GEMZAR 1 GR

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
GEMCITABINE AS HYDROCHLORIDE
Available from:
ELI LILLY ISRAEL LTD
ATC code:
L01BC
Pharmaceutical form:
LYOPHILIC POWDER FOR CONCENTRATED INFUSION
Composition:
GEMCITABINE AS HYDROCHLORIDE 1 G/VIAL
Administration route:
I.V
Prescription type:
Required
Manufactured by:
LILLY FRANCE S.A.S., FRANCE
Therapeutic group:
PYRIMIDINE ANALOGUES
Therapeutic indications:
Palliative treatment of patients with locally advanced or metastatic non-small cell lung cancer and locally advanced or metastatic adenocarcinoma of the pancreas and for patients with 5-FU refractory pancreatic cancer. Gemcitabine is indicated for the treatment of patients with bladder cancer at the invasive stage. Breast cancer: 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. Ovarian cancer: Gemcitabine in combination with carboplatin is indicated for the treatment of patients with recurrent epithelial ovarian carcinoma whom have relapsed at least six months after platinum - based therapy.
Authorization number:
103 73 28802 01
Authorization date:
2012-07-17

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ךיראת

07

-

Oct-2014

םש

רישכת

תילגנאב

רפסמו

:םושירה

Gemzar 200 mg

רפסמ

:םושיר

103-72-28801-00/01

Gemzar 1000 mg

רפסמ

:םושיר

103-73-2880100/201

םש

לעב

םושירה

:

ילא

יליל

לארשי

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Special Warnings and

Special Precautions

for Use

תפסות

4.4 Special warnings and precautions

for use

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.

Adverse events

תפסות

4.8 Undesirable effects

Nervous system disorders

Very rare

Posterior reversible encephalopathy

syndrome

(see section 4.4.)

ב"צמ

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םייק

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ןכרצל

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:השקבל

SPC 5Jun2014

אתכמסאה

ב"צמ

יונישה

ל"נה

רשוא

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ידי

תויושר

תואירבה

ינויל

2014

תחקורה ,ינא

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לארשי

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,היוותה תפסותל השקב תרגסמב ןולע ןוכדע :ןוגכ( תרחא תרגסמב ליבקמב לפוטמ אל הז ןולע .תאז ןייצל שי -תרחא תרגסמב ליבקמ לופיט םייקו הדימב . )'וכו הרמחה

תמיתח

חקורה

הנוממה

םש(

)המיתחו

___________________________

X GEMZVL F 05

1.

TRADE NAME OF THE MEDICINAL PRODUCT

GEMZAR 1,000 mg powder for solution for infusion.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial contains gemcitabine hydrochloride equivalent to 1,000 mg gemcitabine.

After reconstitution, the solution contains 38 mg/ml of gemcitabine.

Excipients:

Each 1,000 mg vial contains 17.5 mg (<1 mmol) sodium.

For a full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM

Powder for solution for infusion.

White to off-white plug or powder.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Non-Small Cell Lung Cancer:

Gemcitabine is indicated for the palliative treatment of patients with locally advanced

or metastatic non-small cell lung cancer.

Breast cancer:

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.

Pancreatic Cancer:

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

metastatic adenocarcinoma of the pancreas and for patients with 5-FU refractory

pancreatic cancer.

Bladder Cancer:

Gemcitabine is indicated for the treatment of patients with bladder cancer at the

invasive stage.

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1

21

X GEMZVL F 05

Ovarian cancer:

Gemcitabine in combination with carboplatin, is indicated for the treatment of

patients with recurrent epithelial ovarian carcinoma who have relapsed at least six

months after platinum-based therapy.

4.2

Posology and method of administration

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

cancer chemotherapy.

Recommended posology:

Non-Small Cell Lung Cancer:

Single-agent use:

Adults: The recommended dose of gemcitabine is 1,000 mg/m

given by 30 minute intravenous infusion. This should be repeated once weekly for

three weeks, followed by a one week rest period. This four week cycle is then

repeated. Dosage reduction is applied based upon the amount of toxicity experienced

by the patient.

Combination use:

Adults: Gemcitabine in combination with cisplatin: The

recommended dose for gemcitabine is 1,250 mg/ m

body surface area given as a 30-

minute intravenous infusion on Days 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

: Adults: 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 (1,250

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

amount of toxicity experienced by the patient. Patients should have an absolute

granulocyte count of at least 1,500 (x10

/L) prior to initiation of gemcitabine +

paclitaxel combination.

Pancreatic Cancer:

Adults

: The recommended dose of gemcitabine is 1,000 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 is applied

based upon the amount of toxicity experienced by the patient.

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21

X GEMZVL F 05

Bladder Cancer:

Combination use:

Adults: 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 four

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

be applied based upon the amount of toxicity experienced by the patient.

Ovarian cancer

Combination use

: Adults: 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 AUC of 4.0 mg/mlmin. Dosage reduction

with each cycle or within a cycle may be applied based upon the amount 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 judgment 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:

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3

21

X GEMZVL F 05

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

GEMZAR (%)

> 1,000

> 100,000

500-1,000

50,000-100,000

< 500

< 50,000

Omit dose *

*Treatment omitted will not be re-instated within a cycle before the absolute

granulocyte count reaches at least 500 (x 10

/l) and the platelet count reaches

50,000 (x 10

/l).

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

in combination with paclitaxel

Absolute granulocyte count

(x 10

6

/l)

Platelet count

(x 10

6

/l)

Percentage of

standard dose of

GEMZAR (%)

≥ 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 (x 10

and the platelet count reaches 100,000 (x 10

/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

GEMZAR (%)

> 1,500 and

≥ 100,000

1,000-1,500 or

75,000-100,000

< 1,000 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 (x 10

and the platelet count reaches 100,000 (x 10

/l).

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X GEMZVL F 05

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

for more than 5 days

Absolute granulocyte count < 100 x 10

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

GEMZAR 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 reconstitution, 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.

Breast-feeding (see section 4.6).

4.4

Special warnings and precautions for use

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21

X GEMZVL F 05

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 leucopenia,

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

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).

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 impairment.

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

should be performed periodically.

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

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21

X GEMZVL F 05

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 recognized 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).

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).

Sodium

GEMZAR 1,000 mg contains 17.5 mg (<1 mmol) sodium per vial

ie essentially sodium

free.

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21

X GEMZVL F 05

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

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21

X GEMZVL F 05

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 they do

not become somnolent.

4.8

Undesirable effects

The most commonly reported adverse drug reactions associated with Gemzar

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% of 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 (≥1/1,000 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.

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X GEMZVL F 05

System Organ Class

Frequency grouping

Blood and lymphatic system disorders

Very Common

Leucopenia (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

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)

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X GEMZVL F 05

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)

Gastro-intestinal disorders

Very Common

Vomiting

Nausea

Common

Diarrhoea

Stomatitis and ulceration of the mouth

Constipation

Very rare

Ischaemic colitis

Hepato-biliary 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)

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X GEMZVL F 05

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

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X GEMZVL F 05

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.

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X GEMZVL F 05

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 suspected adverse reactions after authorization of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product.

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

National Regulation by using an online form

Page

14

21

X GEMZVL F 05

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

@moh.health.gov.il).

4.9

Overdose

There is no known

antidote for overdose of gemcitabine. Doses as high as 5,700

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

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, anti-tumoural activity of gemcitabine is schedule

dependent. When gemcitabine is administered daily, high mortality among the

animals but minimal anti-tumoural activity is observed. If, however, gemcitabine is

given

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

substantial anti-tumoural

activity against a broad spectrum of mouse tumours.

Mechanisms 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).

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15

21

X GEMZVL F 05

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.

Clinical data

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

Page

16

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X GEMZVL F 05

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.

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.

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17

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X GEMZVL F 05

Metabolism

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.

Excretion

Systemic clearance ranged from 29.2 l/hr/m

to 92.2 l/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

1,000 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

/30-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, 1,000

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.

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18

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X GEMZVL F 05

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 perinatal and postnatal development.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Mannitol (E421)

Sodium acetate (E262)

Hydrochloric acid (E507) (for pH adjustment)

Sodium hydroxide (E524) (for pH adjustment)

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

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19

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X GEMZVL F 05

Unopened vials:

3 years.

Reconstituted solution:

Chemical and physical in-use stability has been demonstrated for 24 hours at 30

From a microbiological point of view, the product 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 room

temperature, unless reconstitution (and further dilution, if applicable) has taken place

in controlled and validated aseptic conditions.

Solutions of reconstituted gemcitabine should not be refrigerated, as crystallisation

may occur.

6.4

Special precautions for storage

Unopened vial: Store below 30

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5

Nature and contents of container

Type I flint glass vials, with a rubber stopper and sealed with an aluminium seal,

combined with a polypropylene cap.

Each pack contains 1 vial.

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. 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 reconstitution (and further dilution, if performed)

The only approved diluent for reconstitution of gemcitabine sterile powder is sodium

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

solubility considerations, the maximum concentration for gemcitabine upon

reconstitution is 40 mg/ml. Reconstitution at concentrations greater than 40 mg/ml

may result in incomplete dissolution and should be avoided.

Page

20

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X GEMZVL F 05

Use aseptic technique during the reconstitution and any further dilution of

gemcitabine for intravenous infusion administration.

To reconstitute, add 25 ml sterile sodium chloride 9 mg/ml (0.9 %) solution

for injection, without preservative, to the 1,000 mg vial. The total volume

after reconstitution is 26.3 ml. This yields a gemcitabine concentration of

38 mg/ml, which includes accounting for the displacement volume of the

lyophilised powder. Shake to dissolve. Further dilution with sterile sodium

chloride 9 mg/ml (0.9 %) solution for injection, without preservative, can be

done. Reconstituted solution is a clear, colourless to 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.

Manufacturer

: Lilly France S.A.S., Fegersheim, France

License Holder

: Eli Lilly Israel Ltd., POB 2160 Herzeliya Pituach 4672511, Israel

This leaflet format was set by the MOH and its content has been reviewed and

approved on Dec 2015.

X GEMZVL F 05

Page

21

21

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ןכדועמ( ןכדועמ(

08.2013

08.2013

ךיראת

29/08/2013

םש

רישכת

תילגנאב

רפסמו

םושירה

Gemzar 200 mg,1000 mg

103722880101

,

103732880201

םש

לעב

םושירה

Eli Lilly Israel Ltd

.

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Posology, dosage &

administration

4.2 Posology and method of

administration

Patients with renal or hepatic

impairment

Gemcitabine should be used

with caution in patients with

hepatic or renal insufficiency 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).

4.2 Posology and method of

administration

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).

Special Warnings and

Special Precautions

for Use

4.4 Special warnings and

precautions for use

Hepatic

insufficiency

...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.

תפסות

4.4 Special warnings and

precautions for use

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 impairment.

Capillary leak syndrome

Capillary leak syndrome has been

reported in patients receiving

gemcitabine as single agent or in

combination with other

chemotherapeutic agents. 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

Renal

Clinical findings consistent

with the haemolytic uraemic

syndrome (HUS) were rarely

reported in patients receiving

gemcitabine (see section 4.8).

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.

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.

Renal

Haemolytic uraemic syndrome

Clinical findings consistent with

the haemolytic uraemic

syndrome (HUS) were rarely

reported 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.

Adverse events

תפסות

Added AE that were at the ‘post

marketing’ section and had an

unknown frequency to the

‘undesirable effects’ table with

known frequency (see table

below)

Nervous system disorders

Common

Headache

Insomnia

Somnolence

Uncommon

Cerebrovascular accident

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.)

Gastro-intestinal disorders

Very Common

Vomiting

Nausea

Common

Diarrhoea

Stomatitis and ulceration

of the mouth

Constipation

Very rare

Ischaemic colitis

Hepato-biliary 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

ב"צמ

ובש ,ןולעה

נמוסמ תו

תורמחהה

תושקובמה

לע

עקר

בוהצ

טסקט

רשא

קחמנ

ןמוסמ

םע

וק

הצוח

עבצב

םודא

.

טסקט

ףסוותהש

ןמוסמ

עבצב

לוחכ

.

רבעוה

ראודב

ינורטקלא

ךיראתב

29/08/2013

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