Summary of medicine characteristics - Topotecan Eagle
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml of concentrate for solution for infusion contains 3 mg topotecan (as hydrochloride).
Each 1 ml single dose vial contains 3 mg of topotecan.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Concentrate for solution for infusion.
A clear light yellow to orange solution, pH < 1.2.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Topotecan monotherapy is indicated for the treatment of patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate (see section 5.1).
Topotecan in combination with cisplatin is i recurrent after radiotherapy and for patients cisplatin require a sustained treatment section 5.1).
ted for patients with carcinoma of the cervix Stage IVB disease. Patients with prior exposure to al to justify treatment with the combination (see
Posology
4.2 Posology and method of administration
Prior to a
of > 1.5
When used in com consulted.
ell Lung Carcinoma
with cisplatin, the full prescribing information for cisplatin should be
tion of the first course of topotecan, patients must have a baseline neutrophil count , a platelet count of > 100 × 109/1 and a haemoglobin level of > 9 g/dl (after transfusion
Initial dose
The recommended dose of topotecan is 1.5 mg/m2 body surface area/day administered by intravenous infusion over 30 minutes daily for five consecutive days with a three week interval between the start of each course. If well tolerated, treatment may continue until disease progression (see sections 4.8 and 5.1).
Subsequent doses
Topotecan should not be re-administered unless the neutrophil count is > 1 × 109/l, the platelet count is > 100 × 109/l, and the haemoglobin level is > 9 g/dl (after transfusion if necessary).
Standard oncology practice for the management of neutropenia is either to administer topotecan with other medications (e.g. G-CSF) or to dose reduce to maintain neutrophil counts.
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count < 0.5 × 109/l) for seven days or more, or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose should be reduced by 0.25 mg/m2/day to 1.25 mg/m2/day (or subsequently down to 1.0 mg/m2/day if necessary).
Doses should be similarly reduced if the platelet count falls below 25 × 109/l. In clinical trials, topotecan was discontinued if the dose had been reduced to 1.0 mg/m2 and a further dose reduction was required to manage adverse effects.
Cervical Carcinoma
ay 1 at a ed every
re than or equal to aemoglobin level is more
Initial dose
The recommended dose of topotecan is 0.75 mg/m2/day administered as 30 minu infusion daily on days 1, 2 and 3. Cisplatin is administered as an intravenous in dose of 50 mg/m2/day and following the topotecan dose. This treatment schedul 21 days for six courses or until progressive disease.
Subsequent doses
Topotecan should not be re-administered unless the neutrophil coun 1.5 × 109/l, the platelet count is more than or equal to 100 × 109/l, an than or equal to 9 g/dl (after transfusion if necessary).
Standard oncology practice for the management of neutro is either to administer topotecan with other medicinal products (e.g. G-CSF) or to dose reduce t ntain neutrophil counts.
If dose reduction is chosen for patients who expe
0.5 × 109/l) for seven days or more, or sever have had treatment delayed due to neutropen 0.60 mg/m2/day for subsequent courses (or s
severe neutropenia (neutrophil count less than a associated with fever or infection or who
, the dose should be reduced by 20 % to sequently down to 0.45 mg/m2/day if necessary).
Doses should be similarly reduced if the platelet count falls below 25 × 109/l.
Dosage in renally impaired patients
Monotherapy (Small cell lung carcinoma)
Insufficient data are available to make a recommendation for patients with a creatinine clearance < 20 ml/min. Limited data indicate that the dose should be reduced in patients with moderate renal impairment. The recommended monotherapy dose of topotecan in patients with small cell lung carcinoma anreatinine clearance between 20 and 39 ml/min is 0.75 mg/m2/day for five consecuti therapy (Cervical carcinoma)
In
studies with topotecan in combination with cisplatin for the treatment of cervical cancer, y 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 topotecan can be given (see sections 5.1 and 5.2).
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).
The concentration of topotecan in the 1 ml vial is higher (3 mg/ml) than with other topotecan products.
It is important that Topotecan Eagle is further diluted before use (see section 6.6).
ipients
4.3 Contraindications
Topotecan is contraindicated in patients who
have a history of severe hypersensitivity to the active substance or to any of are breast feeding (see section 4.6)
already have severe bone marrow depression prior to starting first course, as baseline neutrophils < 1.5 × 109/l and/or a platelet count of < 100 × 109/l.
videnced by
4.4
Topotecan Eagle requires appropriate dilution before use. The concentration of topotecan in Topotecan Eagle differs from other topotecan products (see section 6.6 for further instructions on dilution).
Topotecan Eagle contains a higher dose c for intravenous infusion (usually 1 mg/ concentration between 25 gg/ml and
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 been repo comp
neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have clinical trials with topotecan. In patients presenting with fever, neutropenia, and a ttern of abdominal pain, the possibility of neutropenic colitis should be considered.
Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been fatal (see section 4.8). Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation and use of pneumotoxic substances and/or colony stimulating factors. Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, dyspnoea and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed.
Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated with clinically relevant thrombocytopenia. This should be taken into account when prescribing topotecan, e.g. in case patients at increased risk of tumour bleeds are considered for therapy.
As expected, patients with poor performance status (PS>1) have a lower response rate and an increased incidence of complications such as fever, infection and sepsis (see section 4.8).
Accurate assessment of performance status at the time therapy is given is important, to ensure that patients have not deteriorated to performance status 3.
There is insufficient experience of the use of topotecan in patients with severely impaired renal function (creatinine clearance < 20 ml/min) or severely impaired hepatic function (serum bilirubin > 10 mg/dl) due to cirrhosis. Topotecan is not recommended to be used in these patient groups.
A small number of hepatically impaired patients (serum bilirubin between 1.5 and 10 mg/dl) were given intravenous topotecan at 1.5 mg/m2 for five days every three weeks. A reduction in topotecan clearance was observed. However there are insufficient data available to make a dose recommendation for this patient group.
4.5 Interaction with other medicinal products and other forms of interaction
No in vivo human pharmacokinetic interaction studies have been performed.
Topotecan does not inhibit human P450 enzymes (see section 5.2). In an intraveno the co-administration of granisetron, ondansetron, morphine or corticosteroids di significant effect on the pharmacokinetics of total topotecan (active and inactiv
lation study, ppear to have a
In combining topotecan with other chemotherapy agents, reduction of the doses of each medicinal
product may be required to improve tolerability. However, in com a distinct sequence-dependent interaction depending on whethe or 5 of the topotecan dosing. If either cisplatin or carboplatin is dosing, a lower dose of each agent must be given to improve agent which can be given if the platinum agent is given on d
ng with platinum agents, there is atinum agent is given on day 1 on day 1 of the topotecan
ility compared to the dose of each
When topotecan (0.75 mg/m2/day for five consecutive days) and cisplatin (60 mg/m2/day on Day 1) were administered in 13 patients with ovarian cancer, a slight increase in AUC (12 %, n = 9) and Cmax (23 %, n = 11) was noted on day 5. This increase is considered unlikely to be of clinical relevance.
4.6 Fertility, pregnancy and lact
Contraception in males an
As with all cytotoxic partner is treated wit
Women of childbeari
ential
effective contraceptive methods must be advised when either
Topotecan has
therefore therapy w
n shown to cause embryo-foetal lethality and malformations in preclinical studies s with other cytotoxic medicinal products, topotecan may cause foetal harm and of childbearing potential should be advised to avoid becoming pregnant during ecan.
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.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. However, caution should be observed when driving or operating machines if fatigue and asthenia persist.
4.8 Undesirable effects
In dose-finding trials involving 523 patients with relapsed ovarian cancer and 631 patients with relapsed small cell lung cancer, the dose limiting toxicity of topotecan monotherapy was found to be haematological. Toxicity was predictable and reversible. There were no signs of cumulative haematological or non-haematological toxicity.
The adverse event profile for topotecan when given in combination with cisplatin in the cervical cancer clinical trials is consistent with that seen with topotecan monotherapy. The overall haematological toxicity is lower in patients treated with topotecan in combination with cisplatin compared to topotecan monotherapy, but higher than with cisplatin alone.
Additional adverse events were seen when topotecan was given in combination with cisplatin, however, these events were seen with cisplatin monotherapy and not attributable to topotecan. The prescribing information for cisplatin should be consulted for a full list of adverse events associated cisplatin use.
The integrated safety data for topotecan monotherapy are presen
Adverse reactions are listed below, by system organ class and absolute frequency (all reported events).
Frequencies are defined as: very common (> 1/10), commons 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, undesira
cts are presented in order of decreasing seriousness.
Very common: febrile neutropenia, neutropenia (see Gastrointestinal disorders), thrombocytopenia, anaemia, leucopenia
Common: pancytop Not known: severe
Rare: inters
g (associated with thrombocytopenia)
ng disease (some cases have been fatal)
mon: nausea, vomiting and diarrhoea (all of which may be severe), constipation, inal pain1, mucositis
utropenic colitis, including fatal neutropenic colitis, has been reported to occur as a complication of topotecan-induced neutropenia (see section 4.4)
Very common: alopecia
Common: pruritus
Very common: anorexia (which may be severe)
Very common: infection
Common: sepsis2
-
2 Fatalities due to sepsis have been reported in patients treated with topotecan (see section 4.4)
Very common: pyrexia, asthenia, fatigue Common: malaise
3
Very rare: extravasation
-
3 Extravasation has been reported very rarely. Reactions have been mild and have not generally required specific therapy.
Common: hypersensitivity reaction including rash Rare: anaphylactic reaction, angioedema, urticaria
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 C jk
Neutropenia: Severe (neutrophil count < 0.5 × 109/l) during course 1 was seen in 55 % of the patients and with duration > seven days in 20 % and overall in 77 %^fpatients (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 sectio
Thrombocytopenia: Severe (platelets less than 25 × 109/l) in 25 % of patients (8 % of courses); moderate (platelets between 25.0 and 50.0 × 109/l) in 25 % of patients (15 % of courses). Median time to onset of severe thrombocytopenia was Day 15 and the median duration was five days. Platelet transfusions were given in 4 % of courses. Reports of significant sequelae associated with thrombocytopenia including fatalities due to tumour bleeds have been infrequent.
Anaemia: Mo
transfusi
Non-
loderatpto severe (Hb < 8.0 g/dl) in 37 % of patients (14 % of courses). Red cell were given in 52 % of patients (21 % of courses).
oilogiical
reported non-haematological effects were gastrointestinal such as nausea (52 %), vomiting
), and diarrhoea (18 %), constipation (9 %) and mucositis (14 %). Severe (grade 3 or 4) nausea,
vomiting, diarrhoea and mucositis incidence was 4, 3, 2 and 1 % respectively.
Mild abdominal pain was also reported amongst 4 % of patients.
Fatigue was observed in approximately 25 % and asthenia in 16 % of patients whilst receiving topotecan. Severe (grade 3 or 4) fatigue and asthenia incidence was 3 and 3 % respectively.
Total or pronounced alopecia was observed in 30 % of patients and partial alopecia in 15 % of patients.
Other severe events occurring in patients that were recorded as related or possibly related to topotecan treatment were anorexia (12 %), malaise (3 %) and hyperbilirubinaemia (1 %).
Hypersensitivity reactions including rash, urticaria, angioedema and anaphylactic reactions have been reported rarely. In clinical trials, rash was reported in 4 % of patients and pruritus in 1.5 % of patients.
4.9 Overdose
There is no known antidote for topotecan overdose. The primary complications of overdose are anticipated to be bone marrow suppression and mucositis.
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX17.
The anti-tumour activity of topotecan involves the inhibition of topoisomerase-nzyme intimately involved in DNA replication as it relieves the torsional strain introduced the moving replication fork. Topotecan inhibits topoisomerase-I by stabilising the covcomplex of enzyme and strand-cleaved DNA which is an intermediate of the catalytic mechanism. The cellular sequela of inhibition of topoisomerase-I by topotecan is the induction of protein-associated DNA single-strand breaks.
Relapsed SCLC
A phase III trial (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: 8 whom retreatment with intravenous chemot BSC group had a statistically significant im
alone group (Log-rank p = 0.0104). relative to BSC alone group was 0.6 with topotecan + BSC was 25.9 we 18.6) for patients receiving BSC alo
days for oral topotecan + BSC, 90 days for BSC) and for erapy was not considered appropriate. Oral topotecan plus rovement in overall survival compared with the BSC djusted hazard ratio for oral topotecan plus BSC group CI: 0.45, 0.90). The median survival for patients treated 95 % C.I. 18.3, 31.6) compared to 13.9 weeks (95 % C.I. 11.1, 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 s
efficacy completi associ
report
tudy 065) and one Phase 3 study (Study 396) were conducted to evaluate the otecan versus intravenous topotecan in patients who had relapsed > 90 days after
ne prior regimen of chemotherapy (see Table 1). Oral and intravenous topotecan were ith similar symptom palliation in patients with relapsed sensitive SCLC in patient selfan unblinded symptom scale assessment in each of these two studies.
Table 1. Summary of survival, response rate and time to progression in SCLC patients treated with oral
or intravenous
| Study 065 | Study 396 | |||
| Oral topotecan | Intravenous topotecan | Oral topotecan | Intravenous topotecan | |
| (N = 52) | (N = 54) | (N = 153) | (N = 151) | |
| Median survival (weeks) (95 % CI) | 32.3 (26.3, 40.9) | 25.1 (21.1, 33.0) | 33.0 (29.1, 42.4) | 35.0 (31.0, 37.1) |
| Hazard ratio (95 % CI) | 0.88 (0.59, 1.31) | 0.88 (0.7, 1.11) | ||
| Response rate (%) (95 % CI) | 23.1 (11.6, 34.5) | 14.8 (5.3, 24.3) | 18.3 (12.2, 24.4) | 21.9 (15.3, 28.5) |
| Difference in response rate (95 % CI) | 8.3 (-6.6, 23.1) | –3.6 (-12.6, 5.5) | ||
| Median time to progression (weeks) (95 % CI) | 14.9 (8.3, 21.3) | 13.1 (11.6, 18.3) | 11.9 (9.7, 14.1) | |
| Hazard ratio (95 % CI) | 0.90 (0.60, 1.35) | 1.21 (0.96,4X3)* | ||
N = total number of patients treated. CI = Confidence interval.
cyclophosphamide, itive SCLC, the overall. Median time to
In another randomised phase III trial which compared intravenous topotecan to Adriamycin (doxorubicin) and vincristine (CAV) in patients with relapsed, sens response rate was 24.3 % for topotecan compared to 18.3 % for the C progression was similar in the two groups (13.3 weeks and 12.3 week for the two groups were 25.0 and 24.7 weeks respectively. The hazard topotecan relative to CAV was 1.04 (95 % CI 0.78 –
respectively). Median survivals ratio for survival of IV
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 response rate to topotecan was 4.0 %
not responding to first line therapy), the
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 wirgery and/or radiation was not considered appropriate. Topotecan plus y significant benefit in overall survival relative to cisplatin monotherapy after im analyses (Log-rank p = 0.033).
cisplatin had a s adjusting for i
Table 2. Study results Study GOG-0179
| ITT population | ||
| Cisplatin 50mg/m 2 d.1 q21 d. | Cisplatin 50mg/m2 d.1 + Topotecan 0.75mg/m2 dx3 q21 | |
| Survival (months) | (n = 146) | (n = 147) |
| Median (95 % C.I.) | 6.5 (5.8, 8.8) | 9.4 (7.9, 11.9) |
| Hazard ratio (95 % C.I.) | 0.76 (0.59–0.98) | |
| Log rank p-value | 0.033 | |
| Patients without prior Cisplatin chemoradiotherapy X. | ||
| Cisplatin | Topotecan/Cisplatin C\ | |
| Survival (months) | (n = 46) | (n = 44) |
| Median (95 % C.I.) | 8.8 (6.4, 11.5) | ________15.7 (11.9, 47/L^ |
| 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) | /v\79 (5.5, 10.9) |
| Hazard ratio (95 % C.I.) | 0.85 (0.59, 1.21ÎZ | |
5.2 Pharmacokinetic properties
Following intravenous administration of topotecan at doses of 0.5 to 1.5 mg/m2 as a 30 minute infusion daily for five days, topotecan demonstrated a high plasma clearance of 62 l/h (SD 22), corresponding to approximately 2/3 of liver blood flow. Topotecan also had a high volume of distribution, about 132 l, (SD 57) and a relatively short half-life of 2–3 hours. Comparison of pharmacokinetic parameters did not suggest any change in pharmacokinetics over the 5 days of dosing. Area under the curve increased approximately in proportion to the increase in dose. There is little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change in the PK after multiple doses. Preclinical studies indicate plasma protein binding of topotecan is low (35 %) and distribution between blood cells and plasma was fairly homogeneous.
The elimination of topotecan has only been partly investigated in man. A major route of clearance of topotecan was by hydrolysis of the lactone ring to form the 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.
n e nal
Overall recovery of medicinal product-related material following five daily doses of topotecan 71 to 76 % of the administered intravenous dose. Approximately 51 % was excreted as tota and 3 % was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total top accounted for 18 % while faecal elimination of N-desmethyl topotecan was 1.7 %. Overall,
N-desmethyl metabolite contributed a mean of less than 7 % (range 4–9 %) of the t product related material accounted for in the urine and faeces. The topotecan-O-glu N-desmethyl topotecan-O-glucuronide in the urine were less than 2.0 %.
uronide and
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/m2 compared to 21.3 l/h/m2 [n = 9]) (see section 4.5).
Plasma clearance in patients with hepatic im irment (serum bilirubin between 1.5 and 10 mg/dl) decreased to about 67 % when compared wi ontrol group of patients. Topotecan half-life was
increased by about 30 % but no clear ch of total topotecan (active and inactiv about 10 % compared with the con
in volume of distribution was observed. Plasma clearance in patients with hepatic impairment only decreased by up of patients.
Plasma clearance in patients with renal impairment (creatinine clearance 41–60 ml/min.) decreased to
about 67 % compared half-life only increase clearance was reduced to 4.9 hours.
ontrol patients. Volume of distribution was slightly decreased and thus
4 %. In patients with moderate renal impairment topotecan plasma
% of the value in control patients. Mean half-life increased from 1.9 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).
c population
The pharmacokinetics of topotecan given as a 30-minute infusion for 5 days were evaluated in two studies. One study included a dose range of 1.4 mg/m2 to 2.4 mg/m2 in children (aged 2 up to 12 years, n = 18), adolescents (aged 12 up to 16 years, n = 9), and young adults (aged 16 to 21 years, n = 9) with refractory solid tumours. The second study included a dose range of 2.0 mg/m2 to 5.2 mg/m2 in children (n = 8), adolescents (n = 3), and young adults (n = 3) with leukaemia. In these studies, there were no apparent differences in the pharmacokinetics of topotecan among children, adolescents, and young adult patients with solid tumours or leukaemia, but data are too limited to draw definite conclusions.
5.3 Preclinical safety data
Resulting from its mechanism of action, topotecan is genotoxic to mammalian cells (mouse lymphoma cells and human lymphocytes) in vitro and mouse bone marrow cells in vivo. Topotecan was also shown to cause embryo-foetal lethality when given to rats and rabbits.
In reproductive toxicity studies with topotecan in rats there was no effect on male or female fertility; however, in females super-ovulation and slightly increased pre-implantation loss were observed.
The carcinogenic potential of topotecan has not been studied.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Hydrochloric acid (E507) (for pH adjustment) Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Vial before opening 18 months.
Diluted solution
From a microbiological point of view, the ion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 2
at 20°C – 25°C and ambient lighting conditions.
6.4 Special precautions for storage
Do not store above 25°C.
Keep the vial in the
arton in order to protect from light.
For storage conditions of once-opened and diluted medicinal product, see section 6.3.
6.5
nd contents of container
Eac
6.6
entrate in type 1 clear glass vial, together with grey butyl rubber stopper and aluminium seal lue polypropylene flip-off cap, and with yellow vial ring collar.
pack contains 1 vial.
General precautions
The normal procedures for proper handling and disposal of anticancer medicinal products should be adopted, namely:
-
– Personnel should be trained to dilute the medicinal product.
-
– Pregnant staff should be excluded from working with this medicinal product.
-
– Personnel handling this medicinal product during dilution should wear protective clothing
including mask, goggles and gloves.
In patients (n = 39) with recurrence within 180 days after chemor median survival in the topotecan plus cisplatin arm was 4.6 months 4.5 months (95 % C.I.: 2.9, 9.6) for the cisplatin arm with an ha
rapy with cisplatin, the % C.I.: 2.6, 6.1) versus tio of 1.15 (0.59, 2.23). In those
(n = 102) with recurrence after 180 days, the median s 9.9 months (95 % C.I.: 7, 12.6) versus 6.3 months (95 hazard ratio of 0.75 (0.49, 1.16).
the topotecan plus cisplatin arm was 4.9, 9.5) for the cisplatin arm with an
Paediatric population
Topotecan was also evaluated in the pa safety are available.
population; however, only limited data on efficacy and
In an open-label trial involving children (n = 108, age range: infant to 16 years) with recurrent or progressive solid tumours, topotecan was administered at a starting dose of 2.0 mg/m2 given as a 30-minute infusion for 5 days repeated every 3 weeks for up to one year depending on response to luded were Ewing's Sarcoma/primitive neuroectodermal tumour, a, and rhabdomyosarcoma. Antitumour activity was demonstrated primarily in paties neuroblastoma. Toxicities of topotecan in paediatric patients with recurrent and refractory sid tumours were similar to those historically seen in adult patients. In this study, ) patients received G-CSF over 192 (42.1 %) courses; sixty-five (60 %) received Packed Red Blood Cells and fifty (46 %) of platelets over 139 and 159 courses 4.9 %) respectively. Based on the dose-limiting toxicity of myelosuppression, the
s
therapy. Tumour types neuroblastoma, oste
forty-six transfusi (30.5 maxi
tolerated dose (MTD) was established at 2.0 mg/m2/day with G-CSF and 1.4 mg/m2/day
without G-CSF in a pharmacokinetic study in paediatric patients with refractory solid tumours (see section 5.2).
All items for administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags for high-temperature incineration. Liquid waste may be flushed with large amounts of water.
Accidental contact with the skin or eyes should be treated immediately with copious amounts of water.
Instructions for dilution
Topotecan Eagle concentrate is clear yellow to orange in colour and contains 3 mg/ml of topoteca which is a higher concentration than found in other topotecan products for intravenous infusion.
The user is requested to report any medication errors.
The following dosing tables should be used as reference:
Instructions
for Intravenous Administration for Small Cell Lun
| Body surface area (m 2 ) | For recommended dose ‚1.5 mg/m2‘ | For reduced dose ‚1.25 mg/m2‘ | Forreduced dose ^1^‚10 mg/m2‘ | |||
| Volume of solution required (ml) | Total dose (mg) | Volume of solution required (ml) | Total doseA (mg)^ | Volume of solution * required (ml) | Total dose (mg) | |
| 1 | 0.50 | 1.50 | 0.42 | 0.33 | 0.99 | |
| 1.1 | 0.55 | 1.65 | 0.46 | 0^.38 | 0.37 | 1.11 |
| 1.2 | 0.60 | 1.80 | 0’50r\ | 1.50 | 0.40 | 1.20 |
| 1.3 | 0.65 | 1.95 | 1.62 | 0.43 | 1.29 | |
| 1.4 | 0.70 | 2.10 | X(J’58 | 1.74 | 0.47 | 1.41 |
| 1.5 | 0.75 | 2.25 | £j0.63 | 1.89 | 0.50 | 1.50 |
| 1.6 | 0.80 | 2.4°Z^ | 0.67 | 2.01 | 0.53 | 1.59 |
| 1.7 | 0.85 | 2*5^ | 0.71 | 2.13 | 0.57 | 1.71 |
| 1.8 | 0.90 À | 7×0 | 0.75 | 2.25 | 0.60 | 1.80 |
| 1.9 | 0.95 v | 2.85 | 0.79 | 2.37 | 0.63 | 1.89 |
| 2 | 1.00V | 3.00 | 0.83 | 2.49 | 0.67 | 2.01 |
| 2.1 | 3.15 | 0.88 | 2.64 | 0.70 | 2.10 | |
| 2.2 ♦ | çN’10 | 3.30 | 0.92 | 2.76 | 0.73 | 2.19 |
| 2.3 ¿s | 1.15 | 3.45 | 0.96 | 2.88 | 0.77 | 2.31 |
| ¿0° | 1.20 | 3.60 | 1.00 | 3.00 | 0.80 | 2.40 |
| 1.25 | 3.75 | 1.04 | 3.12 | 0.83 | 2.49 | |
Instructions for
for Intravenous Administration for Cervical Cancer
| Body surface area (m 2 ) | For recommended dose ‚0.75 mg/m2‘ | For reduced dose ‚0.60 mg/m2‘ | For reduced dose ‚0.45 mg/m2‘ | |||
| Volume of solution required (ml) | Total dose (mg) | Volume of solution required (ml) | Total dose (mg) | Volume of solution required (ml) | Total dose (mg) | |
| 1 | 0.25 | 0.75 | 0.20 | 0.60 | 0.15 | 0.45 |
| 1.1 | 0.28 | 0.84 | 0.22 | 0.66 | 0.17 | 0.51 |
| 1.2 | 0.30 | 0.90 | 0.24 | 0.72 | 0.18 | 0.54 |
| 1.3 | 0.33 | 0.99 | 0.26 | 0.78 | 0.20 | 0.60 |
| 1.4 | 0.35 | 1.05 | 0.28 | 0.84 | 0.21 | 0.63 Q |
| 1.5 | 0.38 | 1.14 | 0.30 | 0.90 | 0.23 | |
| 1.6 | 0.40 | 1.20 | 0.32 | 0.96 | 0.24 | /-& |
| 1.7 | 0.43 | 1.29 | 0.34 | 1.02 | 0.26 | ^Z0.78 |
| 1.8 | 0.45 | 1.35 | 0.36 | 1.08 | 0.27 | 0 0.81 |
| 1.9 | 0.48 | 1.44 | 0.38 | 1.14 | °59r | 0.87 |
| 2 | 0.50 | 1.50 | 0.40 | 1.20 | > 0.W | 0.90 |
| 2.1 | 0.53 | 1.59 | 0.42 | 1.26 i | 70.32 | 0.96 |
| 2.2 | 0.55 | 1.65 | 0.44 | 1.320 | 0.33 | 0.99 |
| 2.3 | 0.58 | 1.74 | 0.46 | ^138^ * | 0 0.35 | 1.05 |
| 2.4 | 0.60 | 1.80 | 0.48 | ^UÄ4 | 0.36 | 1.08 |
| 2.5 | 0.63 | 1.89 | 0.50 | 1.50 | 0.38 | 1.14 |
Further dilution of Topotecan Eagle is requi
solution for injection or glucose 50 mg/ml topotecan concentration of between 25 Dilution should be performed under
with either sodium chloride 9 mg/ml (0.9 % w/v) /v) solution for injection in order to reach a final nd 50 ng/ml in the solution for infusion to the patient.
septic conditions (e.g. an LAF bench).
Disposal <
Topotecan Eagle 3 mg/1 ml is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.
7. MARK
s Limited
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 22/12/2011
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) /.