HYCAMTIN 0.25 MG

Patient leaflet in accordance with the

Pharmacists' Regulations (Preparations) – 1986

The medicine is dispensed according to

a physician's prescription only

Hycamtin

TM

0.25 mg

Hycamtin

TM

1 mg

Hard capsules

The active ingredient and its quantity:

Each Hycamtin 0.25 mg capsule contains 0.25 mg

Topotecan (as Hydrochloride).

Each Hycamtin 1 mg capsule contains 1 mg

Topotecan (as Hydrochloride).

List of the additional ingredients detailed in

section 6.

Read the entire leaflet carefully before using

the medicine. This leaflet contains concise

information about the medicine. If you have any

other questions, refer to the physician or the

pharmacist.

This medicine has been prescribed for you. Do

not pass it on to others. It may harm them even

if it seems to you that their medical condition

is similar.

1. What is the medicine intended

for?

Hycamtin is used to treat:

small cell lung cancer that has come back

after chemotherapy.

Your physician will decide with you whether

Hycamtin therapy is better than further treatment

with your initial chemotherapy.

Therapeutic group

Antineoplastic agent

2. Before using the medicine

Do not use the medicine:

If you are sensitive (allergic) to topotecan

or to any of the additional ingredients

contained in the medicine (listed in Section

Do not use the medicine if you are pregnant,

think you are pregnant, are planning to

become pregnant or if you are breast-

feeding.

If your blood cell counts are too low. Your

physician will tell you, based on the results

of your last blood test.

→

Tell your physician if any of these applies

to you.

Special warnings regarding the use of the

medicine

Before the treatment with Hycamtin, tell the

physician:

If you have any kidney or liver problems.

Your dose of Hycamtin may need to be

adjusted.

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

physician for advice.

→

Tell your physician if any of these applies to

you.

Other medicines and Hycamtin

If you are taking or have recently taken

other medicines including non -prescription

medicines and food supplements, tell the

physician or the pharmacist.

If you are also being treated with cyclosporin A,

there may be a higher than usual chance of you

getting side effects. You will be monitored closely

while you are taking these two medicines.

Remember to tell your physician if you start

to take any other medicine while you’re taking

Hycamtin.

Using the medicine with food and drink

Hycamtin capsules may be taken with or without

food.

The capsules must be swallowed whole, and

must not be chewed, crushed or divided.

Using the medicine and alcohol

There is no known interaction between Hycamtin

and alcohol. However, you should check with your

physician 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 physician for advice.

For women: Do not try and become pregnant

at least a month after the end of treatment,

until a physician will advise you it is safe

to do so. For men: Do not try and become

father a child at least 3 months after the end

of treatment, until a physician will advise you

it is safe to do so.

Male patients who may wish to father a

child should ask their physician for family

planning advice or treatment. If pregnancy

occurs during treatment, tell your physician

immediately.

Do not breast-feed if you are being treated

with Hycamtin. Do not restart breast-feeding

until the physician 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

should

you

use

the

medicine?

Always use according to the physician's

instructions. You should check with the physician

or the pharmacist if you are unsure.

The dose (and number of capsules) of Hycamtin

you are given will be worked out by your

physician, 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.

The duration of the treatment will be determined

by the physician.

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

the capsule's content in your eyes, wash them

immediately with gently flowing water for at least

15 minutes. Consult your physician/healthcare

provider after eye contact or if you experience

a skin reaction.

Do not exceed the recommended dose

If you accidently have taken a higher dosage

Refer to a physician or pharmacist immediately

for advice if you have taken too many capsules.

If a child has accidentally swallowed the medicine,

refer immediately to a physician or to a hospital

emergency room and bring the package of the

medicine with you.

If you forgot to take the medicine

Do not take a double dose to make up for a

forgotten dose. Just take the next dose at the

scheduled time.

Persist with the treatment as recommended by

the physician.

Do not take medicines in the dark! Check the

label and the dose each time you take a medicine.

Wear glasses if you need them.

If you have any other questions regarding the

use of the medicine, consult the physician or the

pharmacist.

4. Side effects

As with any medicine, use of Hycamtin may

cause side effects in some of the users. Do not

be alarmed by reading the list of side effects. You

may not experience any of them.

Serious side effects: tell your physician

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 physician 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 physician immediately if you

get any symptoms of these conditions, as

hospitalisation may be necessary.

Additional side effects

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 physician

for advice on how to minimize the risk of

bleeding.

Weight loss and loss of appetite (anorexia);

tiredness; weakness.

Nausea (feeling sick), vomiting (being sick).

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

High body temperature (fever)

Stomach pain, constipation, indigestion

Feeling unwell

Itching sensation.

Uncommon side effect

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

fluid

build-up

(angioedema)

Itchy rash (or hives)

Collapse.

If a side effect has appeared, if any of the side

effects get worse or when you suffer from a side

effect that has not been mentioned in the leaflet,

you should consult the physician.

5. How to store the medicine?

Avoid poisoning! This medicine and any other

medicine should be kept in a closed place

out of the sight and reach of children and/

or infants in order to avoid poisoning. Do not

induce vomiting without an explicit instruction

from the physician.

Do not use the medicine after the expiry date

(exp. date) appearing on the carton. The expiry

date refers to the last day of that month.

Store in a refrigerator at temperature of

2°C-8°C.

Keep the medicine in its package to protect from

light.

Do not freeze.

6. Additional information

In addition to the active ingredient the medicine

also contains –

Hydrogenated vegetable oil, gelatin, glyceryl

monostearate, titanium dioxide (E171), black

iron oxide (E172), shellac, anhydrous ethanol,

propylene glycol, isopropyl alcohol, butanol,

concentrated ammonia solution, potassium

hydroxide.

For 1 mg capsules only, red iron oxide (E172).

What does the medicine look like and what is the

content of the package-

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.

License Holder: GlaxoSmithKline (Israel) Ltd., 25

Basel St., Petach Tikva.

Manufacturer: GlaxoSmithKline Manufacturing

SPA, Verona, Italy.

This leaflet was checked and approved by the

Ministry of Health in: 01/2015

Registration number of the medicine in the

National Drug Registry of the Ministry of Health:

Hycamtin 0.25 mg: 141-37-31862

Hycamtin 1 mg:

141-38-31863

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.

Hyc Cap PT v3

21041

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

checked and approved in January 2015

HYCAMTIN

™

0.25 mg

HYCAMTIN

™

1 mg

1.

NAME OF THE MEDICINAL PRODUCT

HYCAMTIN 0.25 mg

HYCAMTIN 1 mg

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains topotecan hydrochloride equivalent to 0.25 mg of topotecan.

Each capsule contains topotecan hydrochloride equivalent to 1 mg of topotecan.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Hard gelatin capsule.

Topotecan capsule, 0.25 mg: Opaque white to yellowish white and imprinted with ‘HYCAMTIN’

and ‘0.25 mg’.

Topotecan capsule, 1 mg: Opaque pink and imprinted with ‘HYCAMTIN’ and ‘1 mg’.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

HYCAMTIN capsules are 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).

4.2 Posology and method of administration

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

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

/l, a platelet count of

100 x 10

/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

/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 0.4 mg/m

/day

to 1.9 mg/m

/day (or subsequently down to 1.5 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 needed to be reduced below 1.5 mg/m

For patients who experience Grade 3 or 4 diarrhoea, the dose should be reduced by 0.4 mg/m

/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

The recommended monotherapy dose of oral topotecan in patients with small cell lung carcinoma

with a creatinine clearance between 30 and 49 ml/min is 1.9 mg/m

/day for five consecutive days.

If well tolerated, the dose may be increased to 2.3 mg/m

/day in subsequent cycles (see section

5.2).

Limited data in Korean patients with creatinine clearance less than 50 ml/min suggest a further

lowering of dose may be required (see section 5.2).

Insufficient data are available to make a recommendation for patients with a creatinine clearance

< 30 ml/min.

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).

Older people

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).

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 pregnant or 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.

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

creatinine clearance less than 30 ml/min have not been established. 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

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.

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).

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

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.

4.6 Fertility, pregnancy and lactation

Contraception in females

As with all cytotoxic chemotherapy, effective contraceptive methods must be advised during and

for 1 month following treatment with topotecan.

Contraception in males

As with all cytotoxic chemotherapy, effective contraceptive methods must be advised during and

for 3 month following treatment 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.

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 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 (≥ 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

, constipation, mucositis, dyspepsia

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

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: 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

/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 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

/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

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.

Reporting of suspected adverse reactions

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. Healthcare

professionals are asked to report any suspected adverse reactions 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.health.gov.il

) or

by email (

adr@moh.health.gov.il

). Additionally, you should also report to GSK Israel

il.safety@gsk.com

4.9 Overdose

There is no known antidote for topotecan overdose. Overdoses have been reported in patients

being treated with topotecan capsules (up to 5 fold of the recommended dose) and intravenous

topotecan (up to 10 fold of the recommended dose). The observed signs and symptoms for

overdose were consistent with the known undesirable events associated with topotecan (see

section 4.8). The primary complications of overdose are anticipated to be bone marrow

suppression and mucositis. In addition, elevated hepatic enzymes have been reported with

intravenous topotecan overdose.

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 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

Intravenou

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 %

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 %

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

/day and 4 mg/m

/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

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 hepatic impairment

(see section 4.2 and 4.4).

Results of a cross-study analysis suggest that the exposure to topotecan lactone, the active moiety

following topotecan administration, increases at decreased renal function. Geometric mean

topotecan lactone dose-normalized AUC

values were 9.4, 11.1 and 12.0 ng*h/mL in subjects

with creatinine clearance values of more than 80 mL/min, 50 to 80 mL/min and 30 to 49 mL/min,

respectively. In this analysis, creatinine clearance was calculated using the Cockcroft-Gault

method. Similar results were obtained if glomerular filtration rate (ml/min) was estimated using

the MDRD formula corrected for body weight. Patients with creatinine clearance >60 ml/min have

been included in efficacy/safety studies of topotecan. Therefore, use of the normal starting dose in

patients with a mild decrease in renal function is considered established (see section 4.2).

Korean patients with renal impairment had generally higher exposure than non-Asian patients with

the same degree of renal impairment. The clinical significance of this finding is unclear.

Geometric mean topotecan lactone dose-normalized AUC

values for Korean patients were 7.9,

12.9 and 19.7 ng*h/mL in subjects with creatinine clearance values of more than 80 mL/min, 50 to

80 mL/min and 30 to 49 mL/min, respectively (see section 4.2 and 4.4). There are no data from

Asian patients with renal impairment other than Koreans.

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.

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

Capsule contents:

Hydrogenated vegetable oil

Glyceryl monostearate

Capsule shell:

Gelatin

Titanium dioxide (E171)

HYCAMTIN 1 mg hard capsules: 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

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

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.

7.

MANUFACTURER

GlaxoSmithKline Manufacturing SPA, Verona, Italy.

8.

LICENSE HOLDER AND IMPORTER

GlaxoSmithKline (Israel) Ltd., 25 Basel St., Petach Tikva.

9.

LICENSE NUMBER

HYCAMTIN 0.25 mg: 141-37-31862

HYCAMTIN 1 mg: 141-38-31863

Hyc Cap DR v3