ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
HYCAMTIN 1 mg powder for concentrate for solution for infusion
2.
Each vial contains 1 mg topotecan (as hydrochloride), with a 10 % overage of fill.
For a full list of excipients, see section 6.1.
3.
Powder for concentrate for solution for infusion.
Light yellow to greenish powder.
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
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 medications (e.g. G-CSF) or to dose reduce to maintain neutrophil counts.
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count
< 0.5 x 10
9
/l) for 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 medications (e.g. G-CSF) or to dose reduce to maintain neutrophil counts.
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count less than
0.5 x 10
9
/l) for 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 1.5 mg/dl, it is recommended that
3
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 HYCAMTIN can be given (see sections 5.1 and 5.2).
HYCAMTIN is contraindicated in patients who
−
have a history of severe hypersensitivity to the active substance or to any of the excipients
−
are breast feeding (see section 4.6)
−
already have severe bone marrow depression prior to starting first course, as evidenced by
baseline neutrophils < 1.5 x 10
9
/l and/or a platelet count of < 100 x 10
9
/l.
Haematological toxicity is dose-related and full blood count including platelets should be monitored
regularly (see section 4.2).
As with other cytotoxic medicinal products, topotecan can cause severe myelosuppression.
Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients treated
with topotecan (see section 4.8).
Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have
been reported in clinical trials with topotecan. In patients presenting with fever, neutropenia, and a
compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered.
Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been
fatal (see section 4.8). Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer,
thoracic exposure to radiation and use of pneumotoxic drugs and/or colony stimulating factors.
Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, dyspnoea
and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed.
Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated with
clinically relevant thrombocytopenia. This should be taken into account when prescribing
HYCAMTIN, 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 childbearing 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.
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.
5
The adverse event profile for topotecan when given in combination with cisplatin in the cervical
cancer clinical trials is consistent with that seen with topotecan monotherapy. The overall
haematological toxicity is lower in patients treated with topotecan in combination with cisplatin
compared to topotecan monotherapy, but higher than with cisplatin alone.
Additional adverse events were seen when topotecan was given in combination with cisplatin,
however, these events were seen with cisplatin monotherapy and not attributable to topotecan. The
prescribing information for cisplatin should be consulted for a full list of adverse events associated
cisplatin use.
The integrated safety data for topotecan monotherapy are presented below.
Adverse reactions are listed below, by system organ class and absolute frequency (all reported events).
Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon
(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), including isolated
reports and not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic system disorders
Very common: febrile neutropenia, neutropenia (see Gastrointestinal disorders),
thrombocytopenia, anaemia, leucopenia
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
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
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
6
Very common: infection
Common: malaise
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
7
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.
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
8
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 HYCAMTIN or intravenous HYCAMTIN
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, 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
q21 d.
Cisplatin
50 mg/m
2
d. 1 +
Topotecan
0.75 mg/m
2
dx3
q21
Survival (months)
(n= 146)
(n = 147)
Median (95 % C.I.)
6.5 (5.8, 8.8)
9.4 (7.9, 11.9)
Hazard ratio (95 % C.I.)
0.76 (0.59-0.98)
Log rank p-value
0.033
Patients without Prior Cisplatin Chemoradiotherapy
Cisplatin
Topotecan/Cisplatin
Survival (months)
(n= 46)
(n = 44)
Median (95 % C.I.)
8.8 (6.4, 11.5)
15.7 (11.9, 17.7)
Hazard ratio (95 % C.I.)
0.51 (0.31, 0.82)
Patients with Prior Cisplatin Chemoradiotherapy
Cisplatin
Topotecan/Cisplatin
Survival (months)
(n= 72)
(n = 69)
Median (95 % C.I)
5.9 (4.7, 8.8)
7.9 (5.5, 10.9)
Hazard ratio (95 % C.I.)
0.85 (0.59, 1.21)
In patients (n=39) with recurrence within 180 days after chemoradiotherapy with cisplatin, the median
survival in the topotecan plus cisplatin arm was 4.6 months (95 % C.I.: 2.6, 6.1) versus 4.5 months
(95 %C.I.: 2.9, 9.6) for the cisplatin arm with an hazard ratio of 1.15 (0.59, 2.23). In those (n=102)
with recurrence after 180 days, the median survival in the topotecan plus cisplatin arm was 9.9 months
(95 % C.I.: 7, 12.6) versus 6.3 months (95 %C.I.: 4.9, 9.5) for the cisplatin arm with an hazard ratio of
0.75 (0.49, 1.16).
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
10
distribution, about 132 l, (SD 57) and a relatively short half-life of 2-3 hours. Comparison of
pharmacokinetic parameters did not suggest any change in pharmacokinetics over the 5 days of
dosing. Area under the curve increased approximately in proportion to the increase in dose. There is
little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change
in the PK after multiple doses. Preclinical studies indicate plasma protein binding of topotecan is low
(35 %) and distribution between blood cells and plasma was fairly homogeneous.
The elimination of topotecan has only been partly investigated in man. A major route of clearance of
topotecan was by hydrolysis of the lactone ring to form the ring-opened carboxylate.
Metabolism accounts for < 10 % of the elimination of topotecan. An N-desmethyl metabolite, which
was shown to have similar or less activity than the parent in a cell-based assay, was found in urine,
plasma, and faeces. The mean metabolite:parent AUC ratio was less than 10 % for both total topotecan
and topotecan lactone. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has
been identified in the urine.
Overall recovery of medicinal product-related material following five daily doses of topotecan was 71
to 76 % of the administered IV dose. Approximately 51 % was excreted as total topotecan and 3 %
was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted
for 18 % while faecal elimination of N-desmethyl topotecan was 1.7 %. Overall, the N-desmethyl
metabolite contributed a mean of less than 7 % (range 4-9 %) of the total medicinal product related
material accounted for in the urine and faeces. The topotecan-O-glucuronide and N-desmethyl
topotecan-O-glucuronide in the urine were less than 2.0 %.
In vitro
data using human liver microsomes indicate the formation of small amounts of 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
11
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)
Mannitol (E421)
Hydrochloric acid (E507)
Sodium hydroxide
6.2 Incompatibilities
None known.
6.3 Shelf life
Vials
3 years.
Reconstituted and diluted solutions
The product should be used immediately after reconstitution as it contains no antibacterial
preservative. If reconstitution and dilution is performed under strict aseptic conditions (e.g. an LAF
bench) the product should be used (infusion completed) within 12 hours at room temperature or
24 hours if stored at 2-8
0
C after the first puncture of the vial.
6.4 Special precautions for storage
Keep the vial in the outer carton in order to protect from light.
6.5 Nature and contents of container
HYCAMTIN 1 mg is supplied in 5 ml type I flint glass vials, together with 13 mm grey butyl rubber
stoppers and 13 mm aluminium seals with plastic flip-off caps.
HYCAMTIN 1 mg 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
HYCAMTIN 1 mg vials must be reconstituted with 1.1 ml water for injections. Since HYCAMTIN
contains a 10 % overage, the clear, reconstituted solution is yellow to yellow-green in colour and
provides 1 mg per ml of topotecan. Further dilution of the appropriate volume of the reconstituted
12
solution with either 0.9 % w/v sodium chloride intravenous infusion or 5 % w/v glucose intravenous
infusion is required to a final concentration of between 25 and 50 microgram/ml.
The normal procedures for proper handling and disposal of anticancer medicinal products should be
adopted, namely:
−
Personnel should be trained to reconstitute the medicinal product.
−
Pregnant staff should be excluded from working with this medicinal product.
−
Personnel handling this medicinal product during reconstitution should wear protective clothing
including mask, goggles and gloves.
−
All items for administration or cleaning, including gloves, should be placed in 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.
7.
SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom.
8.
1 mg vials:
5 vials
EU/1/96/027/004
1 vial
EU/1/96/027/005
9.
Date of first authorisation: 12/11/1996
Date of latest renewal: 12/11/2006
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
13
1.
HYCAMTIN 4 mg powder for concentrate for solution for infusion
2.
Each vial contains 4 mg topotecan (as hydrochloride).
For a full list of excipients, see section 6.1.
3.
Powder for concentrate for solution for infusion.
Light yellow to greenish powder.
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
14
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 ≥ 9g/dl (after transfusion if necessary).
Standard oncology practice for the management of neutropenia is either to administer topotecan with
other medications (e.g. G-CSF) or to dose reduce to maintain neutrophil counts.
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count
< 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 9g/dl (after transfusion if necessary).
Standard oncology practice for the management of neutropenia is either to administer topotecan with
other medications (e.g. G-CSF) or to dose reduce to maintain neutrophil counts.
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count less than
0.5 x 10
9
/l) for 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,
15
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 HYCAMTIN can be given (see sections 5.1 and 5.2).
HYCAMTIN is contraindicated in patients who
−
have a history of severe hypersensitivity to the active substance or to any of the excipients
−
are breast feeding (see section 4.6)
−
already have severe bone marrow depression prior to starting first course, as evidenced by
baseline neutrophils < 1.5 x 10
9
/l and/or a platelet count of < 100 x 10
9
/l.
Haematological toxicity is dose-related and full blood count including platelets should be monitored
regularly (see section 4.2)
.
As with other cytotoxic medicinal products, topotecan can cause severe myelosuppression.
Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients treated
with topotecan (see section 4.8).
Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have
been reported in clinical trials with topotecan. In patients presenting with fever, neutropenia, and a
compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered.
Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been
fatal (see section 4.8). Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer,
thoracic exposure to radiation and use of pneumotoxic drugs and/or colony stimulating factors.
Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, dyspnoea
and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed.
Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated with
clinically relevant thrombocytopenia. This should be taken into account when prescribing
HYCAMTIN, 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.
16
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 childbearing 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.
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
17
haematological or non-haematological toxicity.
The adverse event profile for topotecan when given in combination with cisplatin in the cervical
cancer clinical trials is consistent with that seen with topotecan monotherapy. The overall
haematological toxicity is lower in patients treated with topotecan in combination with cisplatin
compared to topotecan monotherapy, but higher than with cisplatin alone.
Additional adverse events were seen when topotecan was given in combination with cisplatin,
however, these events were seen with cisplatin monotherapy and not attributable to topotecan. The
prescribing information for cisplatin should be consulted for a full list of adverse events associated
cisplatin use.
The integrated safety data for topotecan monotherapy are presented below.
Adverse reactions are listed below, by system organ class and absolute frequency (all reported events).
Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon
(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), including isolated
reports and not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic system disorders
Very common: febrile neutropenia, neutropenia (see Gastrointestinal disorders),
thrombocytopenia, anaemia, leucopenia
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
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
Very rare: extravasation
3
3
Extravasation has been reported very rarely. Reactions have been mild and have not
generally required specific therapy.
18
Very common: infection
Common: malaise
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.
19
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.
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
20
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 HYCAMTIN or intravenous HYCAMTIN
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, 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).
21
Table 2. Study results Study GOG-0179
ITT population
Cisplatin
50 mg/m
2
d. 1
q21 d.
Cisplatin
50 mg/m
2
d. 1 +
Topotecan
0.75 mg/m
2
dx3
q21
Survival (months)
(n= 146)
(n = 147)
Median (95 % C.I.)
6.5 (5.8, 8.8)
9.4 (7.9, 11.9)
Hazard ratio (95 % C.I.)
0.76 (0.59-0.98)
Log rank p-value
0.033
Patients without Prior Cisplatin Chemoradiotherapy
Cisplatin
Topotecan/Cisplatin
Survival (months)
(n= 46)
(n = 44)
Median (95 % C.I.)
8.8 (6.4, 11.5)
15.7 (11.9, 17.7)
Hazard ratio (95 % C.I.)
0.51 (0.31, 0.82)
Patients with Prior Cisplatin Chemoradiotherapy
Cisplatin
Topotecan/Cisplatin
Survival (months)
(n= 72)
(n = 69)
Median (95 % C.I)
5.9 (4.7, 8.8)
7.9 (5.5, 10.9)
Hazard ratio (95 % C.I.)
0.85 (0.59, 1.21)
In patients (n=39) with recurrence within 180 days after chemoradiotherapy with cisplatin, the median
survival in the topotecan plus cisplatin arm was 4.6 months (95 % C.I.: 2.6, 6.1) versus 4.5 months
(95 %C.I.: 2.9, 9.6) for the cisplatin arm with an hazard ratio of 1.15 (0.59, 2.23). In those (n=102)
with recurrence after 180 days, the median survival in the topotecan plus cisplatin arm was 9.9 months
(95 % C.I.: 7, 12.6) versus 6.3 months (95 %C.I.: 4.9, 9.5) for the cisplatin arm with an hazard ratio of
0.75 (0.49, 1.16).
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
22
distribution, about 132 l, (SD 57) and a relatively short half-life of 2-3 hours. Comparison of
pharmacokinetic parameters did not suggest any change in pharmacokinetics over the 5 days of
dosing. Area under the curve increased approximately in proportion to the increase in dose. There is
little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change
in the PK after multiple doses. Preclinical studies indicate plasma protein binding of topotecan is low
(35 %) and distribution between blood cells and plasma was fairly homogeneous.
The elimination of topotecan has only been partly investigated in man. A major route of clearance of
topotecan was by hydrolysis of the lactone ring to form the ring-opened carboxylate.
Metabolism accounts for < 10 % of the elimination of topotecan. An N-desmethyl metabolite, which
was shown to have similar or less activity than the parent in a cell-based assay, was found in urine,
plasma, and faeces. The mean metabolite:parent AUC ratio was less than 10 % for both total topotecan
and topotecan lactone. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has
been identified in the urine.
Overall recovery of medicinal product-related material following five daily doses of topotecan was 71
to 76 % of the administered IV dose. Approximately 51 % was excreted as total topotecan and 3 %
was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted
for 18 % while faecal elimination of N-desmethyl topotecan was 1.7 %. Overall, the N-desmethyl
metabolite contributed a mean of less than 7 % (range 4-9 %) of the total medicinal product related
material accounted for in the urine and faeces. The topotecan-O-glucuronide and N-desmethyl
topotecan-O-glucuronide in the urine were less than 2.0 %.
In vitro
data using human liver microsomes indicate the formation of small amounts of 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).
23
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.
6.1 List of excipients
Tartaric acid (E334)
Mannitol (E421)
Hydrochloric acid(E507)
Sodium hydroxide
6.2 Incompatibilities
None known.
6.3 Shelf life
Vials
3 years.
Reconstituted and diluted solutions
The product should be used immediately after reconstitution as it contains no antibacterial
preservative. If reconstitution and dilution is performed under strict aseptic conditions (e.g. an LAF
bench) the product should be used (infusion completed) within 12 hours at room temperature or 24
hours if stored at 2-8
0
C after the first puncture of the vial.
6.4 Special precautions for storage
Keep the vial in the outer carton in order to protect from light.
6.5 Nature and contents of container
HYCAMTIN 4 mg is supplied in 17 ml type I flint glass vials, together with 20 mm grey butyl rubber
stoppers and 20 mm aluminium seals with plastic flip-off caps.
HYCAMTIN 4 mg is available in cartons containing 1 vial and 5 vials.
24
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
HYCAMTIN 4 mg vials must be reconstituted with 4 ml water for injections. The clear, reconstituted
solution is yellow to yellow-green in colour and provides 1 mg per ml of topotecan. Further dilution of
the appropriate volume of the reconstituted solution with either 0.9 % w/v sodium chloride
intravenous infusion or 5 % w/v glucose intravenous infusion is required to a final concentration of
between 25 and 50 microgram/ml.
The normal procedures for proper handling and disposal of anticancer medicinal products should be
adopted, namely:
−
Personnel should be trained to reconstitute the medicinal product.
−
Pregnant staff should be excluded from working with this medicinal product.
−
Personnel handling this medicinal product during reconstitution should wear protective clothing
including mask, goggles and gloves.
−
All items for administration or cleaning, including gloves, should be placed in 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.
7.
SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom.
8.
4 mg vials:
5 vials
EU/1/96/027/001
1 vial
EU/1/96/027/003
9.
Date of first authorisation: 12/11/1996
Date of latest renewal: 12/11/2006
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
25
1.
HYCAMTIN 0.25 mg hard capsules
2.
Each capsule contains topotecan hydrochloride equivalent to 0.25 mg of topotecan.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
The capsules are opaque white to yellowish white and imprinted with ‘HYCAMTIN’ and ‘0.25 mg’.
4.
HYCAMTIN capsules are indicated as monotherapy for the treatment of adult 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).
Method of administration
HYCAMTIN capsules should only be prescribed and therapy supervised by a physician experienced in
the use of chemotherapeutic agents.
Posology
Initial dose
The recommended dose of HYCAMTIN capsules is 2.3 mg/m
2
body surface area/day administered 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).
The capsule(s) must be swallowed whole, and must not be chewed crushed or divided.
Hycamtin capsules may be taken with or without food (see section 5.2).
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).
Subsequent doses
Topotecan should not be re-administered unless the neutrophil count is ≥ 1 x 10
9
/l, the platelet count is
≥ 100 x 10
9
/l, and the haemoglobin level is ≥ 9 g/dl (after transfusion if necessary).
Standard oncology practice for the management of neutropenia is either to administer topotecan with
other medications (e.g. G-CSF) or to dose reduce to maintain neutrophil counts.
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count
26
< 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 0.4 mg/m
2
/day to
1.9 mg/m
2
/day (or subsequently down to 1.5 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 needed to be reduced below 1.5 mg/m
2
.
For patients who experience Grade 3 or 4 diarrhoea, the dose should be reduced by 0.4 mg/m2/day for
subsequent courses (see section 4.4). Patients with Grade 2 diarrhoea may need to follow the same
dose modification guidelines.
Proactive management of diarrhoea with anti-diarrhoeal agents is important. Severe cases of diarrhoea
may require administration of oral or intravenous electrolytes and fluids, and interruption of topotecan
therapy (see sections 4.4 and 4.8).
Dosage in renally impaired patients
Patients with small cell lung carcinoma who participated in oral topotecan clinical trials had a serum
creatinine less than or equal to 1.5 mg/dl (133 µmol/l) or a creatinine clearance of greater than or equal
to 60 ml/min. Dosing recommendations for patients receiving oral topotecan with Cl
cr
less than
60 ml/min have not been established (see section 4.4).
Dosage in hepatically impaired patients
Pharmacokinetics of HYCAMTIN capsules have not been specifically studied in patients with
impaired hepatic function. There are insufficient data available with HYCAMTIN capsules to make a
dose recommendation for this patient group (see section 4.4).
Paediatric population
The experience in children is limited, therefore no recommendation for treatment of paediatric patients
with HYCAMTIN can be given (see section 5.1).
Elderly
No overall differences in effectiveness were observed between patients over 65 years and younger
adult patients. However in the two studies administering both oral and intravenous topotecan, patients
older than 65 years old receiving oral topotecan experienced an increase in drug related diarrhoea
compared to those younger than 65 years of age (see section 4.4 and 4.8).
HYCAMTIN is contraindicated in patients who
−
have a history of severe hypersensitivity to the active substance or to any of the excipients
−
are breast feeding (see section 4.6)
−
already have severe bone marrow depression prior to starting first course, as evidenced by
baseline neutrophils < 1.5 x 10
9
/l and/or a platelet count of < 100 x 10
9
/l.
Haematological toxicity is dose-related and full blood count including platelets should be monitored
regularly (see section 4.2).
As with other cytotoxic medicinal products, topotecan can cause severe myelosuppression.
Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients treated
with topotecan (see section 4.8).
Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have
been reported in clinical trials with topotecan. In patients presenting with fever, neutropenia, and a
compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered.
27
Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been
fatal (see section 4.8). Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer,
thoracic exposure to radiation and use of pneumotoxic drugs and/or colony stimulating factors.
Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, dyspnoea
and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed.
Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated with
clinically relevant thrombocytopenia. This should be taken into account when prescribing
HYCAMTIN, 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.
Topotecan is partly eliminated via renal excretion and renal impairment might lead to increased
exposure to topotecan. Dosing recommendations for patients receiving oral topotecan with Cl
cr
less
than 60 ml/min have not been established. There is insufficient experience of the use of oral or
intravenous topotecan in patients with severely impaired renal function (creatinine clearance
< 20 ml/min). Topotecan is not recommended to be used in these patients.
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. There is insufficient experience of the use of topotecan in
patients with severely impaired hepatic function (serum bilirubin ≥ 10 mg/dl). Topotecan is not
recommended to be used in these patients.
Diarrhoea, including severe diarrhoea requiring hospitalization, has been reported during treatment
with oral topotecan. Diarrhoea related to oral topotecan can occur at the same time as drug-related
neutropenia and its sequelae. Communication with patients prior to drug administration regarding
these side effects and proactive management of early and all signs and symptoms of diarrhoea is
important.
Cancer treatment-induced diarrhoea (CTID) is associated with significant morbidity and
may be life-threatening. Should diarrhoea occur during treatment with oral topotecan, physicians are
advised to aggressively manage diarrhoea. Clinical guidelines describing the aggressive management
of CTID includes specific recommendations on patient communication and awareness, recognition of
early warning signs, use of anti-diarrhoeals and antibiotics, changes in fluid intake and diet, and need
for hospitalization (see sections 4.2 and 4.8).
Intravenous topotecan should be considered in the following clinical situations: uncontrolled emesis,
swallowing disorders, uncontrolled diarrhoea, clinical conditions and medication that may alter
gastrointestinal motility and drug absorption.
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).
Topotecan is a substrate for both ABCB1 (P-glycoprotein) and ABCG2 (BCRP). Inhibitors of ABCB1
and ABCG2 administered with oral topotecan have been shown to increase topotecan exposure.
Cyclosporin A (an inhibitor of ABCB1, ABCC1 [MRP-1], and CYP3A4) administered with oral
28
topotecan increased topotecan AUC to approximately 2 - 2.5-fold of control.
Patients should be carefully monitored for adverse reactions when oral topotecan is administered with
a drug known to inhibit ABCB1 or ABCG2 (see section 5.2).
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. Currently
there is only limited experience in combining oral topotecan with other chemotherapy agents.
The pharmacokinetics of topotecan was generally unchanged when coadministered with ranitidine.
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 childbearing 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.
In clinical trials involving patients with relapsed small cell lung cancer, the dose limiting toxicity of
oral topotecan monotherapy was found to be haematological. Toxicity was predictable and reversible.
There were no signs of cumulative haematological or non-haematological toxicity.
The frequencies associated with the haematological and non-haematological adverse events presented
are for adverse events considered to be related/possibly related to oral topotecan therapy.
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
29
(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), including isolated
reports and not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic system disorders
Very common: febrile neutropenia, neutropenia (see Gastrointestinal disorders),
thrombocytopenia, anaemia, leucopenia
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), which may
lead to dehydration (see sections 4.2 and 4.4)
Common: abdominal pain
1
, constipation, mucositis, dyspepsia
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: pruritis
Metabolism and nutrition disorders
Very common: anorexia (which may be severe)
Infections and infestations
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: fatigue
Common : asthenia, pyrexia, malaise
Immune system disorders
Common: hypersensitivity reaction including rash
Not known: anaphylactic reaction, angioedema, urticaria
Hepato-biliary disorders
Uncommon: 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).
Safety data are presented based on an integrated data set of 682 patients with relapsed lung cancer
administered 2536 courses of oral topotecan monotherapy (275 patients with relapsed SCLC and 407
with relapsed non-SCLC).
Haematological
Neutropenia
: Severe neutropenia (Grade 4 - neutrophil count < 0.5 x 10
9
/l) occurred in 32 % of
patients in 13 % of courses. Median time to onset of severe neutropenia was Day 12 with a median
duration of 7 days. In 34 % of courses with severe neutropenia, the duration was > 7 days. In course 1
30
Very common: infection
the incidence was 20 %, by courses 4 the incidence was 8 %. Infection, sepsis and febrile neutropenia
occurred in 17 %, 2 %, and 4 % of patients, respectively. Death due to sepsis occurred in 1 % of
patients. Pancytopenia has been reported. Growth factors were administered to 19 % of patients in 8 %
of courses
.
Thrombocytopenia:
Severe thrombocytopenia (Grade 4 - platelets less than 10 x 10
9
/l) occurred in 6 %
of patients in 2 % of courses. Median time to onset of severe thrombocytopenia was Day 15 with a
median duration of 2.5 days. In 18 % of courses with severe thrombocytopenia the duration was
> 7 days. Moderate thrombocytopenia (Grade 3 - platelets between 10.0 and 50.0 x 10
9
/l) occurred in
29 % of patients in 14 % of courses. Platelet transfusions were given to 10 % of patients in 4 % of
courses. Reports of significant sequelae associated with thrombocytopenia including fatalities due to
tumour bleeds have been infrequent.
Anaemia:
Moderate to severe anaemia (Grade 3 and 4 – Hb ≤ 8.0 g/dl) occurred in 25 % of patients
(12 % of courses). Median time to onset of moderate to severe anaemia was Day 12 with a median
duration of 7 days. In 46 % of courses with moderate to severe anaemia, the duration was > 7 days.
Red blood cell transfusions were given in 30 % of patients (13 % of courses). Erythropoietin was
administered to 10 % of patients in 8 % of courses.
Non-haematological
The most frequently reported non-haematological effects were nausea (37 %), diarrhoea (29 %),
fatigue (26 %), vomiting (24 %), alopecia (21 %) and anorexia (18 %). All cases were irrespective of
associated causality. For severe cases (CTC grade 3/4) reported as related / possibly related to
topotecan administration the incidence was diarrhoea 5 % (see section 4.4), fatigue 4 %, vomiting 3 %,
nausea 3 % and anorexia 2 %.
The overall incidence of drug-related diarrhoea was 22 %, including 4 % with Grade 3 and 0.4 % with
Grade 4. Drug-related diarrhoea was more frequent in patients ≥65 years of age (28 %) compared to
those less than 65 years of age (19 %).
Complete alopecia related/possibly related to topotecan administration was observed in 9 % of patients
and partial alopecia related/possibly related to topotecan administration in 11 % of patients.
Therapeutic interventions associated with non-haematological effects included anti-emetic agents,
given to 47 % of patients in 38 % of courses and anti-diarrhoeal agents, given to 15 % of patients in
6 % of courses. A 5-HT3 antagonist was administered to 30 % of patients in 24 % of courses.
Loperamide was administered to 13 % of patients in 5 % of courses. The median time to onset of
grade 2 or worse diarrhoea was 9 days.
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
31
breaks.
Relapsed SCLC
A phase III trial (study 478) compared oral topotecan plus Best Supportive Care (BSC) (n=71) with
BSC alone (n=70) in patients who had relapsed following first line therapy (median time to
progression [TTP] from first-line therapy: 84 days for oral topotecan + BSC, 90 days for BSC) and for
whom retreatment with intravenous chemotherapy was not considered appropriate. Oral topotecan plus
BSC group had a statistically significant improvement in overall survival compared with the BSC
alone group (Log-rank p=0.0104). The unadjusted hazard ratio for oral topotecan plus BSC group
relative to BSC alone group was 0.64 (95 % CI: 0.45, 0.90). The median survival for patients treated
with topotecan + BSC was 25.9 weeks (95 % C.I. 18.3, 31.6) compared to 13.9 weeks
(95 % C.I. 11.1, 18.6) for patients receiving BSC alone (p=0.0104).
Patient self-reports of symptoms using an unblinded assessment showed a consistent trend for
symptom benefit for oral topotecan + BSC.
One Phase 2 study (Study 065) and one Phase 3 study (Study 396) were conducted to evaluate the
efficacy of oral topotecan versus intravenous topotecan in patients who had relapsed ≥ 90 days after
completion of one prior regimen of chemotherapy (see Table 1). Oral and intravenous topotecan were
associated with similar symptom palliation in patients with relapsed sensitive SCLC in patient self-
reports on an unblinded symptom scale assessment in each of these two studies.
Table 1. Summary of survival, response rate, and time to progression in SCLC patients treated
with oral HYCAMTIN or intravenous HYCAMTIN
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.
Paediatrics
Safety and effectiveness of oral topotecan in paediatric patients have not been established.
5.2 Pharmacokinetic properties
The pharmacokinetics of topotecan after oral administration have been evaluated in cancer patients
following doses of 1.2 to 3.1 mg/m
2
/day and 4 mg/m
2
/day administered daily for 5 days. The
bioavailability of oral topotecan (total and lactone) in humans is approximately 40 %. Plasma
concentrations of total topotecan (i.e. lactone and carboxylate forms) and topotecan lactone (active
moiety) peak at approximately 2.0 hours and 1.5 hours, respectively, and decline bi-exponentially with
mean terminal half-life of approximately 3.0 to 6.0 hour. Total exposure (AUC) increases
32
approximately proportionally with 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.
A major route of clearance of topotecan is by hydrolysis of the lactone ring to form the ring-opened
carboxylate. Other than hydrolysis, topotecan is cleared predominantly renally, with a minor
component metabolized to the N-desmethyl metabolite (SB-209780) identified in plasma, urine and
faeces. Overall recovery of topotecan-related material following five daily doses of topotecan was 49
to 72 % (mean 57 %) of the administered oral dose. Approximately 20 % was excreted as total
topotecan and 2 % was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total
topotecan accounted for 33 % while faecal elimination of N-desmethyl topotecan was 1.5 %. Overall,
the N-desmethyl metabolite contributed a mean of less than 6 % (range 4-8 %) of the total topotecan
related material accounted for in the urine and faeces. O-glucuronides of both topotecan and N-
desmethyl topotecan have been identified in the urine. The mean metabolite: parent plasma AUC ratio
was less than 10 % for both total topotecan and topotecan lactone.
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.
Following coadministration of the ABCB1 (P-gp) and ABCG2 (BCRP) inhibitor, elacridar
(GF120918) at 100 to 1,000 mg with oral topotecan, the AUC0-∞ of topotecan lactone and total
topotecan increased approximately 2.5-fold (see section 4.5 for guidance).
Administration of oral cyclosporine A (15 mg/kg), an inhibitor of transporters ABCB1 (P-gp) and
ABCC1 (MRP-1) as well as the metabolising enzyme CYP3A4, within 4 hours of oral topotecan
increased the dose normalised AUC0-24h of topotecan lactone and total topotecan approximately 2.0-
and 2.5-fold, respectively (see section 4.5).
The extent of exposure was similar following a high fat meal and fasted state while tmax was delayed
from 1.5 to 3 hours (topotecan lactone) and from 3 to 4 hours (total topotecan).
The pharmacokinetics of oral topotecan has not been studied in patients with renal or hepatic
impairment (see section 4.2 and 4.4).
A cross-study analysis in 217 patients with advanced solid tumours indicated that gender did not affect
the pharmacokinetics of HYCAMTIN capsules
to a clinically relevant extent. There are insufficient
data to determine an effect of race on pharmacokinetics of oral topotecan.
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.
33
6.
6.1 List of excipients
Capsule contents:
Hydrogenated vegetable oil
Glyceryl monostearate
Capsule shell:
Gelatin
Titanium dioxide (E171)
Sealing band:
Gelatin
Black ink comprising:
black iron oxide (E172)
shellac
anhydrous ethanol – see leaflet for further information
propylene glycol
isopropyl alcohol
butanol
concentrated ammonia solution
potassium hydroxide
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in a refrigerator (2ºC - 8ºC).
Keep the blister card in the outer carton in order to protect from light.
Do not freeze.
6.5 Nature and contents of container
White polyvinyl chloride / polychlorotrifluoroethylene blister sealed with aluminium /
Polyethylenterephtalate (PET) / paper foil lidding.
The blisters are sealed with a peel-push child resistant opening feature.
Each blister card contains 10 capsules.
6.6 Special precautions for disposal and other handling
HYCAMTIN capsules should not be opened or crushed.
Any unused product or waste material should be disposed of in accordance with local requirements.
34
7.
SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom.
8.
EU/1/96/027/006
9.
Date of first authorisation: 12/11/1996
Date of latest renewal: 12/11/2006
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu/.
35
1.
HYCAMTIN 1 mg hard capsules
2.
Each capsule contains topotecan hydrochloride equivalent to 1 mg of topotecan.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
The capsules are opaque pink and imprinted with ‘HYCAMTIN’ and ‘1 mg’.
4.
HYCAMTIN capsules are indicated as monotherapy for the treatment of adult 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).
Method of administration
HYCAMTIN capsules should only be prescribed and therapy supervised by a physician experienced in
the use of chemotherapeutic agents.
Posology
Initial dose
The recommended dose of HYCAMTIN capsules is 2.3 mg/m
2
body surface area/day administered 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).
The capsule(s) must be swallowed whole, and must not be chewed crushed or divided.
Hycamtin capsules may be taken with or without food (see section 5.2).
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).
Subsequent doses
Topotecan should not be re-administered unless the neutrophil count is ≥ 1 x 10
9
/l, the platelet count is
≥ 100 x 10
9
/l, and the haemoglobin level is ≥ 9 g/dl (after transfusion if necessary).
Standard oncology practice for the management of neutropenia is either to administer topotecan with
other medications (e.g. G-CSF) or to dose reduce to maintain neutrophil counts.
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count
< 0.5 x 10
9
/l) for seven days or more, or severe neutropenia associated with fever or infection, or who
36
have had treatment delayed due to neutropenia, the dose should be reduced by 0.4 mg/m
2
/day to
1.9 mg/m
2
/day (or subsequently down to 1.5 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 needed to be reduced below 1.5 mg/m
2
.
For patients who experience Grade 3 or 4 diarrhoea, the dose should be reduced by 0.4 mg/m
2
/day for
subsequent courses (see section 4.4). Patients with Grade 2 diarrhoea may need to follow the same
dose modification guidelines.
Proactive management of diarrhoea with anti-diarrhoeal agents is important. Severe cases of diarrhoea
may require administration of oral or intravenous electrolytes and fluids, and interruption of topotecan
therapy (see sections 4.4 and 4.8).
Dosage in renally impaired patients
Patients with small cell lung carcinoma who participated in oral topotecan clinical trials had a serum
creatinine less than or equal to 1.5 mg/dl (133 µmol/l) or a creatinine clearance of greater than or equal
to 60 ml/min. Dosing recommendations for patients receiving oral topotecan with Cl
cr
less than
60 ml/min have not been established (see section 4.4).
Dosage in hepatically impaired patients
Pharmacokinetics of HYCAMTIN capsules have not been specifically studied in patients with
impaired hepatic function. There are insufficient data available with HYCAMTIN capsules to make a
dose recommendation for this patient group (see section 4.4).
Paediatric population
The experience in children is limited, therefore no recommendation for treatment of paediatric patients
with HYCAMTIN can be given (see section 5.1).
Elderly
No overall differences in effectiveness were observed between patients over 65 years and younger
adult patients. However in the two studies administering both oral and intravenous topotecan, patients
older than 65 years old receiving oral topotecan experienced an increase in drug related diarrhoea
compared to those younger than 65 years of age (see section 4.4 and 4.8).
HYCAMTIN is contraindicated in patients who
−
have a history of severe hypersensitivity to the active substance or to any of the excipients
−
are breast feeding (see section 4.6)
−
already have severe bone marrow depression prior to starting first course, as evidenced by
baseline neutrophils < 1.5 x 10
9
/l and/or a platelet count of < 100 x 10
9
/l.
Haematological toxicity is dose-related and full blood count including platelets should be monitored
regularly (see section 4.2).
As with other cytotoxic medicinal products, topotecan can cause severe myelosuppression.
Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients treated
with topotecan (see section 4.8).
Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have
been reported in clinical trials with topotecan. In patients presenting with fever, neutropenia, and a
compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered.
37
Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been
fatal (see section 4.8). Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer,
thoracic exposure to radiation and use of pneumotoxic drugs and/or colony stimulating factors.
Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, dyspnoea
and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed.
Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated with
clinically relevant thrombocytopenia. This should be taken into account when prescribing
HYCAMTIN, 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.
Topotecan is partly eliminated via renal excretion and renal impairment might lead to increased
exposure to topotecan. Dosing recommendations for patients receiving oral topotecan with Cl
cr
less
than 60 ml/min have not been established. There is insufficient experience of the use of oral or
intravenous topotecan in patients with severely impaired renal function (creatinine clearance
< 20 ml/min). Topotecan is not recommended to be used in these patients.
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. There is insufficient experience of the use of topotecan in
patients with severely impaired hepatic function (serum bilirubin ≥ 10 mg/dl). Topotecan is not
recommended to be used in these patients.
Diarrhoea, including severe diarrhoea requiring hospitalization, has been reported during treatment
with oral topotecan. Diarrhoea related to oral topotecan can occur at the same time as drug-related
neutropenia and its sequelae. Communication with patients prior to drug administration regarding
these side effects and proactive management of early and all signs and symptoms of diarrhoea is
important. Cancer treatment-induced diarrhoea (CTID) is associated with significant morbidity and
may be life-threatening. Should diarrhoea occur during treatment with oral topotecan, physicians are
advised to aggressively manage diarrhoea. Clinical guidelines describing the aggressive management
of CTID includes specific recommendations on patient communication and awareness, recognition of
early warning signs, use of anti-diarrhoeals and antibiotics, changes in fluid intake and diet, and need
for hospitalization (see sections 4.2 and 4.8).
Intravenous topotecan should be considered in the following clinical situations: uncontrolled emesis,
swallowing disorders, uncontrolled diarrhoea, clinical conditions and medication that may alter
gastrointestinal motility and drug absorption.
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).
Topotecan is a substrate for both ABCB1 (P-glycoprotein) and ABCG2 (BCRP) . Inhibitors of
ABCB1 and ABCG2 administered with oral topotecan have been shown to increase topotecan
exposure.
Cyclosporin A (an inhibitor of ABCB1, ABCC1 [MRP-1], and CYP3A4) administered with oral
38
topotecan increased topotecan AUC to approximately 2-2.5-fold of control.
Patients should be carefully monitored for adverse reactions when oral topotecan is administered with
a drug known to inhibit ABCB1 or ABCG2 (see section 5.2).
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. Currently
there is only limited experience in combining oral topotecan with other chemotherapy agents.
The pharmacokinetics of topotecan was generally unchanged when coadministered with ranitidine.
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 childbearing 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.
In clinical trials involving patients with relapsed small cell lung cancer, the dose limiting toxicity of
oral topotecan monotherapy was found to be haematological. Toxicity was predictable and reversible.
There were no signs of cumulative haematological or non-haematological toxicity.
The frequencies associated with the haematological and non-haematological adverse events presented
are for adverse events considered to be related/possibly related to oral topotecan therapy.
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
39
(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), including isolated
reports and not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic system disorders
Very common: febrile neutropenia, neutropenia (see Gastrointestinal disorders),
thrombocytopenia, anaemia, leucopenia
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), which may
lead to dehydration (see sections 4.2 and 4.4)
Common: abdominal pain
1
, constipation, mucositis, dyspepsia
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: pruritis
Metabolism and nutrition disorders
Very common: anorexia (which may be severe)
Infections and infestations
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: fatigue
Common : asthenia, pyrexia, malaise
Immune system disorders
Common: hypersensitivity reaction including rash
Not known: anaphylactic reaction, angioedema, urticaria
Hepato-biliary disorders
Uncommon: 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).
Safety data are presented based on an integrated data set of 682 patients with relapsed lung cancer
administered 2536 courses of oral topotecan monotherapy (275 patients with relapsed SCLC and 407
with relapsed non-SCLC).
Haematological
Neutropenia
: Severe neutropenia (Grade 4 - neutrophil count < 0.5 x 10
9
/l) occurred in 32 % of
patients in 13 % of courses. Median time to onset of severe neutropenia was Day 12 with a median
duration of 7 days. In 34 % of courses with severe neutropenia, the duration was > 7 days. In course 1
40
Very common: infection
the incidence was 20 %, by courses 4 the incidence was 8 %. Infection, sepsis and febrile neutropenia
occurred in 17 %, 2 %, and 4 % of patients, respectively. Death due to sepsis occurred in 1 % of
patients. Pancytopenia has been reported. Growth factors were administered to 19 % of patients in 8 %
of courses.
Thrombocytopenia:
Severe thrombocytopenia (Grade 4 - platelets less than 10 x 10
9
/l) occurred in 6 %
of patients in 2 % of courses. Median time to onset of severe thrombocytopenia was Day 15 with a
median duration of 2.5 days. In 18 % of courses with severe thrombocytopenia the duration was
> 7 days. Moderate thrombocytopenia (Grade 3 - platelets between 10.0 and 50.0 x 10
9
/l) occurred in
29 % of patients in 14 % of courses. Platelet transfusions were given to 10 % of patients in 4 % of
courses. Reports of significant sequelae associated with thrombocytopenia including fatalities due to
tumour bleeds have been infrequent.
Anaemia:
Moderate to severe anaemia (Grade 3 and 4 – Hb ≤ 8.0 g/dl) occurred in 25 % of patients
(12 % of courses). Median time to onset of moderate to severe anaemia was Day 12 with a median
duration of 7 days. In 46 % of courses with moderate to severe anaemia, the duration was > 7 days.
Red blood cell transfusions were given in 30 % of patients (13 % of courses). Erythropoietin was
administered to 10 % of patients in 8 % of courses.
Non-haematological
The most frequently reported non-haematological effects were nausea (37 %), diarrhoea (29 %),
fatigue (26 %), vomiting (24 %), alopecia (21 %) and anorexia (18 %). All cases were irrespective of
associated causality. For severe cases (CTC grade 3/4) reported as related / possibly related to
topotecan administration the incidence was diarrhoea 5 % (see section 4.4), fatigue 4 %, vomiting 3 %,
nausea 3 % and anorexia 2 %.
The overall incidence of drug-related diarrhoea was 22 %, including 4 % with Grade 3 and 0.4 % with
Grade 4. Drug-related diarrhoea was more frequent in patients ≥65 years of age (28 %) compared to
those less than 65 years of age (19 %).
Complete alopecia related/possibly related to topotecan administration was observed in 9 % of patients
and partial alopecia related/possibly related to topotecan administration in 11 % of patients.
Therapeutic interventions associated with non-haematological effects included anti-emetic agents,
given to 47 % of patients in 38 % of courses and anti-diarrhoeal agents, given to 15 % of patients in
6 % of courses. A 5-HT3 antagonist was administered to 30 % of patients in 24 % of courses.
Loperamide was administered to 13 % of patients in 5 % of courses. The median time to onset of
grade 2 or worse diarrhoea was 9 days.
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
41
breaks.
Relapsed SCLC
A phase III trial (study 478) compared oral topotecan plus Best Supportive Care (BSC) (n=71) with
BSC alone (n=70) in patients who had relapsed following first line therapy (median time to
progression [TTP] from first-line therapy: 84 days for oral topotecan + BSC, 90 days for BSC) and for
whom retreatment with intravenous chemotherapy was not considered appropriate. Oral topotecan plus
BSC group had a statistically significant improvement in overall survival compared with the BSC
alone group (Log-rank p=0.0104). The unadjusted hazard ratio for oral topotecan plus BSC group
relative to BSC alone group was 0.64 (95 % CI: 0.45, 0.90).
The median survival for patients treated
with topotecan + BSC was 25.9 weeks (95 % C.I. 18.3, 31.6) compared to 13.9 weeks (95 % C.I. 11.1,
18.6) for patients receiving BSC alone (p=0.0104).
Patient self-reports of symptoms using an unblinded assessment showed a consistent trend for
symptom benefit for oral topotecan + BSC.
One Phase 2 study (Study 065) and one Phase 3 study (Study 396) were conducted to evaluate the
efficacy of oral topotecan versus intravenous topotecan in patients who had relapsed ≥ 90 days after
completion of one prior regimen of chemotherapy (see Table 1). Oral and intravenous topotecan were
associated with similar symptom palliation in patients with relapsed sensitive SCLC in patient self-
reports on an unblinded symptom scale assessment in each of these two studies.
Table 1. Summary of survival, response rate, and time to progression in SCLC patients treated
with oral HYCAMTIN or intravenous HYCAMTIN
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.
Paediatrics
Safety and effectiveness of oral topotecan in paediatric patients have not been established.
5.2 Pharmacokinetic properties
The pharmacokinetics of topotecan after oral administration have been evaluated in cancer patients
following doses of 1.2 to 3.1 mg/m
2
/day and 4 mg/m
2
/day administered daily for 5 days. The
bioavailability of oral topotecan (total and lactone) in humans is approximately 40 %. Plasma
concentrations of total topotecan (i.e. lactone and carboxylate forms) and topotecan lactone (active
moiety) peak at approximately 2.0 hours and 1.5 hours, respectively, and decline bi-exponentially with
mean terminal half-life of approximately 3.0 to 6.0 hour. Total exposure (AUC) increases
42
approximately proportionally with 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.
A major route of clearance of topotecan is by hydrolysis of the lactone ring to form the ring-opened
carboxylate. Other than hydrolysis, topotecan is cleared predominantly renally, with a minor
component metabolized to the N-desmethyl metabolite (SB-209780) identified in plasma, urine and
faeces. Overall recovery of topotecan-related material following five daily doses of topotecan was 49
to 72 % (mean 57 %) of the administered oral dose. Approximately 20 % was excreted as total
topotecan and 2 % was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total
topotecan accounted for 33 % while faecal elimination of N-desmethyl topotecan was 1.5 %. Overall,
the N-desmethyl metabolite contributed a mean of less than 6 % (range 4-8 %) of the total topotecan
related material accounted for in the urine and faeces. O-glucuronides of both topotecan and N-
desmethyl topotecan have been identified in the urine. The mean metabolite: parent plasma AUC ratio
was less than 10 % for both total topotecan and topotecan lactone.
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.
Following coadministration of the ABCB1 (P-gp) and ABCG2 (BCRP) inhibitor, elacridar
(GF120918) at 100 to 1,000 mg with oral topotecan, the AUC0-∞ of topotecan lactone and total
topotecan increased approximately 2.5-fold (see section 4.5 for guidance).
Administration of oral cyclosporine A (15 mg/kg), an inhibitor of transporters ABCB1 (P-gp) and
ABCC1 (MRP-1) as well as the metabolising enzyme CYP3A4, within 4 hours of oral topotecan
increased the dose normalised AUC0-24h of topotecan lactone and total topotecan approximately 2.0-
and 2.5-fold, respectively (see section 4.5).
The extent of exposure was similar following a high fat meal and fasted state while tmax was delayed
from 1.5 to 3 hours (topotecan lactone) and from 3 to 4 hours (total topotecan).
The pharmacokinetics of oral topotecan has not been studied in patients with renal or hepatic
impairment (see section 4.2 and 4.4).
A cross-study analysis in 217 patients with advanced solid tumours indicated that gender did not affect
the pharmacokinetics of HYCAMTIN capsules to a clinically relevant extent. There are insufficient
data to determine an effect of race on pharmacokinetics of oral topotecan.
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.
43
6.
6.1 List of excipients
Capsule contents:
Hydrogenated vegetable oil
Glyceryl monostearate
Capsule shell:
Gelatin,
Titanium dioxide (E171)
red iron oxide (E172)
Sealing band:
Gelatin
Black ink comprising:
black iron oxide (E172)
shellac
anhydrous ethanol – see leaflet for further information
propylene glycol
isopropyl alcohol
butanol
concentrated ammonia solution
potassium hydroxide
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in a refrigerator (2ºC - 8ºC).
Keep the blister card in the outer carton in order to protect from light.
Do not freeze.
6.5 Nature and contents of container
White polyvinyl chloride / polychlorotrifluoroethylene blister sealed with aluminium /
Polyethylenterephtalate (PET) / paper foil lidding.
The blisters are sealed with a peel-push child resistant opening feature.
Each blister card contains 10 capsules.
6.6 Special precautions for disposal and other handling
HYCAMTIN capsules should not be opened or crushed.
Any unused product or waste material should be disposed of in accordance with local requirements.
44
7.
SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom.
8.
EU/1/96/027/007
9.
Date of first authorisation: 12/11/1996
Date of latest renewal: 12/11/2006
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu/.
45
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
46
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
GlaxoSmithKline Manufacturing S.p.A.
Strada Provinciale Asolana 90
43056 San Polo di Torrile
Parma
Italy
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 7.2 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
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 03 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency.
47
ANNEX III
LABELLING AND PACKAGE LEAFLET
48
A. LABELLING
49
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1 x 1 mg vial
5x 1 mg vial
1.
HYCAMTIN 1 mg powder for concentrate for solution for infusion
topotecan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
The total content of active substance in the vial provides 1 mg per ml of active substance when
reconstituted as recommended (see Package Leaflet).
3.
LIST OF EXCIPIENTS
tartaric acid (E334), mannitol (E421), hydrochloric acid (E507), sodium hydroxide.
4.
1 x 1 mg
5 x 1 mg
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use. Reconstitute before use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Keep the vial in the outer carton in order to protect from light.
50
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
WARNING: Cytotoxic agents, special handling instructions (see Package Leaflet). 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.
SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom.
EU/1/96/027/005 1 x 1 mg vial
EU/1/96/027/004 5 x 1 mg vials
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
51
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
HYCAMTIN 1 mg powder for concentrate for solution for infusion
topotecan
IV use
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 vial
6.
OTHER
52
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1 x 4 mg vial
5 x 4 mg vial
1.
HYCAMTIN 4 mg powder for concentrate for solution for infusion
topotecan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
The total content of active substance in the vial provides 1 mg per ml of active substance when
reconstituted as recommended (see Package Leaflet).
3.
LIST OF EXCIPIENTS
tartaric acid (E334), mannitol (E421), hydrochloric acid (E507), sodium hydroxide.
4.
1 x 4 mg
5 x 4 mg
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use. Reconstitute before use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Keep the vial in the outer carton in order to protect from light.
53
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
WARNING: Cytotoxic agents, special handling instructions (see Package Leaflet). 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.
SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom.
EU/1/96/027/003 1 x 4 mg vial
EU/1/96/027/001 5 x 4 mg vials
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
54
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
HYCAMTIN 4 mg powder for concentrate for solution for infusion
topotecan
IV use
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 vial
6. OTHER
55
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
HYCAMTIN 0.25 mg hard capsules
topotecan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains topotecan hydrochloride equivalent to 0.25 mg of topotecan.
3.
LIST OF EXCIPIENTS
4.
10 capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
HYCAMTIN capsules should not be broken or crushed.
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2ºC - 8ºC).
Keep the blister card in the outer carton in order to protect from light.
Do not freeze.
56
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
WARNING: Cytotoxic agent, special handling instructions (see Package Leaflet)
SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom.
EU/1/96/027/006
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16 INFORMATION IN BRAILLE
hycamtin 0.25 mg
57
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS
1.
HYCAMTIN 0.25 mg hard capsules
topotecan
2.
SmithKline Beecham Ltd
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
58
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
HYCAMTIN 1 mg hard capsules
topotecan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains topotecan hydrochloride equivalent to 1 mg of topotecan.
3.
LIST OF EXCIPIENTS
4.
10 capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
HYCAMTIN capsules should not be broken or crushed.
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2ºC - 8ºC).
Keep the blister card in the outer carton in order to protect from light.
Do not freeze.
59
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
WARNING: Cytotoxic agent, special handling instructions (see Package Leaflet)
SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom.
EU/1/96/027/007
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
hycamtin 1 mg
60
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
HYCAMTIN 1 mg hard capsules
topotecan
2.
SmithKline Beecham Ltd
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
61
B. PACKAGE LEAFLET
62
Package leaflet: Information for the user
Hycamtin 1 mg
Hycamtin 4 mg
powder for 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.
•
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1.
What Hycamtin is and what it is used for
3.
How to use Hycamtin
4.
Possible side effects
5.
How to store Hycamtin
6.
Further information
1.
What Hycamtin is and what it is used for
Hycamtin
helps to destroy tumours. A doctor or a nurse will give you the medicine as an infusion into
a vein (a drip) in hospital.
Hycamtin 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, Hycamtin
is combined with another drug called
cisplatin
.
Your doctor will decide with you whether Hycamtin therapy is better than further treatment with your
initial chemotherapy.
2.
Before you are given Hycamtin
You should not receive Hycamtin:
•
if you are allergic
(
hypersensitive
) to topotecan or any of the other ingredients of Hycamtin.
•
if you are breast feeding.
•
if your blood cell counts are too low.
Your doctor will tell you, based on the results of your last
blood test.
→
Tell your doctor
if any of these applies to you.
Take special care with Hycamtin
Your doctor needs to know before you are given this medicine:
•
if you have any kidney or liver problems.
Your dose of Hycamtin may need to be adjusted.
•
if you are pregnant or plan to become pregnant
•
if you plan to father a child
Hycamtin may harm a baby conceived before, during or soon after treatment. You should use
an effective method of contraception. Ask your doctor for advice.
→
Tell your doctor
if any of these applies to you.
63
2.
Before you are given Hycamtin
Taking other medicines
Please tell your doctor if you are taking
or have recently taken any other medicines, including any
herbal products or medicines obtained without a prescription.
Remember to tell your doctor if you start to take any other medicines while you’re on Hycamtin.
Using Hycamtin with food and drink
There is no known interaction between Hycamtin and alcohol. However, you should check with your
doctor whether drinking alcohol is advisable for you.
Pregnancy and breast feeding
Hycamtin is not recommended for pregnant women.
It may harm the baby if conceived before,
during or soon after treatment. You should use an effective method of contraception. Ask your
doctor for advice. Do not try and become pregnant/father a child until a doctor advises you it is
safe to do so.
Male patients who may wish to father a child, should ask their doctor for family planning advice
or treatment. If pregnancy occurs during treatment, tell your doctor immediately.
Do not breast-feed if you are being treated with Hycamtin.
Do not restart breast-feeding until the
doctor tells you it is safe to do so.
Driving and using machines
Hycamtin can make people feel tired.
If you feel tired or weak, do not drive and do not use machines.
3.
How Hycamtin is used
The dose of Hycamtin you are given will be worked out by your doctor, based on:
•
your body size
(surface area measured in square metres)
•
the results of blood tests
carried out before treatment
•
the disease being treated.
The usual dose
•
For ovarian and small cell lung cancer:
1.5 mg
per square metres of body surface area per day.
•
For cervical cancer:
0.75 mg per square metres
of body surface area per day.
When treating cervical cancer,
Hycamtin is combined with another medicine, called
cisplatin
. Your
doctor will advise you about the correct dose of
cisplatin
.
How Hycamtin is given
A doctor or nurse will give you
a suitable dose of Hycamtin as an infusion (a drip). It is usually
dripped into your arm over about 30 minutes.
•
For ovarian and small cell lung cancer,
you will have treatment once a day for 5 days.
•
For cervical cancer,
you will have treatment once a day for 3 days.
This pattern of treatments will normally be repeated
every three weeks, for all cancers.
The treatment may vary, depending on the results of your regular blood tests.
Stopping treatment
Your doctor will decide when to stop the treatment.
64
4.
Possible side effects
Like all medicines, Hycamtin can cause side effects, although not everybody gets them.
Serious side effects: tell your doctor
These
very common
side effects may affect
more than 1 in 10
people treated with Hycamtin:
•
Signs of infections:
Hycamtin may reduce the number of white blood cells and lower your
resistance to infection. This can even be life threatening. Signs include:
-
fever
-
serious deterioration of your general condition
-
local symptoms such as sore throat or urinary problems (for example, a burning
sensation when urinating, which may be a urinary infection).
•
Occasionally severe stomach pain, fever and possibly diarrhoea (rarely with blood) can be
signs of bowel inflammation (
colitis
).
This
rare
side effect may affect
up to 1 in 1000 people
treated with Hycamtin):
•
Lung inflammation
(interstitial lung disease)
: You are most at risk if you have existing lung
disease, had radiation treatment to your lungs, or have previously taken medicines that caused
lung damage. Signs include:
-
difficulty in breathing
-
cough
-
fever.
→
Tell your doctor immediately
if you get any symptoms of these conditions, as hospitalisation may
be necessary.
Very common side effects
These may affect
more than 1 in 10 people
treated with Hycamtin:
•
Feeling generally weak and tired (temporary
anaemia
). In some cases you may need a blood
transfusion.
•
Unusual bruising or bleeding, caused by a decrease in the number of clotting cells in the blood.
This can lead to severe bleeding from relatively 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.
•
Weight loss and loss of appetite (
anorexia
); tiredness; weakness; feeling unwell.
•
Feeling sick (nausea), being sick (vomiting); diarrhoea; stomach pain; constipation.
•
Inflammation and ulcers of the mouth tongue or gums.
•
High body temperature (fever).
•
Hair loss.
Common side effects
These may affect
up to 1 in 10 people
treated with Hycamtin:
•
Allergic or
hypersensitivity
reactions (including rash)
•
Yellow skin
•
Itching sensation
•
Muscle pain.
Rare side effects
These may affect
up to 1 in 1000 people
treated with Hycamtin:
•
Severe allergic or
anaphylactic
reactions
•
Swelling caused by fluid build up (
angioedema
)
•
Mild pain and inflammation at the site of injection
•
Itchy rash (or
hives
).
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 Hycamtin. Those effects are described in the cisplatin
65
patient information.
If you get side effects
→
Tell your doctor or pharmacist
if any of the side effects become
severe or troublesome
, or if
you notice any side effects not listed in this leaflet.
5.
How to store Hycamtin
Keep out of the reach and sight of children.
Do not use Hycamtin after the expiry date which is stated on the carton.
Keep the vial in the outer carton in order to protect from light.
6.
Further information
What Hycamtin contains
•
The active substance is
topotecan. Each vial contains topotecan hydrochloride equivalent to
1 mg or 4 mg of topotecan.
•
The other ingredients are:
tartaric acid (E334), mannitol (E421), hydrochloric acid (E507) and
sodium hydroxide.
What Hycamtin looks like and contents of the pack
Hycamtin comes as a powder for concentrate for solution for intravenous infusion.
It is available in packs containing either 1 or 5 vials; each vial contains 1 mg or 4 mg of topotecan.
The powder needs to be reconstituted and diluted before infusion.
The powder in the vial provides 1 mg per ml of active substance when reconstituted as recommended.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
SmithKline Beecham Ltd, 980 Great West Road, Brentford,
Middlesex, TW8 9GS, United Kingdom.
Manufacturer:
GlaxoSmithKline Manufacturing S.p.A, Strada Provinciale Asolana 90, 43056 San
Polo di Torrile, Parma, Italy.
66
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 (0)2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 21 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
dk-info@gsk.com
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 6938100
nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel.: + 49 (0)89 36044 8701
produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
Eesti
GlaxoSmithKline Eesti OÜ
Tel: + 372 6676 900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
at.info@gsk.com
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (0)22 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
Portugal
Beecham Portuguesa, Produtos
Farmacêuticos e Químicos, Lda
Tel: + 351 21 412 95 00
France
Laboratoire GlaxoSmithKline
Tél.: + 33 (0)1 39 17 84 44
diam@gsk.com
România
GlaxoSmithKline (GSK) S.R.L.
Tel: + 4021 3028 208
Ireland
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0)1 280 25 00
medical.x.si@gsk.com
67
Ísland
GlaxoSmithKline ehf.
Simi: + 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
Italia
GlaxoSmithKline S.p.A.
Tel: + 39 (0)45 9218 111
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30
Finland.tuoteinfo@gsk.com
Κύπρος
GlaxoSmithKline Cyprus Ltd
Τηλ: + 357 22 39 70 00
Sverige
GlaxoSmithKline AB
Tel: + 46 (0) 8 638 93 00
info.produkt@gsk.com
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
GlaxoSmithKline UK
Tel: +44 (0) 800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
Information for the health care professional only
Instructions on how to reconstitute, store and dispose of Hycamtin
Reconstitution
Hycamtin 1 mg powder
for concentrate for solution for infusion should be reconstituted with 1.1 ml
of water for injections to provide 1 mg per ml of topotecan.
Hycamtin 4 mg powder
for concentrate for solution for infusion should be reconstituted with 4 ml of
water for injections to provide 1 mg per ml of topotecan.
Further dilution is required.
The appropriate volume of the reconstituted solution should be diluted
with
either
0.9 % w/v sodium chloride intravenous infusion
or
5 % w/v glucose intravenous infusion,
to a final concentration of between 25 and 50 microgram per ml.
Storage of the prepared solution
The product should be used immediately after it is prepared for infusion. If reconstitution is performed
under strict aseptic conditions Hycamtin infusion may be completed within 12 hours at room
temperature (or 24 hours if stored at 2-8
o
C).
Handling and disposal
The normal procedures for proper handling and disposal of anti-tumour medicinal products should be
adopted:
•
Staff should be trained to reconstitute the medicinal product.
•
Pregnant staff should be excluded from working with this medicinal product.
68
•
Staff handling this medicinal product during reconstitution should wear protective clothing
including mask, goggles and gloves.
•
All items for administration or cleaning, including gloves, should be placed in 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.
69
Package leaflet: Information for the user
Hycamtin 0.25 mg
Hycamtin 1 mg
hard capsules
topotecan
Read all of this leaflet carefully before you start taking this medicine.
•
Keep this leaflet. You may need to read it again.
•
If you have any further questions, ask your doctor or pharmacist
•
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms seem to be the same as yours.
•
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Hycamtin is and what it is used for
2.
Before you take Hycamtin
4.
Possible side effects
5.
How to store Hycamtin
6.
Further information
1.
What Hycamtin is and what it is used for
Hycamtin helps to destroy tumours.
Hycamtin is used to treat:
•
small cell lung cancer
that has come back after chemotherapy.
Your doctor will decide with you whether Hycamtin therapy is better than further treatment with your
initial chemotherapy.
2.
Before you take Hycamtin
Do not take Hycamtin:
•
if you are allergic
(
hypersensitive
) to topotecan or any of the other ingredients of Hycamtin.
•
if you are breast feeding
.
•
if your blood cell counts are too low.
Your doctor will tell you, based on the results of your last
blood test.
→
Tell your doctor
if any of these applies to you.
Take special care with Hycamtin
Your doctor needs to know before you are given this medicine:
•
if you have any kidney or liver problems.
Your dose of Hycamtin may need to be adjusted.
•
if you are pregnant or plan to become pregnant
•
if you plan to father a child
Hycamtin may harm a baby conceived before, during or soon after treatment. You should use
an effective method of contraception. Ask your doctor for advice.
70
3.
How to take Hycamtin
→
Tell your doctor
if any of these applies to you.
Taking other medicines
Please tell your doctor if you are taking
or have recently taken any other medicines, including any
herbal products or medicines obtained without a prescription.
There may be a higher than usual chance of you getting side effects if you are also being treated with
cyclosporin A. You will be monitored closely while you are taking these two medicines.
Remember to tell your doctor if you start to take any other medicines while you’re on Hycamtin.
Taking Hycamtin with food and drink
There is no known interaction between Hycamtin and alcohol. However, you should check with your
doctor whether drinking alcohol is advisable for you.
Hycamtin capsules may be taken with or without food.
The capsule(s) must be swallowed whole, and must not be chewed, crushed or divided.
Pregnancy and breast-feeding
Hycamtin is not recommended for pregnant women. It may harm the baby if conceived before,
during or soon after treatment. You should use an effective method of contraception. Ask your
doctor for advice. Do not try and become pregnant/father a child until a doctor advises you it is
safe to do so.
Male patients who may wish to father a child, should ask their doctor for family planning advice
or treatment. If pregnancy occurs during treatment, tell your doctor immediately.
Do not breast-feed if you are being treated with Hycamtin.
Do not restart breast-feeding until the
doctor tells you it is safe to do so.
Driving and using machines
Hycamtin can make people feel tired.
If you feel tired or weak, do not drive and do not use machines.
Important information about some of the ingredients of Hycamtin
This medicinal product contains a trace amount of ethanol (alcohol).
3.
How to take Hycamtin
Always take Hycamtin exactly as your doctor has told you. You should always check with your doctor
or pharmacist if you are not sure.
The dose (and number of capsules) of Hycamtin you are given will be worked out by your doctor,
based on:
•
your body size
(surface area measured in square metres)
•
the results of blood tests
carried out before treatment
•
the disease being treated
.
The prescribed number of capsules should be swallowed whole, once a day for 5 days.
Hycamtin capsules must not be opened or crushed.
If the capsules are punctured or leaking, you
should immediately wash your hands thoroughly with soap and water. If you get it in your eyes, wash
them immediately with gently flowing water for at least 15 minutes. Consult your doctor/healthcare
provider after eye contact or if you experience a skin reaction.
71
Taking out a capsule
These capsules come in special packaging to prevent children removing them
1.
Separate one capsule:
tear along the cutting lines to separate one “pocket” from the strip.
2.
Peel back the outer layer:
starting at the coloured corner, lift and peel over the pocket.
3.
Push out the capsule:
gently push one end of the capsule through the foil layer.
If you take more Hycamtin than you should
Contact a doctor or pharmacist immediately for advice if you have taken too many capsules or if a
child has accidentally taken the medicine.
If you forget to take Hycamtin
Do not take a double dose to make up for a forgotten dose. Just take the next dose at the scheduled
time.
72
4.
Possible side effects
Like all medicines, Hycamtin can cause side effects, although not everybody gets them.
Serious side effects: tell your doctor
These
very common
side effects may affect
more than 1 in 10
people treated with Hycamtin:
•
Signs of infections:
Hycamtin may reduce the number of white blood cells and lower your
resistance to infection. This can even be life threatening. Signs include:
-
fever
-
serious deterioration of your general condition
-
local symptoms such as sore throat or urinary problems (for example, a burning
sensation when urinating, which may be a urinary infection).
•
Diarrhoea.
This can be serious. If you have more than 3 episodes of diarrhoea per day you
should contact your doctor immediately.
Occasionally severe stomach pain, fever and possibly diarrhoea (rarely with blood) can be signs of
bowel inflammation (
colitis
)
This
rare
side effect may affect
up to 1 in 1000 people
treated with Hycamtin).
•
Lung inflammation (interstitial lung disease): You are most at risk if you have existing lung
disease, had radiation treatment to your lungs, or have previously taken medicines that caused
lung damage. Signs include:
-
difficulty in breathing
-
cough
-
fever
-
→
Tell your doctor immediately
if you get any symptoms of these conditions, as hospitalisation may
be necessary.
Very common side effects
These may affect
more than 1 in 10 people
treated with Hycamtin:
•
Feeling generally weak and tired (temporary
anaemia
). In some cases you may need a blood
transfusion.
•
Unusual bruising or bleeding, caused by a decrease in the number of clotting cells in the blood.
This can lead to severe bleeding from relatively 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.
•
Weight loss and loss of appetite (
anorexia
); tiredness; weakness; feeling unwell.
•
Feeling sick (nausea), being sick (vomiting); stomach pain; constipation.
•
High body temperature (fever).
•
Hair loss.
Common side effects
These may affect
up to 1 in 10 people
treated with Hycamtin:
•
Allergic or
hypersensitivity
reactions (including rash)
•
Inflammation and ulcers of the mouth, tongue or gums
•
Itching sensation
•
Muscle pain.
Uncommon side effects
These may affect
up to 1 in 100 people
treated with Hycamtin:
•
Yellow skin
Rare side effects
These may affect
up to 1 in 1000 people
treated with Hycamtin:
•
Severe allergic or
anaphylactic
reactions
•
Swelling caused by fluid build up (
angioedema
)
73
•
Itchy rash (or
hives
).
If you get side effects
→
Tell your doctor or pharmacist
if any of the side effects become
severe or troublesome
, or if
you notice any side effects not listed in this leaflet.
5.
How to store Hycamtin
Keep out of the reach and sight of children.
Do not use Hycamtin after the expiry date which is stated on the carton.
Store in a refrigerator (2ºC - 8ºC).
Keep the blister card in the outer carton in order to protect from light.
Do not freeze.
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 Hycamtin contains
•
The active substance is
topotecan. Each capsule contains topotecan hydrochloride equivalent to
0.25 mg or 1 mg of topotecan.
•
The other ingredients are:
hydrogenated vegetable oil, glyceryl monostearate, gelatin, titanium
dioxide (E171), and for 1 mg capsules only, red iron oxide (E172). Capsules are printed with
black ink that contains black iron oxide (E172), shellac, anhydrous ethanol, propylene glycol,
isopropyl alcohol, butanol, concentrated ammonia solution and potassium hydroxide.
What Hycamtin looks like and contents of the pack
Hycamtin 0.25 mg capsules are white to yellowish white and imprinted with ‘Hycamtin’ and
‘0.25 mg’.
Hycamtin 1 mg capsules are pink and imprinted with ‘Hycamtin’ and ‘1 mg’.
Hycamtin is available in packs containing 10 capsules of 0.25 mg or 1 mg topotecan.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
SmithKline Beecham Ltd, 980 Great West Road, Brentford,
Middlesex, TW8 9GS, United Kingdom.
Manufacturer:
GlaxoSmithKline Manufacturing S.p.A, Strada Provinciale Asolana 90, 43056 San
Polo di Torrile, Parma, Italy.
74
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 (0)2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 21 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
dk-info@gsk.com
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 6938100
nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel.: + 49 (0)89 36044 8701
produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
Eesti
GlaxoSmithKline Eesti OÜ
Tel: + 372 6676 900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
at.info@gsk.com
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (0)22 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
Portugal
Beecham Portuguesa, Produtos
Farmacêuticos e Químicos, Lda
Tel: + 351 21 412 95 00
France
Laboratoire GlaxoSmithKline
Tél.: + 33 (0)1 39 17 84 44
diam@gsk.com
România
GlaxoSmithKline (GSK) S.R.L.
Tel: + 4021 3028 208
Ireland
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0)1 280 25 00
medical.x.si@gsk.com
75
Ísland
GlaxoSmithKline ehf.
Simi: + 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
Italia
GlaxoSmithKline S.p.A.
Tel: + 39 (0)45 9218 111
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30
Finland.tuoteinfo@gsk.com
Κύπρος
GlaxoSmithKline Cyprus Ltd
Τηλ: + 357 22 39 70 00
Sverige
GlaxoSmithKline AB
Tel: + 46 (0) 8 638 93 00
info.produkt@gsk.com
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
GlaxoSmithKline UK
Tel: +44 (0) 800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was last approved in
Detailed information on this medicine product is available on the European Medicines Agency web
site:
http://www.ema.europa.eu/
.
76
Source: European Medicines Agency
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