HYCAMTIN IV

אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

02/2014

םושירה רפסמו תילגנאב רישכת םש

HYCAMTIN: 104-89-28936

םושירה לעב םש

GlaxoSmithKline )ISRAEL( Ltd

:

! דבלב תורמחהה טורפל דעוימ הז ספוט אפורל ןולעב אפורל ןולעב תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט

Undesirable effects

Blood and lymphatic system

disorders

Very Common: Anaemia, febrile

neutropenia, leucopenia,

neutropenia, thrombocytopenia

Not known: Severe bleeding

)associated with

thrombocytopenia(

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(

Skin and subcutaneous

disorders

Very Common: Alopecia

Skin and subcutaneous tissue

disorders

Very common: alopecia

Common: pruritus

Infections and infestations

Common: Infection, sepsis )see

Warnings and Precautions(

Infections and infestations

Very common: infection

Common: sepsis

Immune system disorders

Common: Hypersensitivity,

including rash

Immune system disorders

Common: hypersensitivity reaction

including rash

Rare: anaphylactic reaction,

angioedema, urticaria

-

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(.

Overdosage

Symptoms and Signs

The primary complications of

overdosage are anticipated to

be bone marrow suppression

and stomatitis.

Treatment

There is no known antidote

for topotecan overdosage.

Overdoses (up to 10-fold of the

prescribed dose) occurred in

patients treated with intravenous

topotecan. The primary

complication of overdosage is

bone marrow suppression. The

observed signs and symptoms of

overdose are consistent with the

known adverse reactions

associated with HYCAMTIN for

intravenous use. In addition,

elevated hepatic enzymes and

mucositis have been reported

following overdose. One patient

received a single dose of 40 mg/

of intravenous topotecan and

developed gastrointestinal

toxicity, skin toxicity, and

myelosuppresion leading to septic

shock. Another patient received a

single dose of 35 mg/m

experienced severe, reversible

neutropenia.

There is no known antidote for

overdosage with HYCAMTIN. If

an overdose is suspected, monitor

the patient for bone marrow

suppression and institute

supportive-care measures (such as

prophylactic G-CSF and antibiotic

therapy) as appropriate.

תושקובמה תורמחהה תונמוסמ ובש ,ןולעה ב"צמ .בוהצ עקר לע

ונמוס תורמחה רדגב םניאש םייוניש עבצב )ןולעב( קורי

HYC IV API FEB16 CL V1 COR MAT CL

The format of this leaflet was determined by the Ministry of Health and its content was

checked and approved in February 2016

Hycamtin

®

I.V.

1.

NAME OF THE MEDICINAL PRODUCT

HYCAMTIN I.V.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 4 mg topotecan (as hydrochloride).

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder for solution for infusion.

Light yellow to greenish powder.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

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).

4.2

Posology and method of administration

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

1.5 x 10

/l, a platelet count of

100 x 10

/l and a haemoglobin level of

9 g/dl (after transfusion

if necessary).

Ovarian and Small Cell Lung Carcinoma

Initial dose

The recommended dose of topotecan is 1.5 mg/m

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

/l, the platelet count is

100 x 10

/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

/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

/day to

1.25 mg/m

/day (or subsequently down to 1.0 mg/m

/day if necessary).

Doses should be similarly reduced if the platelet count falls below 25 x 10

/l. In clinical trials,

topotecan was discontinued if the dose had been reduced to 1.0 mg/m

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

/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

/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

/l, the platelet count is more than or equal to 100 x 10

/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

/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

/day

for subsequent courses (or subsequently down to 0.45 mg/m

/day if necessary).

Doses should be similarly reduced if the platelet count falls below 25 x 10

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

/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

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).

4.3

Contraindications

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

/l and/or a platelet count of

100 x 10

4.4

Special warnings and precautions for use

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

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 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

/day for 5 consecutive days) and cisplatin (60 mg/m

/day on Day 1) were

administered in 13 patients with ovarian cancer, a slight increase in AUC (12 %, n=9) and C

(23 %,

n=11) was noted on day 5. This increase is considered unlikely to be of clinical relevance.

4.6

Fertility, pregnancy and lactation

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 and pregnancy

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 and to inform the treating physician immediately should this occur.

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 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

, mucositis

Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a

complication of topotecan-induced neutropenia (see section 4.4)

Skin and subcutaneous tissue disorders

Very common: alopecia

Common: pruritus

Metabolism and nutrition disorders

Very common: anorexia (which may be severe)

Infections and infestations

Very common: infection

Common: sepsis

Fatalities due to sepsis have been reported in patients treated with topotecan

(see section 4.4)

General disorders and administration site conditions

Very common: pyrexia, asthenia, fatigue

Common: malaise

Very rare: extravasation

Extravasation has been reported very rarely. Reactions have been mild and have not

generally required specific therapy.

Immune system disorders

Common: hypersensitivity reaction including rash

Rare: anaphylactic reaction, angioedema, urticaria

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

/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

/l) in 25 % of patients (8 % of courses);

moderate (platelets between 25.0 and 50.0 x 10

/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.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.g

ov.il ).

4.9

Overdose

Overdoses (up to 10-fold of the prescribed dose) occurred in patients treated with intravenous

topotecan. The primary complication of overdosage is bone marrow suppression. The observed signs

and symptoms of overdose are consistent with the known adverse reactions associated with

HYCAMTIN for intravenous use. In addition, elevated hepatic enzymes and mucositis have been

reported following overdose. One patient received a single dose of 40 mg/m

of intravenous topotecan

and developed gastrointestinal toxicity, skin toxicity, and myelosuppression leading to septic shock.

Another patient received a single dose of 35 mg/m

and experienced severe, reversible neutropenia.

There is no known antidote for overdosage with HYCAMTIN. If an overdose is suspected, monitor

the patient for bone marrow suppression and institute supportive-care measures (such as prophylactic

G-CSF and antibiotic therapy) as appropriate.

5.

PHARMACOLOGICAL PROPERTIES

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

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).

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 a hazard ratio of

0.75 (0.49, 1.16).

Paediatrics

Topotecan was also evaluated in the paediatric population; however, only limited data on efficacy and

safety are available.

In an open-label trial involving children (n = 108, age range: infant to 16 years) with recurrent or

progressive solid tumours, topotecan was administered at a starting dose of 2.0 mg/m

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

/day with G-CSF and 1.4 mg/m

/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

as a 30 minute

infusion daily for five days, topotecan demonstrated a high plasma clearance of 62 l/h (SD 22),

corresponding to approximately 2/3 of liver blood flow. Topotecan also had a high volume of

distribution, about 132 l, (SD 57) and a relatively short half-life of 2-3 hours. Comparison of

pharmacokinetic parameters did not suggest any change in pharmacokinetics over the 5 days of

dosing. Area under the curve increased approximately in proportion to the increase in dose. There is

little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change

in the PK after multiple doses. Preclinical studies indicate plasma protein binding of topotecan is low

(35 %) and distribution between blood cells and plasma was fairly homogeneous.

The elimination of topotecan has only been partly investigated in man. A major route of clearance of

topotecan was by hydrolysis of the lactone ring to form the ring-opened carboxylate.

Metabolism accounts for < 10 % of the elimination of topotecan. An N-desmethyl metabolite, which

was shown to have similar or less activity than the parent in a cell-based assay, was found in urine,

plasma, and faeces. The mean metabolite:parent AUC ratio was less than 10 % for both total topotecan

and topotecan lactone. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has

been identified in the urine.

Overall recovery of medicinal product-related material following five daily doses of topotecan was 71

to 76 % of the administered IV dose. Approximately 51 % was excreted as total topotecan and 3 %

was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted

for 18 % while faecal elimination of N-desmethyl topotecan was 1.7 %. Overall, the N-desmethyl

metabolite contributed a mean of less than 7 % (range 4-9 %) of the total medicinal product related

material accounted for in the urine and faeces. The topotecan-O-glucuronide and N-desmethyl

topotecan-O-glucuronide in the urine were less than 2.0 %.

In vitro data using human liver microsomes indicate the formation of small amounts of 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

compared to 21.3 l/h/m

[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

to 2.4 mg/m

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

to 5.2 mg/m

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 PARTICULARS

6.1

List of excipients

Mannitol

Tartaric acid

Hydrochloric acid

Sodium hydroxide

Nitrogen

6.2

Incompatibilities

None known.

6.3

Shelf life

The expiry date of the product is indicated on the label and packaging.

Reconstituted and diluted solutions

The product should be used immediately after reconstitution as it contains no antibacterial

preservative. If reconstitution and dilution are 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

C after breakage.

6.4

Special precautions for storage

Keep the vial in the outer carton in order to protect from light.

Store below 30°C.

6.5

Nature and contents of container

HYCAMTIN 4 mg is supplied in 17 ml type I 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 a carton containing 1 vial.

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.

MANUFACTURER

GlaxoSmithKline Manufacturing S.P.A., Parma, Italy.

8.

REGISTRATION HOLDER

Novartis Israel Ltd.,

36 Shacham St., Petach Tikva

9.

LICENSE NUMBER

104 89 28936