Adults
Ovarian cancer 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 medicines containing
cisplatin. For more information about cisplatin, please refer to the corresponding package
leaflet.
Children
The experience in children is limited and treatment is therefore not recommended.
How Potactasol is prepared
Topotecan is supplied as a powder for concentrate for solution for infusion. The powder must be
dissolved, and the resulting concentrate further diluted before administration.
How Potactasol is given
40
A doctor or nurse will give you the reconstituted and diluted Potactasol solution as an infusion
(drip), usually into your arm, over about 30 minutes.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Potactasol 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.
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)
Potactasol 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, see also section 2 “Take special care with Potactasol”. This condition can
be fatal.
Other side effects with Potactasol 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.
-
Decrese in number of circulating white blood cells (leucotyes) in the blood. Abnormal
low number of neutrophil granulocytes (a type of white blood cell) in the blood, with or
without fever.
-
Unusual bruising or bleeding, sometimes severe, caused by a decrease in the number of
blood clotting cells (platelets).
-
Feeling sick (nausea), vomiting; diarrhoea; stomach pain; constipation.
-
Inflammation of the lining of the mouth and digestive tract.
-
Fever.
-
Infections.
-
Hair loss.
Common side effects
-
Allergic (hypersensitivity) reactions (including rash).
41
-
Weight loss and loss of appetite (anorexia); tiredness; weakness.
-
Abnormal high level of bilirubin, a waste product produced by the liver during
breakdown of red blood cells. Symptoms may include yellow skin (jaundice).
-
Decrease in the number of all blood cells (pancytopenia).
-
Feeling unwell.
-
Serious blood infection, which can be fatal.
-
Itching (pruritus).
Rare side effects
-
Severe allergic (anaphylactic) reactions.
-
Swelling caused by fluid build-up (angioedema) e.g. around the eyes and lips as well as
hands, feet and throat. If severe it may cause breathing difficulties.
-
Itchy rash (or hives).
Very rare side effects
-
Mild pain and inflammation at the site of injection due to accidental administration of the
medicinal product into the surrounding tissue (extravasation) e.g. by leakage.
If you are being treated for cervical cancer, you may get side effects from the other medicine
(cisplatin) that you will be given along with Potactasol.
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 POTACTASOL
Keep out of the reach and sight of children.
Do not use Potactasol after the expiry date which is stated on the vial and carton.
Keep the vial in the outer carton in order to protect from light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Potactasol contains
−
The active substance is topotecan. Each vial contains 1 mg (with 10 % overage of fill) or
4 mg topotecan (as hydrochloride). After reconstitution 1 ml concentrate contains 1 mg
topotecan.
−
The other ingredients are: mannitol (E421), tartaric acid (E334), hydrochloric acid (E507)
and sodium hydroxide.
What Potactasol looks like and contents of the pack
Potactasol is supplied in type I colourless glass vials with grey bromobutylic stopper and
aluminium seals with plastic flip-off caps.
Packs:
1 vial containing 1 mg topotecan
1 vial containing 4 mg topotecan
Marketing Authorisation Holder
Actavis Group PTC ehf.
Reykjavíkurvegi 76-78
Hafnarfjörður
42
Iceland
Manufacturer
S.C. Sindan-Pharma S.R.L.
11 Ion Mihalache Blvd
Bucharest
Romania
For any information about this medicine, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
ALL-in-1 bvba
Tél/Tel: +32 (0)32 86 88 88
Luxembourg/Luxemburg
ALL-in-1 bvba
Belgique/Belgien
Tél/Tel: +32 (0)32 86 88 88
България
Актавис ЕАД
Teл.: + 359 2 9321 680
Magyarország
Actavis Hungary Kft
Tel.: +36 1 501 7001
Česká republika
Actavis CZ a.s.
Tel: +420251001680
Malta
Actavis Ltd.
Tel: + 35621693533
Danmark
Actavis A/S
Tlf: +
45 72 22 30 00
Nederland
Actavis B.V.
Tel: 035 -54 299 33
Deutschland
Actavis Deutschland GmbH & Co. KG
Telefon: +49 (0)2173/1674 – 0
Norge
Actavis Norway AS
Tlf: +47 815 22 099
Eesti
UAB “Actavis Baltics” Eesti Filiaal
Tel: +372 6100 565
Österreich
Actavis GmbH
Tel: + 43 (0)662 435 235 00
Ελλάδα
PharOS - Pharmaceutical Oriented
Services Ltd
Tel : +30 210 66 64 667 – 8
Polska
Actavis Polska Sp. z o.o.
Tel.: + 48 22 512 29 00
España
Actavis Spain, S.A.
Tfno.: +34 91 630 86 45
Portugal
Actavis A/S Sucursal
Tel: + 351 21 722 06 50
France
Actavis
Tél: + 33 1 40 83 77 77
România
Actavis SRL
Tel: + 40 21 318 17 77
Ireland
Actavis UK Limited
United Kingdom
Tel: + 441271311200
Slovenija
Sanolabor d.d.
phone: +386 (0)1 585-4211
Ísland
Slovenská republika
43
Actavis Group PTC ehf
Sími: + 354-550 3300
Actavis s.r.o.
Tel: +421 2 3255 3801
Italia
Actavis Italy S.p.A.
Tel: +39 0331 583111
Suomi/Finland
Actavis Oy
Puh/Tel: +358 (0)9 348 233
Κύπρος
A. Potamitis Medicare Ltd
Τηλ: +35722313611
Sverige
Actavis AB
Tel: + 46 8 13 63 70
Latvija
Actavis Baltics pārstāvniecība Latvijā
Tel: +371 67067873
United Kingdom
Actavis UK Limited
Tel: + 441271311200
Lietuva
UAB “Actavis Baltics”
Tel: +370 5 260 9615
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/.
--------------------------------------------------------------------------------------------------------------------
------
The following information is intended for medical or healthcare professionals only:
Potactasol
INSTRUCTIONS ON USE
Guidelines for the safe handling and disposal of antineoplastic agents
1.
Reconstitution and dilution of the medicinal product must be performed by trained personnel.
2.
The preparation should be performed in a designated area under aseptic conditions.
3.
Adequate protective disposable gloves, goggles, gown and mask should be worn.
4.
Precautions should be taken to avoid the medicinal product accidentally coming into contact
with the eyes. In the event of contact with the eyes, irrigate with large amounts of water. Then
seek medical evaluation by a physician.
5.
In case of skin contact, thoroughly wash the affected area with large amount of water. Always
wash hands after removing gloves.
6.
Pregnant staff should not handle the cytotoxic preparation.
7.
Adequate care and precautions should be taken in the disposal of items (syringes, needles etc)
used to reconstitute and/or dilute cytotoxic medicinal products. Any unused product or waste
material should be disposed of in accordance with local requirements.
Reconstitution and dilution prior to administration
44
Before infusion, Potactasol powder for concentrate for solution for infusion must be
reconstituted with an appropriate volume of water for injections, as follows:
-
Potactasol 1 mg with 1.1 ml water for injections (as it contains 10 % overage of fill)
-
Potactasol 4 mg with 4 ml water for injections
Reconstitution will result in a concentrate containing 1 mg topotecan per ml.
This concentrate (1 mg/ml) must be diluted prior to administration.
The volume of reconstituted concentrate corresponding to the calculated individual dose, should
be further diluted with either sodium chloride 9 mg/ml (0.9 %) solution for injection or
50 mg/ml (5 %) glucose solution for infusion, to a final concentration of between
25 and 50 microgram per ml in the solution for infusion, for example:
Volume for
50 microgram/ml solution
1 ml of 1 mg/ml topotecan solution Add 39 ml to give 40 ml Add 19 ml to give 20 ml
4 ml of 1 mg/ml topotecan solution Add 156 ml to give 160 ml Add 76 ml to give 80 ml
Storage after reconstitution and dilution
Chemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C, in
normal light conditions and 24 hours at 2 to 8°C, protected from light.
Chemical and physical stability of the solution obtained
after dilution
of the concentrate in sodium
chloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %) glucose solution for infusion has
been demonstrated for 4 hours at 25 ± 2°C, in normal lighting conditions .The concentrates tested were
reconstituted and stored at 25 ± 2°C for 12 hours and 24 hours respectively after reconstitution, and
then diluted.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place
in controlled and validated aseptic conditions.
Disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
All items for administration or cleaning, including gloves, should be placed in high-risk, waste
disposal bags for high-temperature incineration. Liquid waste may be flushed with large
amounts of water.
45
Volume for
25 microgram/ml solution
Source: European Medicines Agency
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