Gemcitabine 1g/25ml concentrate for solution for infusion vials

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Gemcitabine hydrochloride
Available from:
Actavis UK Ltd
ATC code:
L01BC05
INN (International Name):
Gemcitabine hydrochloride
Dosage:
40mg/1ml
Pharmaceutical form:
Solution for infusion
Administration route:
Intravenous
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: ; GTIN: 5012617026132
Authorization number:
PL 30306/0654

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Gemcitabine 40mg/ml Concentrate for Solution for Infusion PIL - UK

item no: AAAI6631

print proof no: 3

origination date: 13.01.16

originated by: S.Anson

revision date: 14.01.16

revised by: S.Anson

dimensions: 124 x 640

pharmacode:

colours/plates:

approved for print/date

Non Printing Colours

1. Black

date sent: 13.01.16

supplier: Actavis Nerviano

technically app. date: 13.01.16

min pt size: 9

Technical Approval

10 mm

10 mm

5 mm

10 mm

306 mm

14 mm

14 mm

20 mm

-1 mm

20 mm

+1 mm

ITF 6 mm

306 mm

N. 000000000.0

Gemcitabine 40mg/ml

Concentrate for Solution for

Infusion

Package leaflet: Information for the user

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Handling

The normal safety precautions for

cytostatic agents must be observed

when preparing and disposing of the

infusion solution. Pregnant personnel

should not handle the product.

Handling of the solution for infusion

should be done in a safety box and

protective coats and gloves should be

used. If no safety box is available, the

equipment should be supplemented

with a mask and protective glasses.

If the preparation comes into contact

with the eyes, this may cause serious

irritation. The eyes should be rinsed

immediately and thoroughly with

water. If there is lasting irritation, a

doctor should be consulted. If the

solution is spilled on the skin, rinse

thoroughly with water.

Instructions for dilution

The only approved diluent for

dilution of Gemcitabine Concentrate

for Solution for Infusion is sodium

chloride 9mg/ml (0.9%) solution for

injection (without preservative).

Use aseptic technique during

dilution of gemcitabine for

intravenous infusion administration.

Diluted solution is a clear colourless

or light straw-coloured solution.

Parenteral medicinal products

should be inspected visually

for particulate matter and

discolouration prior to

administration. If particulate matter

is observed, do not administer.

The following information is intended for healthcare professionals only:

Instruction for use

Gemcitabine 40mg/ml Concentrate for Solution for Infusion

Cytotoxic

AAAI6631

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if you are breast-feeding.

Warnings and precautions

Before the first infusion you will have

samples of your blood taken to check

if your liver and kidneys are working

well enough for you to receive this

medicine. Before each infusion you

will have samples of your blood taken

to check if you have enough blood

cells to receive Gemcitabine. Your

doctor may decide to change the

dose or delay treating you depending

on your general condition and if

your blood cell counts are too low.

Periodically you will have samples of

your blood taken to check how well

your kidneys and liver are working.

Talk to your doctor, nurse or hospital

pharmacist before using Gemcitabine.

If you have, or have previously had

liver disease, heart disease, vascular

disease or problems with your

kidneys talk to your doctor or hospital

pharmacist as you may not be able to

receive Gemcitabine.

If you have recently had or are

going to have radiotherapy, please

tell your doctor as there may be an

early or late radiation reaction with

Gemcitabine.

If you have been vaccinated recently,

please tell your doctor as this can

possibly cause bad effects with

Gemcitabine.

If during treatment with this

medicine you get symptoms such as

headache with confusion, seizures

(fits) or changes in vision, call your

doctor right away. This could be

a very rare nervous system side

effect named posterior reversible

encephalopathy syndrome.

If you develop breathing difficulties

or feel very weak and are very pale,

please tell your doctor as this may be

a sign of kidney failure or problems

with your lungs.

area of your body. Your doctor will

use this body surface area to work out

the right dose for you. This dosage

may be adjusted, or treatment may

be delayed depending on your blood

cell counts and on your general

condition.

How frequently you receive your

Gemcitabine infusion depends on

the type of cancer that you are being

treated for.

A hospital pharmacist or doctor

will have diluted the Gemcitabine

concentrate before it is given to you.

You will always receive Gemcitabine

by infusion into one of your veins.

The infusion will last approximately

30 minutes.

This medicinal product is not

recommended for use in children

under 18 years of age.

If you have further questions on the

use of this product ask your doctor or

pharmacist.

4

Possible side effects

Like all medicines, this medicine

can cause side effects, although not

everybody gets them.

You must contact your doctor

immediately if you notice any

of the following:

Bleeding from the gums, nose or

mouth or any bleeding that would

not stop, reddish or pinkish urine,

unexpected bruising (since you

might have less platelets than

normal which is very common).

Tiredness, feeling faint, becoming

easily breathless or if you look

pale (since you might have less

haemoglobin than normal which is

very common).

Continued below

Continued below

Read all of this leaflet carefully

before you start using this

medicine because it contains

important information for you.

Keep this leaflet. You may need

to read it again.

If you have any further

questions, ask your doctor,

pharmacist or nurse.

If you get any side effects, talk

to your doctor, pharmacist or

nurse. This includes any possible

side effects not listed in this

leaflet. See section 4.

The full name of this medicine

is Gemcitabine 40mg/ml

Concentrate for Solution

for Infusion but within the

leaflet it will be referred to as

Gemcitabine.

What is in this leaflet

1

What Gemcitabine is and

what it is used for

2

What you need to

know before you use

Gemcitabine

3

How to use Gemcitabine

4

Possible side effects

5

How to store Gemcitabine

6

Contents of the pack and

other information

1

What Gemcitabine is and

what it is used for

Gemcitabine belongs to a group of

medicines called “cytotoxics”. These

medicines kill dividing cells, including

cancer cells.

Gemcitabine may be given alone or in

combination with other anti-cancer

medicines, depending on the type of

cancer.

Gemcitabine is used in the treatment

of the following types of cancer:

Non-small cell lung cancer (NSCLC),

alone or together with cisplatin.

Pancreatic cancer.

Breast cancer, together with

paclitaxel.

Ovarian cancer, together with

carboplatin.

Bladder cancer, together with

cisplatin.

2

What you need to

know before you use

Gemcitabine

Do not use Gemcitabine:

if you are allergic to gemcitabine or

any of the other ingredients of this

medicine (listed in section 6).

If you develop generalised swelling,

shortness of breath or weight gain,

please tell your doctor as these may

be a sign of fluid leaking from your

small blood vessels into the tissues.

Children and adolescents

This medicine is not recommended

for use in children under 18 years of

age due to insufficient data on safety

and efficacy.

Other medicines and

Gemcitabine

Tell your doctor or hospital

pharmacist if you are taking,

have recently taken or might take

any other medicines, including

vaccinations and medicines obtained

without a prescription; or if you have

recently undergone radiotherapy or

are going to have radiotherapy.

Pregnancy, breast-feeding and

fertility

Pregnancy

If you are pregnant or breast-feeding,

think you may be pregnant or are

planning to have a baby, ask your

doctor or pharmacist for advice

before taking this medicine. The use

of Gemcitabine should be avoided

during pregnancy. Your doctor

will discuss with you the potential

risk of taking Gemcitabine during

pregnancy.

Breast-feeding

If you are breast-feeding, tell your

doctor.

You must discontinue breast-feeding

during Gemcitabine treatment.

Fertility

Men are advised not to father a child

during and up to 6 months following

treatment with Gemcitabine. If you

would like to father a child during

the treatment or in the 6 months

following treatment, seek advice from

your doctor or pharmacist. You may

want to seek counselling on sperm

storage before starting your therapy.

Driving and using machines

Gemcitabine may make you feel

sleepy.

Do not drive a car or use machinery

until you are sure that Gemcitabine

treatment is not affecting your

alertness.

3

How to use Gemcitabine

The recommended dose of

Gemcitabine is 1000-1250mg for

every square metre of your body’s

surface area. Your height and weight

are measured to work out the surface

Gemcitabine 40mg/ml Concentrate for Solution for Infusion PIL - UK

item no: AAAI6631

print proof no: 3

origination date: 13.01.16

originated by: S.Anson

revision date: 14.01.16

revised by: S.Anson

dimensions: 124 x 640

pharmacode:

colours/plates:

approved for print/date

Non Printing Colours

1. Black

date sent: 13.01.16

supplier: Actavis Nerviano

technically app. date: 13.01.16

min pt size: 9

Technical Approval

10 mm

10 mm

N. 000000000.0

Actavis, Barnstaple, EX32 8NS, UK

Any unused product or waste

material should be disposed of in

accordance with local requirements.

Storage conditions

After first opening

Chemical and physical in use stability

has been demonstrated for 28 days

at 25°C.

From a microbiological point of

view, unless the method of opening

precludes the risk of microbial

contamination, the product should

be used immediately. If not used

immediately, in-use storage times

and conditions are the responsibility

of the user.

Solution for infusion

Chemical and physical in-use stability

has been demonstrated for 28 days

at 2°C to 8°C and about 25°C upon

dilution in 0.9% sodium chloride

solution to a final concentration in

the range between 2 – 25mg/ml

(2.0mg/ml, 12mg/ml and 25mg/ml).

The pH of the diluted solution is in

the range of 2-3 and the osmolality is

approximately 285 mOsm/kg. Diluted

solutions are stable when packaged

into either PVC or PE infusion bags.

From a microbiological point of

view, the solution for infusion should

be used immediately. If not used

immediately, in-use storage times

and conditions prior to use are the

responsibility of the user and would

normally not be longer than 24 hours

at 2°C to 8°C unless dilution has taken

place in controlled and validated

aseptic conditions.

AAAI6631

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AAAI6631

Allergic reactions: Mild to moderate

skin rash (very common); itching

(common); or fever (very common).

Temperature of 38ºC or greater,

sweating or other signs of

infection (since you might have

less white blood cells than normal

accompanied by fever also known as

febrile neutropenia) (common).

Pain, redness, swelling or sores in

your mouth (stomatitis) (common).

Irregular heart rate (arrhythmia)

(uncommon).

Extreme tiredness and weakness,

purpura or small areas of bleeding

in the skin (bruises), acute renal

failure (low urine output /or no

urine output), and signs of infection

(haemolytic uraemic syndrome).

It may be fatal (uncommon).

Difficulty breathing (it is common

to have mild breathing difficulty

soon after the Gemcitabine infusion

which soon passes, however

uncommonly or rarely there can be

more severe lung problems).

Severe chest pain (myocardial

infarction) (rare).

Severe hypersensitivity/allergic

reaction with severe skin rash

including red itchy skin, swelling

of the hands, feet, ankles, face,

lips, mouth or throat (which may

cause difficulty in swallowing or

breathing), wheezing, fast beating

heart and you may feel you are

going to faint (anaphylactic

reaction) (very rare).

Generalised swelling, shortness of

breath or weight gain, as you might

have fluid leakage from small blood

vessels into the tissues (capillary

leak syndrome) (very rare).

Headache with changes in vision,

confusion, seizures or fits (posterior

reversible encephalopathy

syndrome) (very rare).

Severe rash with itching, blistering

or peeling of the skin, often

accompanied by flu-like symptoms

(Stevens-Johnson syndrome, toxic

epidermal necrolysis) (very rare).

Other side effects with

Gemcitabine may include:

Very common side effects (may

affect more than 1 in 10 people)

Low white blood cells

Difficulty breathing

Vomiting

Nausea

Hair loss

Liver problems: found through

abnormal blood test results

Blood in urine

Abnormal urine tests: protein in urine

Flu like symptoms including fever

Swelling of ankles, fingers, feet, face

(oedema)

Low Haemoglobin level (anaemia).

Common side effects (may affect

up to 1 in 10 people)

Poor appetite (anorexia)

Headache

Insomnia

Sleepiness

Cough

Runny nose

Constipation

Diarrhoea

Itching

Sweating

Muscle pain

Back pain

Fever

Weakness

Chills.

Uncommon side effects (may affect

up to 1 in 100 people)

Scarring of the air sacs of the lung

(interstitial pneumonitis)

Wheeze (spasm of the airways)

Scarring of the lungs (abnormal chest

X ray/scan)

Heart failure

Kidney failure

Serious liver damage, including liver

failure which could be life- threatening

Stroke.

Rare side effects (may affect up to 1

in 1,000 people)

Low blood pressure

Skin scaling, ulceration or blister

formation

Sloughing of the skin and severe skin

blistering

Injection site reactions

Severe lung inflammation causing

respiratory failure (adult respiratory

distress syndrome)

A skin rash like severe sunburn which

can occur on skin that has previously

been exposed to radiotherapy

(radiation recall)

Fluid in the lungs

Scarring of the air sacs of the lung

associated with radiation therapy

(radiation toxicity)

Gangrene of fingers or toes

Inflammation of the blood vessels

(peripheral vasculitis).

Very rare side effects (may affect

up to 1 in 10,000 people)

Increased platelet count

Inflammation of the lining of the

large bowel, caused by reduced

blood supply (ischemic colitis).

Low haemoglobin level (anaemia),

low white blood cells and low platelet

count will be detected by a blood

test.

You might have any of these

symptoms and/or conditions. You

must tell your doctor as soon as

possible when you start experiencing

any of these side effects.

Actavis, Barnstaple, EX32 8NS, UK

Reporting of side effects

If you get any side effects, talk to your

doctor, pharmacist or nurse.

This includes any possible side effects

not listed in this leaflet. You can also

report side effects directly via the

Yellow Card Scheme Website:

www.mhra.gov.uk/yellowcard

By reporting side effects you can help

provide more information on the

safety of this medicine.

5

How to store Gemcitabine

Keep this medicine out of the sight

and reach of children.

Unopened container

Store in a refrigerator (2°C – 8°C).

After first opening

Chemical and physical in use stability

has been demonstrated for 28 days

at 25°C.

From a microbiological point of

view, unless the method of opening

precludes the risk of microbial

contamination, the product should

be used immediately. If not used

immediately, in-use storage times

and conditions are the responsibility

of the user.

Solution for infusion

Chemical and physical in-use stability

has been demonstrated for 28 days

at 2°C to 8°C and about 25°C upon

dilution in 0.9% sodium chloride

solution to a final concentration in

the range between 2 – 25mg/ml

(2.0mg/ml, 12mg/ml and 25mg/ml).

Diluted solutions are stable when

packaged into either PVC or PE

infusion bags.

From a microbiological point of

view, the solution for infusion should

be used immediately. If not used

immediately, in-use storage times

and conditions prior to use are the

responsibility of the user and would

normally not be longer than 24 hours

at 2°C to 8°C unless dilution has taken

place in controlled and validated

aseptic conditions.

Do not use this medicine after the

expiry date which is stated on the

carton and the vial after EXP. The

expiry date refers to the last day of

that month.

Do not use this medicine if you notice

any signs of particles.

6

Contents of the pack and

other information

What Gemcitabine contains

The active substance is gemcitabine

(as gemcitabine hydrochloride).

Each ml of concentrate for solution

for infusion contains 40mg

gemcitabine (as gemcitabine

hydrochloride). Each 5ml vial

contains 200mg gemcitabine (as

gemcitabine hydrochloride). Each

25ml vial contains 1g gemcitabine

(as gemcitabine hydrochloride).

Each 50ml vial contains 2g

gemcitabine (as gemcitabine

hydrochloride).

The other ingredients are

hydrochloric acid (E-507) for pH

adjustment, water for injections.

What Gemcitabine looks like

and contents of the pack

Gemcitabine Concentrate for Solution

for Infusion is a clear, colourless or

pale yellow solution.

Gemcitabine is contained in type I

colourless glass vials with bromobutyl

rubber stoppers and sealed with

aluminium caps with polypropylene

disc. Each vial will be packed with or

without a protective plastic overwrap.

Pack sizes

1 x 5ml vial

1 x 25ml vial

1 x 50ml vial

Marketing Authorisation Holder

Actavis Group PTC ehf.

Reykjavíkurvegi 76-78

220 Hafnarfjörður

Iceland

Manufacturer

Actavis Italy S.p.A.

Nerviano Plant

Viale Pasteur 10

20014 Nerviano (MI)

Italy

This leaflet was last revised in

January 2016

If you would like a

leaflet with larger text,

please contact

01271 385257.

Continued on top of next column

Read the complete document

Object 1

Gemcitabine 40mg/ml Concentrate for Solution

for Infusion

Summary of Product Characteristics Updated 12-May-2017 | Accord-UK Ltd

1. Name of the medicinal product

Gemcitabine 40mg/ml Concentrate for Solution for Infusion

2. Qualitative and quantitative composition

Each ml of concentrate for solution for infusion contains 40 mg gemcitabine (as gemcitabine

hydrochloride).

Each 5 ml vial contains 200 mg gemcitabine (as gemcitabine hydrochloride)

Each 25 ml vial contains 1 g gemcitabine (as gemcitabine hydrochloride)

Each 50 ml vial contains 2 g gemcitabine (as gemcitabine hydrochloride)

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Concentrate for solution for infusion.

The pH of the concentrate is 2.4 ± 0.4 and the osmolarity is 270-280 mOsmol/kg.

Clear, colourless or pale yellow solution.

4. Clinical particulars

4.1 Therapeutic indications

Gemcitabine is indicated for the treatment of locally advanced or metastatic bladder cancer in

combination with cisplatin.

Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of

the pancreas.

Gemcitabine, in combination with cisplatin is indicated as first line treatment of patients with locally

advanced or metastatic non-small cell lung cancer (NSCLC). Gemcitabine monotherapy can be

considered in elderly patients or those with performance status 2.

Gemcitabine is indicated for the treatment of patients with locally advanced or metastatic epithelial

ovarian carcinoma, in combination with carboplatin, in patients with relapsed disease following a

recurrence-free interval of at least 6 months after platinum-based, first-line therapy.

Gemcitabine, in combination with paclitaxel, is indicated for the treatment of patients with unresectable,

locally recurrent or metastatic breast cancer who have relapsed following adjuvant / neoadjuvant

chemotherapy. Prior chemotherapy should have included an anthracycline unless clinically

contraindicated.

4.2 Posology and method of administration

Gemcitabine should only be prescribed by a physician qualified in the use of anti-cancer chemotherapy.

Posology

Bladder cancer

Combination use

The recommended dose for gemcitabine is 1000 mg/m

, given by 30-minute infusion. The dose should be

given on Days 1, 8 and 15 of each 28-day cycle in combination with cisplatin. Cisplatin is given at a

recommended dose of 70 mg/m

on Day 1 following gemcitabine or day 2 of each 28-day cycle. This 4-

week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied based

upon the grade of toxicity experienced by the patient.

Pancreatic cancer

The recommended dose of gemcitabine is 1000 mg/m

, given by 30-minute intravenous infusion. This

should be repeated once weekly for up to 7 weeks followed by a week of rest. Subsequent cycles should

consist of injections once weekly for 3 consecutive weeks out of every 4 weeks. Dosage reduction with

each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.

Non-small cell lung cancer

Monotherapy

The recommended dose of gemcitabine is 1000 mg/m

, given by 30-minute intravenous infusion. This

should be repeated once weekly for 3 weeks, followed by a 1-week rest period. This 4-week cycle is then

repeated. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of

toxicity experienced by the patient.

Combination use

The recommended dose for gemcitabine is 1250 mg/m

body surface area given as a 30-minute

intravenous infusion on Day 1 and 8 of the treatment cycle (21 days). Dosage reduction with each cycle

or within a cycle may be applied based upon the grade of toxicity experienced by the patient.

Cisplatin has been used at doses between 75-100 mg/m

once every 3 weeks.

Breast cancer

Combination use

Gemcitabine in combination with paclitaxel is recommended using paclitaxel (175 mg/m

) administered

on Day 1 over approximately 3-hours as an intravenous infusion, followed by gemcitabine (1250 mg/m

as a 30-minute intravenous infusion on Days 1 and 8 of each 21-day cycle. Dose reduction with each

cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.

Patients should have an absolute granulocyte count of at least 1,500 (x 10

/l) prior to initiation of

gemcitabine + paclitaxel combination.

Ovarian cancer

Combination use

Gemcitabine in combination with carboplatin is recommended using gemcitabine 1000 mg/m

administered on Days 1 and 8 of each 21-day cycle as a 30-minute intravenous infusion. After

gemcitabine, carboplatin will be given on Day 1 consistent with a target Area under curve (AUC) of 4.0

mg/ml∙min. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of

toxicity experienced by the patient.

Monitoring for toxicity and dose modification due to toxicity

Dose modification due to non-haematological toxicity

Periodic physical examination and checks of renal and hepatic function should be made to detect non-

haematological toxicity.

Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity

experienced by the patient. In general, for severe (Grade 3 or 4) non-haematological toxicity, except

nausea/vomiting, therapy with gemcitabine should be withheld or decreased depending on the judgement

of the treating physician. Doses should be withheld until toxicity has resolved in the opinion of the

physician.

For cisplatin, carboplatin, and paclitaxel dosage adjustment in combination therapy, please refer to the

corresponding Summary of Product Characteristics.

Dose modification due to haematological toxicity

Initiation of a cycle

For all indications, the patient must be monitored before each dose for platelet and granulocyte counts.

Patients should have an absolute granulocyte count of at least 1,500 (x 10

/l) and platelet count of

100,000 (x 10

/l) prior to the initiation of a cycle.

Within a cycle

Dose modifications of gemcitabine within a cycle should be performed according to the following tables:

Dose modification of gemcitabine within a cycle for bladder cancer, NSCLC and pancreatic cancer,

given in monotherapy or in combination with cisplatin

Absolute granulocyte count

(x 10

6

/l)

Platelet count

(x 10

6

/l)

Percentage of standard dose

of gemcitabine (%)

> 1,000 and

> 100,000

500-1,000 or

50,000-100,000

<500 or

< 50,000

Omit dose *

*Treatment omitted will not be re-instated within a cycle before the absolute granulocyte count reaches at

least 500 (x10

/l) and the platelet count reaches 50,000 (x10

/l).

Dose modification of gemcitabine within a cycle for breast cancer, given in combination with

paclitaxel

Absolute granulocyte count

(x 10

Platelet count

(x 10

6

/l)

Percentage of standard dose

of gemcitabine (%)

≥ 1,200 and

>75,000

1,000- <1,200 or

50,000-75,000

700- <1,000 and

≥ 50,000

<700 or

<50,000

Omit dose*

*Treatment omitted will not be re-instated within a cycle. Treatment will start on day 1 of the next cycle

once the absolute granulocyte count reaches at least 1,500 (x10

/l) and the platelet count reaches 100,000

(x10

/l).

Dose modification of gemcitabine within a cycle for ovarian cancer, given in combination with

carboplatin

Absolute granulocyte count

(x 10

6

/l)

Platelet count

(x 10

6

/l)

Percentage of standard dose

of gemcitabine (%)

> 1,500 and

≥ 100,000

1000-1,500 or

75,000-100,000

<1000 or

< 75,000

Omit dose*

*Treatment omitted will not be re-instated within a cycle. Treatment will start on day 1 of the next cycle

once the absolute granulocyte count reaches at least 1,500 (x10

/l) and the platelet count reaches 100,000

(x10

/l).

Dose modifications due to haematological toxicity in subsequent cycles, for all indications

- The gemcitabine dose should be reduced to 75% of the original cycle initiation dose, in the case of the

following haematological toxicities:

- Absolute granulocyte count < 500 x 10

/l for more than 5 days

- Absolute granulocyte count < 100 x 10

/l for more than 3 days

- Febrile neutropenia

- Platelets < 25,000 x 10

- Cycle delay of more than 1 week due to toxicity

Method of administration

Gemcitabine is tolerated well during infusion and may be administered ambulant. If extravasation occurs,

generally the infusion must be stopped immediately and started again in another blood vessel. The patient

should be monitored carefully after the administration.

For instructions on dilution of the medicinal product before administration, see section 6.6

Special populations

Patients with renal or hepatic impairment

Gemcitabine should be used with caution in patients with hepatic or renal impairment as there is

insufficient information from clinical studies to allow for clear dose recommendations for these patient

populations (see sections 4.4 and 5.2).

Older people (> 65 years)

Gemcitabine has been well tolerated in patients over the age of 65. There is no evidence to suggest that

dose adjustments, other than those already recommended for all patients, are necessary in older people

(see section 5.2).

Paediatric population (< 18 years)

Gemcitabine is not recommended for use in children under 18 years of age due to insufficient data on

safety and efficacy.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6).

4.4 Special warnings and precautions for use

Prolongation of the infusion time and increased dosing frequency have been shown to increase toxicity.

Haematological toxicity

Gemcitabine can suppress bone marrow function as manifested by leukopenia, thrombocytopenia and

anaemia.

Patients receiving gemcitabine should be monitored prior to each dose for platelet, leucocyte and

granulocyte counts. Suspension or modification of therapy should be considered when drug-induced bone

marrow depression is detected (see section 4.2). However, myelosuppression is short lived and usually

does not result in dose reduction and rarely in discontinuation.

Peripheral blood counts may continue to deteriorate after gemcitabine administration has been stopped. In

patients with impaired bone marrow function, the treatment should be started with caution. As with other

cytotoxic treatments, the risk of cumulative bone-marrow suppression must be considered when

gemcitabine treatment is given together with other chemotherapy.

Hepatic and renal impairment

Administration of gemcitabine in patients with concurrent liver metastases or a pre-existing medical

history of hepatitis, alcoholism or liver cirrhosis may lead to exacerbation of the underlying hepatic

insufficiency.

Laboratory evaluation of renal and hepatic function (including virological tests) should be performed

periodically.

Gemcitabine should be used with caution in patients with hepatic or renal function impairment as there is

insufficient information from clinical studies to allow clear dose recommendation for this patient

population (see section 4.2).

Concomitant radiotherapy

Concomitant radiotherapy (given together or ≤7 days apart): Toxicity has been reported (see section 4.5

for details and recommendations for use).

Live vaccinations

Yellow fever vaccine and other live attenuated vaccines are not recommended in patients treated with

gemcitabine (see section 4.5).

Posterior reversible encephalopathy syndrome

Reports of posterior reversible encephalopathy syndrome (PRES) with potentially severe consequences

have been reported in patients receiving gemcitabine as single agent or in combination with other

chemotherapeutic agents. Acute hypertension and seizure activity were reported in most gemcitabine

patients experiencing PRES, but other symptoms such as headache, lethargy, confusion and blindness

could also be present. Diagnosis is optimally confirmed by magnetic resonance imaging (MRI). PRES

was typically reversible with appropriate supportive measures. Gemcitabine should be permanently

discontinued and supportive measures implemented, including blood pressure control and anti-seizure

therapy, if PRES develops during therapy.

Cardiovascular

Due to the risk of cardiac and/or vascular disorders with gemcitabine, particular caution must be

exercised with patients presenting a history of cardiovascular events.

Capillary leak syndrome

Capillary leak syndrome has been reported in patients receiving gemcitabine as single agent or in

combination with other chemotherapeutic agents (see section 4.8). The condition is usually treatable if

recognised early and managed appropriately, but fatal cases have been reported. The condition involves

systemic capillary hyperpermeability during which fluid and proteins from the intravascular space leak

into the interstitium. The clinical features include generalised oedema, weight gain, hypoalbuminaemia,

severe hypotension, acute renal impairment and pulmonary oedema. Gemcitabine should be discontinued

and supportive measures implemented if capillary leak syndrome develops during therapy. Capillary leak

syndrome can occur in later cycles and has been associated in the literature with adult respiratory distress

syndrome.

Pulmonary

Pulmonary effects, sometimes severe (such as pulmonary oedema, interstitial pneumonitis or adult

respiratory distress syndrome (ARDS)) have been reported in association with gemcitabine therapy. If

such effects develop, consideration should be made to discontinuing gemcitabine therapy. Early use of

supportive care measure may help ameliorate the condition.

Renal

Haemolytic uraemic syndrome

Clinical findings consistent with the haemolytic uraemic syndrome (HUS) were rarely reported (post-

marketing data) in patients receiving gemcitabine (see section 4.8). HUS is a potentially life-threatening

disorder. Gemcitabine should be discontinued at the first signs of any evidence of microangiopathic

haemolytic anaemia, such as rapidly falling haemoglobin with concomitant thrombocytopenia, elevation

of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH. Renal failure may not be reversible

with discontinuation of therapy and dialysis may be required.

Fertility

In fertility studies gemcitabine caused hypospermatogenesis in male mice (see section 5.3). Therefore,

men being treated with gemcitabine are advised not to father a child during and up to 6 months after

treatment and to seek further advice regarding cryoconservation of sperm prior to treatment because of

the possibility of infertility due to therapy with gemcitabine (see section 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been performed (see section 5.2)

Radiotherapy

Concurrent (given together or ≤ 7 days apart) - Toxicity associated with this multimodality therapy is

dependent on many different factors, including dose of gemcitabine, frequency of gemcitabine

administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume.

Pre-clinical and clinical studies have shown that gemcitabine has radiosensitising activity. In a single

trial, where gemcitabine at a dose of 1,000 mg/m

was administered concurrently for up to 6 consecutive

weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity

in the form of severe, and potentially life threatening mucositis, especially oesophagitis, and pneumonitis

was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes

4,795 cm

]. Studies done subsequently have suggested that it is feasible to administer gemcitabine at

lower doses with concurrent radiotherapy with predictable toxicity, such as a phase II study in non-small

cell lung cancer, where thoracic radiation doses of 66 Gy were applied concomitantly with an

administration with gemcitabine (600 mg/m

, four times) and cisplatin (80 mg/m

twice) during 6 weeks.

The optimum regimen for safe administration of gemcitabine with therapeutic doses of radiation has not

yet been determined in all tumour types.

Non-concurrent (given >7 days apart)- Analysis of the data does not indicate any enhanced toxicity when

gemcitabine is administered more than 7 days before or after radiation, other than radiation recall. Data

suggest that gemcitabine can be started after the acute effects of radiation have resolved or at least one

week after radiation.

Radiation injury has been reported on targeted tissues (e.g. oesophagitis, colitis, and pneumonitis) in

association with both concurrent and non-concurrent use of gemcitabine.

Others

Yellow fever and other live attenuated vaccines are not recommended due to the risk of systemic,

possibly fatal, disease, particularly in immunosuppressed patients.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of gemcitabine in pregnant women. Studies in animals have

shown reproductive toxicity (see section 5.3). Based on results from animal studies and the mechanism of

action of gemcitabine, this substance should not be used during pregnancy unless clearly necessary.

Women should be advised not to become pregnant during treatment with gemcitabine and to warn their

attending physician immediately, should this occur after all.

Breast-feeding

It is not known whether gemcitabine is excreted in human milk and adverse effects on the suckling child

cannot be excluded. Breast-feeding must be discontinued during gemcitabine therapy.

Fertility

In fertility studies gemcitabine caused hypospermatogenesis in male mice (see section 5.3). Therefore,

men being treated with gemcitabine are advised not to father a child during and up to 6 months after

treatment and to seek further advice regarding cryoconservation of sperm prior to treatment because of

the possibility of infertility due to therapy with gemcitabine.

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,

gemcitabine has been reported to cause mild to moderate somnolence, especially in combination with

alcohol consumption. Patients should be cautioned against driving or operating machinery until it is

established that their alertness is not affected.

4.8 Undesirable effects

The most commonly reported adverse drug reactions associated with gemcitabine treatment include:

nausea with or without vomiting, raised liver transaminases (AST/ALT) and alkaline phosphatase,

reported in approximately 60% of patients; proteinuria and haematuria reported in approximately 50%

patients; dyspnoea reported in 10-40% of patients (highest incidence in lung cancer patients); allergic skin

rashes occur in approximately 25% of patients and are associated with itching in 10% of patients.

The frequency and severity of the adverse reactions are affected by the dose, infusion rate and intervals

between doses (see section 4.4). Dose-limiting adverse reactions are reductions in thrombocyte, leucocyte

and granulocyte counts (see section 4.2).

Clinical trial data

Frequencies are defined as: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to

<1/100), Rare (≥1/10,000 to <1/1,000), Very Rare (<1/10,000).

The following table of undesirable effects and frequencies is based on data from clinical trials. Within

each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class

Frequency grouping

Blood and lymphatic system

disorders

Very common

Leukopenia (Neutropenia Grade 3 = 19.3 %; Grade 4 = 6 %).

Bone-marrow suppression is usually mild to moderate and mostly affects the

granulocyte count (see section 4.2 and 4.4)

Thrombocytopenia

Anaemia

Common

Febrile neutropenia

Very rare

Thrombocytosis

Immune system disorders

Very Rare

Anaphylactoid reaction

Metabolism and nutrition

disorders

Common

Anorexia

Nervous system disorders

Common

Headache

Insomnia

Somnolence

Uncommon

Cerebrovascular accident

Very rare

Posterior reversible encephalopathy syndrome (see section 4.4)

Cardiac disorders

Uncommon

Arrhythmias, predominantly supraventricular in nature

Heart failure

Rare

Myocardial infarct

Vascular disorders

Rare

Clinical signs of peripheral vasculitis and gangrene

Hypotension

Very rare

Capillary leak syndrome (see section 4.4)

Respiratory, thoracic and

mediastinal disorders

Very common

Dyspnoea –usually mild and passes rapidly without treatment

Common

Cough

Rhinitis

Uncommon

Interstitial pneumonitis (see section 4.4)

Bronchospasm –usually mild and transient but may require parenteral

treatment

Rare

Pulmonary oedema

Adult respiratory distress syndrome (see section 4.4)

Gastrointestinal disorders

Very common

Vomiting

Nausea

Common

Diarrhoea

Stomatitis and ulceration of the mouth

Constipation

Very rare

Ischaemic colitis

Hepatobiliary disorders

Very common

Elevation of liver transaminases (AST and ALT) and alkaline phosphatase

Common

Increased bilirubin

Uncommon

Serious hepatotoxicity, including liver failure and death

Rare

Increased gamma-glutamyl transferase (GGT)

Skin and subcutaneous

tissue disorders

Very common

Allergic skin rash frequently associated with pruritus

Alopecia

Common

Itching

Sweating

Rare

Severe skin reactions, including desquamation and bullous skin eruptions

Ulceration

Vesicle and sore formation

Scaling

Very rare

Toxic epidermal necrolysis

Stevens-Johnson Syndrome

Musculoskeletal and

connective tissue disorders

Common

Back pain

Myalgia

Renal and urinary disorders Very Common

Haematuria

Mild proteinuria

Uncommon

Renal failure (see section 4.4)

Haemolytic uraemic syndrome (see section 4.4)

General disorders and

administration site

conditions

Very common

Influenza-like symptoms - the most common symptoms are fever,

headache, chills, myalgia, asthenia and anorexia. Cough, rhinitis, malaise,

perspiration and sleeping difficulties have also been reported.

Oedema/peripheral oedema-including facial oedema. Oedema is usually

reversible after stopping treatment

Common

Fever

Asthenia

Chills

Rare

Injection site reactions-mainly mild in nature

Injury, poisoning, and

procedural Complications

Rare

Radiation toxicity (see section 4.5).

Radiation recall

Combination use in breast cancer

The frequency of grade 3 and 4 haematological toxicities, particularly neutropenia, increases when

gemcitabine is used in combination with paclitaxel. However, the increase in these adverse reactions is

not associated with an increased incidence of infections or haemorrhagic events. Fatigue and febrile

neutropenia occur more frequently when gemcitabine is used in combination with paclitaxel. Fatigue,

which is not associated with anaemia, usually resolves after the first cycle.

Grade 3 and 4 Adverse Events

Paclitaxel versus gemcitabine plus paclitaxel

Number (%) of Patients

Paclitaxel arm

(N=259)

Gemcitabine plus Paclitaxel arm

(N=262)

Grade 3

Grade 4

Grade 3

Grade 4

Laboratory

Anaemia

5 (1.9)

1 (0.4)

15 (5.7)

3 (1.1)

Thrombocytopenia

14 (5.3)

1 (0.4)

Neutropenia

11 (4.2)

17 (6.6)*

82 (31.3)

45 (17.2)*

Non-laboratory

Febrile neutropenia

3 (1.2)

12 (4.6)

1(0.4)

Fatigue

3 (1.2)

1 (0.4)

15 (5.7)

2 (0.8)

Diarrhoea

5 (1.9)

8 (3.1)

Motor neuropathy

2(0.8)

6(2.3)

1(0.4)

Sensory neuropathy

9(3.5)

14(5.3)

1(0.4)

*Grade 4 neutropenia lasting for more than 7 days occurred in 12.6% of patients in the combination arm

and 5.0% of patients in the paclitaxel arm.

Combination use in bladder cancer

Grade 3 and 4 Adverse Events

MVAC versus Gemcitabine plus cisplatin

Number (%) of Patients

MVAC (methotrexate, vinblastine,

doxorubicin and cisplatin) arm

(N=196)

Gemcitabine plus cisplatin arm

(N=200)

Grade 3

Grade 4

Grade 3

Grade 4

Laboratory

Anaemia

30(16)

4(2)

47(24)

7(4)

Thrombocytopenia

15(8)

25(13)

57(29)

57(29)

Non-laboratory

Nausea and vomiting

37(19)

3(2)

44(22)

0(0)

Diarrhoea

15(8)

1(1)

6(3)

0(0)

Infection

19(10)

10(5)

4(2)

1(1)

Stomatitis

34(18)

8(4)

2(1)

0(0)

Combination use in ovarian cancer

Grade 3 and 4 Adverse Events

Carboplatin versus Gemcitabine plus carboplatin

Number (%) of Patients

Carboplatin arm

(N=174)

Gemcitabine plus carboplatin arm

(N=175)

Grade 3

Grade 4

Grade 3

Grade 4

Laboratory

Anaemia

10(5.7)

4(2.3)

39(22.3)

9(5.1)

Neutropenia

19(10.9)

2(1.1)

73(41.7)

50(28.6)

Thrombocytopenia

18(10.3)

2(1.1)

53(30.3)

8(4.6)

Leucopenia

11(6.3)

1(0.6)

84(48.0)

9(5.1)

Non-laboratory

Haemorrhage

0(0.0)

0(0.0)

3(1.8)

(0.0)

Febrile neutropenia

0(0.0)

0(0.0)

2(1.1)

(0.0)

Infection without Neutropenia

0(0)

0(0.0)

(0.0)

1(0.6)

Sensory neuropathy was also more frequent in the combination arm than with single agent carboplatin”

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 via the Yellow Card Scheme Website:

www.mhra.gov.uk/yellowcard

4.9 Overdose

There is no known antidote for overdose of gemcitabine. Doses as high as 5700 mg/m

have been

administered by intravenous infusion over 30 minutes every 2 weeks with clinically acceptable toxicity.

In the event of suspected overdose, the patient should be monitored with appropriate blood counts and

receive supportive therapy, as necessary.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: pyrimidine analogues ATC code: L01BC05

Mechanism of action

Cellular metabolism and mechanism of action: Gemcitabine (dFdC), which is a pyrimidine

antimetabolite, is metabolised intracellularly by nucleoside kinase to the active diphosphate (dFdCDP)

and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is due to inhibition of DNA

synthesis by two mechanisms of action by dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide

reductase, which is uniquely responsible for catalysing the reactions that produce deoxynucleoside

triphosphates (dCTP) for DNA synthesis. Inhibition of this enzyme by dFdCDP reduces the concentration

of deoxynucleosides in general and, in particular, dCTP. Second, dFdCTP competes with dCTP for

incorporation into DNA (self-potentiation).

Likewise, a small amount of gemcitabine may also be incorporated into RNA. Thus, the reduced

intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. DNA polymerase

epsilon lacks the ability to eliminate gemcitabine and to repair the growing DNA strands. After

gemcitabine is incorporated into DNA, one additional nucleotide is added to the growing DNA strands.

After this addition there is essentially a complete inhibition in further DNA synthesis (masked chain

termination). After incorporation into DNA, gemcitabine appears to induce the programmed cell death

process known as apoptosis.

Pharmacodynamic effects

Cytotoxic activity in cell cultures

Gemcitabine shows significant cytotoxic effects against a variety of cultured murine and human tumour

cells. Its action is phase-specific such that gemcitabine primarily kills cells that are undergoing DNA

synthesis (S phase) and, under certain circumstances, blocks the progression of cells at the junction of the

G1/S phase boundary. In vitro, the cytotoxic effect of gemcitabine is dependent on both concentration and

time.

Antitumoural activity in preclinical models

In animal tumour models, antitumoural activity of gemcitabine is schedule-dependent. When gemcitabine

is administered daily, high mortality among the animals but minimal antitumoural activity is observed. If,

however, gemcitabine is given every third or fourth day, it can be administered in non-lethal doses with

substantial antitumoural activity against a broad spectrum of mouse tumours.

Clinical efficacy and safety

Bladder cancer

A randomised phase III study of 405 patients with advanced or metastatic urothelial transitional cell

carcinoma showed no difference between the two treatment arms, gemcitabine/cisplatin versus

methotrexate/vinblastine/adriamycin /cisplatin (MVAC), in terms of median survival (12.8 and 14.8

months respectively, p=0.547), time to disease progression (7.4 and 7.6 months respectively, p=0.842)

and response rate (49.4% and 45.7% respectively, p=0.512). However, the combination of gemcitabine

and cisplatin had a better toxicity profile than MVAC.

Pancreatic cancer

In a randomised phase III study of 126 patients with advanced or metastatic pancreatic cancer,

gemcitabine showed a statistically significant higher clinical benefit response rate than 5-fluorouracil

(23.8% and 4.8% respectively, p=0.0022). Also, a statistically significant prolongation of the time to

progression from 0.9 to 2.3 months (log-rank p<0.0002) and a statistically significant prolongation of

median survival from 4.4 to 5.7 months (log-rank p<0.0024) was observed in patients treated with

gemcitabine compared to patients treated with 5-fluorouracil.

Non-small cell lung cancer

In a randomised phase III study of 522 patients with inoperable, locally advanced or metastatic NSCLC,

gemcitabine in combination with cisplatin showed a statistically significant higher response rate than

cisplatin alone (31.0% and 12.0%, respectively, p<0.0001). A statistically significant prolongation of the

time to progression, from 3.7 to 5.6 months (log-rank p<0.0012) and a statistically significant

prolongation of median survival from 7.6 months to 9.1 months (log-rank p<0.004) was observed in

patients treated with gemcitabine/cisplatin compared to patients treated with cisplatin.

In another randomised phase III study of 135 patients with stage IIIB or IV NSCLC, a combination of

gemcitabine and cisplatin showed a statistically significant higher response rate than a combination of

cisplatin and etoposide (40.6% and 21.2%, respectively, p=0.025). A statistically significant prolongation

of the time to progression, from 4.3 to 6.9 months (p=0.014) was observed in patients treated with

gemcitabine/cisplatin compared to patients treated with etoposide/cisplatin.

In both studies it was found that tolerability was similar in the two treatment arms.

Ovarian carcinoma

In a randomised phase III study, 356 patients with advanced epithelial ovarian carcinoma who had

relapsed at least 6 months after completing platinum based therapy were randomised to therapy with

gemcitabine and carboplatin (GCb), or carboplatin (Cb). A statistically significant prolongation of the

time to progression of disease, from 5.8 to 8.6 months (log-rank p= 0.0038) was observed in the patients

treated with GCb compared to patients treated with Cb. Differences in response rate of 47.2% in the GCb

arm versus 30.9% in the Cb arm (p=0.0016) and median survival 18 months (GCb) versus 17.3 (Cb)

(p=0.73) favoured the GCb arm.

Breast cancer

In a randomised phase III study of 529 patients with inoperable, locally recurrent or metastatic breast

cancer with relapse after adjuvant/neoadjuvant chemotherapy, gemcitabine in combination with paclitaxel

showed a statistically significant prolongation of time to documented disease progression from 3.98 to

6.14 months (log-rank p=0.0002) in patients treated with gemcitabine/paclitaxel compared to patients

treated with paclitaxel. After 377 deaths, the overall survival was 18.6 months versus 15.8 months (log

rank p=0.0489, HR 0.82) in patients treated with gemcitabine/paclitaxel compared to patients treated with

paclitaxel and the overall response rate was 41.4% and 26.2% respectively (p= 0.0002).

5.2 Pharmacokinetic properties

The pharmacokinetics of gemcitabine have been examined in 353 patients in seven studies. The 121

women and 232 men ranged in age from 29 to 79 years. Of these patients, approximately 45% had non-

small cell lung cancer and 35% were diagnosed with pancreatic cancer. The following pharmacokinetic

parameters were obtained for doses ranging from 500 to 2,592 mg/m

that were infused from 0.4 to 1.2

hours.

Absorption

Peak plasma concentrations (obtained within 5 minutes of the end of the infusion) were 3.2 to 45.5 µg/ml.

Plasma concentrations of the parent compound following a dose of 1,000 mg/m

/30 minutes are greater

than 5 µg/ml for approximately 30 minutes after the end of the infusion, and greater than 0.4 µg/ml for an

additional hour.

Distribution

The volume of distribution of the central compartment was 12.4 l/m

for women and 17.5 l/m

for men

(inter individual variability was 91.9%). The volume of distribution of the peripheral compartment was

47.4 l/ m

. The volume of the peripheral compartment was not sensitive to gender.

The plasma protein binding was considered to be negligible.

Half-life: This ranged from 42 to 94 minutes depending on age and gender. For the recommended dosing

schedule, gemcitabine elimination should be virtually complete within 5 to 11 hours of the start of the

infusion. Gemcitabine does not accumulate when administered once weekly.

Biotransformation

Gemcitabine is rapidly metabolised by cytidine deaminase in the liver, kidney, blood and other tissues.

Intracellular metabolism of gemcitabine produces the gemcitabine mono, di and triphosphates (dFdCMP,

dFdCDP and dFdCTP) of which dFdCDP and dFdCTP are considered active. These intracellular

metabolites have not been detected in plasma or urine. The primary metabolite, 2' deoxy 2', 2'

difluorouridine (dFdU), is not active and is found in plasma and urine.

Elimination

Systemic clearance ranged from 29.2 l/hr/m

to 92.2 /hr/m

depending on gender and age (inter individual

variability was 52.2%). Clearance for women is approximately 25% lower than the values for men.

Although rapid, clearance for both men and women appears to decrease with age. For the recommended

gemcitabine dose of 1000 mg/m

given as a 30 minute infusion, lower clearance values for women and

men should not necessitate a decrease in the gemcitabine dose.

Urinary excretion: Less than 10% is excreted as unchanged drug.

Renal clearance was 2 to 7 l/hr/m

During the week following administration, 92 to 98% of the dose of gemcitabine administered is

recovered, 99% in the urine, mainly in the form of dFdU and 1% of the dose is excreted in faeces.

dFdCTP kinetics

This metabolite can be found in peripheral blood mononuclear cells and the information below refers to

these cells. Intracellular concentrations increase in proportion to gemcitabine doses of 35-350 mg/m

minutes, which give steady state concentrations of 0.4-5 µg/ml. At gemcitabine plasma concentrations

above 5 µg/ml, dFdCTP levels do not increase, suggesting that the formation is saturable in these cells.

Half-life of terminal elimination: 0.7-12 hours.

dFdU kinetics

Peak plasma concentrations (3-15 minutes after end of 30 minute infusion, 1000 mg/m

): 28-52 µg/ml.

Trough concentration following once weekly dosing: 0.07-1.12 µg/ml, with no apparent accumulation.

Triphasic plasma concentration versus time curve, mean half-life of terminal phase 65 hours (range 33-84

hr).

Formation of dFdU from parent compound: 91% -98%.

Mean volume of distribution of central compartment: 18 l/m

(range 11-22 l/m

Mean steady state volume of distribution (Vss): 150 l/m

(range 96-228 l/m

Tissue distribution: Extensive.

Mean apparent clearance: 2.5 l/hr/m

(range 1-4 l/hr/m

Urinary excretion: All.

Gemcitabine and paclitaxel combination therapy

Combination therapy did not alter the pharmacokinetics of either gemcitabine or paclitaxel.

Gemcitabine and carboplatin combination therapy

When given in combination with carboplatin the pharmacokinetics of gemcitabine were not altered

Renal impairment

Mild to moderate renal insufficiency (GFR from 30 ml/min to 80 ml/min) has no consistent, significant

effect on gemcitabine pharmacokinetics.

5.3 Preclinical safety data

In repeat dose studies of up to 6 months in duration in mice and dogs, the principal finding was schedule

and dose-dependent haematopoietic suppression which was reversible.

Gemcitabine is mutagenic in an in vitro mutation test and an in vivo bone marrow micronucleus test.

Long term animal studies evaluating the carcinogenic potential have not been performed.

In fertility studies, gemcitabine caused reversible hypospermatogenesis in male mice. No effect on the

fertility of females has been detected.

Evaluation of experimental animal studies has shown reproductive toxicity e.g. birth defects and other

effects on the development of the embryo or foetus, the course of gestation or peri- and postnatal

development

6. Pharmaceutical particulars

6.1 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

Concentrate in unopened vial

2 years.

After first opening

Chemical and physical in use stability has been demonstrated for 28 days at 25°C.

From a microbiological point of view, unless the method of opening precludes the risk of microbial

contamination, the product should be used immediately. If not used immediately, in-use storage times and

conditions are the responsibility of the user.

Solution for infusion

Chemical and physical in-use stability has been demonstrated for 28 days at 2°C to 8°C and about 25°C

upon dilution in 0.9% sodium chloride solution to a final concentration in the range between 2 – 25

mg/ml (2.0 mg/ml, 12 mg/ml and 25 mg/ml). The pH of the diluted solution is in the range of 2-3 and the

osmolality is approximately 285 mOsm/kg. Diluted solutions are stable when packaged into either PVC

or PE infusion bags.

From a microbiological point of view, the solution for infusion should be used immediately. If not used

immediately, in-use storage times and conditions prior to use are the responsibility of the user and would

normally not be longer than 24 hours at 2°C to 8°C unless dilution has taken place in controlled and

validated aseptic conditions.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C)

For storage conditions after first opening the vial and of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container

Colourless glass vial (type I) with bromobutyl rubber stopper and sealed with aluminium caps with

polypropylene disc. The vial will be packed with or without a protective plastic overwrap.

Pack sizes

1 x 5 ml vial

1 x 25 ml vial

1 x 50 ml vial

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Handling

The normal safety precautions for cytostatic agents must be observed when preparing and disposing of the

infusion solution. Pregnant personnel should not handle the product. Handling of the solution for infusion

should be done in a safety box and protective coats and gloves should be used. If no safety box is

available, the equipment should be supplemented with a mask and protective glasses.

If the preparation comes into contact with the eyes, this may cause serious irritation. The eyes should be

rinsed immediately and thoroughly with water. If there is lasting irritation, a doctor should be consulted.

If the solution is spilled on the skin, rinse thoroughly with water.

Instructions for dilution

The only approved diluent for dilution of Gemcitabine concentrate for solution for infusion is sodium

chloride 9 mg/ml (0.9%) solution for injection (without preservative).

- Use aseptic technique during dilution of gemcitabine for intravenous infusion administration.

- Diluted solution is a clear colourless or light straw-coloured solution.

- Parenteral medicinal products should be inspected visually for particulate matter and discolouration

prior to administration. If particulate matter is observed, do not administer.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Actavis Group PTC ehf.

Reykjavíkurvegi 76-78

220 Hafnarfjörður

Iceland

8. Marketing authorisation number(s)

PL 30306/0654

9. Date of first authorisation/renewal of the authorisation

25/01/2016

10. Date of revision of the text

10/04/2017

Company Contact Details

Accord-UK Ltd

Address

Whiddon Valley, Barnstaple, Devon, EX32 8NS, UK

Telephone

+44 (0)1271 385 200

Medical Information Direct Line

+44 (0)1271 385 257

www.accord-healthcare.co.uk

+44 (0)1271 346 106

Medical Information e-mail

[email

protected]

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