GEMCITABIN "EBEWE" 1 G

PRESCRIBING INFORMATION

Gemcitabine “Ebewe”

Powder for solution for Infusion

200 mg vial and 1000 mg vial

COMPOSITION

Powder for solution for infusion:

Vials contain gemcitabine hydrochloride equivalent to

200 mg gemcitabine and 1000 mg.

Each 200 mg vial contains 3.9 mg (< 1 mmol) sodium.

Each 1000 mg vial contains 19.6 mg (< 1 mmol) sodium.

After reconstitution, the solution contains 38 mg/ml of

gemcitabine.

CLINICAL PARTICULARS

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 anthracyclines

unless clinically contraindicated.

Ovarian cancer:Gemcitabine in combination with carboplatin

is indicated for the treatment of patients with recurrent

epithelial ovarian carcinoma that has relapsed at least six

months after platinum based therapy.

Posology and Method of Administration

Gemcitabine should only be prescribed by a physician

qualified in the use of anticancer chemotherapy.

Bladder cancer

Combination use:The recommended dose for gemcitabine

is 1000 mg/m², given by 30-minute intravenous 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/m² 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/m², 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 intravenous infusions

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/m², 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 of gemcitabine

is 1250 mg/m², given as a 30-minute intravenous infusion

on days 1 and 8 of the 21 day treatment cycle. 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/m²

once every 3 weeks.

Breast cancer

Combination use:Gemcitabine in combination with paclitaxel

is recommended using paclitaxel (175 mg/m²) administered

on day 1 over approximately 3 hours as an intravenous

infusion, followed by gemcitabine (1250 mg/m²) as a 30-

minute intravenous infusion on days 1 and 8 of each 21-day

cycle. Dosage 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 (x10 6 /l) prior to initiation of gemcitabine

with paclitaxel combination.

Ovarian cancer

Combination use:Gemcitabine in combination

with carboplatin is recommended using gemcitabine

1000 mg/m 2 administered on days 1 and 8 of each 21-

day cycle as a 30-minute intravenous infusion. After

gemcitabine, carboplatin should 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-hematological toxicity

Periodic physical examination and checks of renal and hepatic

function should be made to detect non-hematological 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 and 4) non-

hematological 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

Physicians Information.

Dose modification due to hematological toxicity

Upon initiation of the 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 (x10 6 /l) and thrombocyte

count of 100,000 (x10 6 /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

as monotherapy or in combination with cisplatin

Absolute

granulocyte

count (x10 6 /l) Platelet count

(x10 6 /l) % of standard

dose of

gemcitabine

> 1,000 and > 100,000 100

500–1,000 or 50,000–100,000 75

< 500 or < 50,000 Omit dose *

* Omitted treatment will not be re-instated within a cycle

before the absolute granulocyte count reaches at least 500

(x10 6 /l) and the platelet count reaches 50,000 (x10 6 /l).

Dose modification of gemcitabine within a cycle for

breast cancer given in combination with paclitaxel

Absolute

granulocyte

count (x10 6 /l) Platelet count

(x10 6 /l) % of standard

dose of

gemcitabine

≥1,200 and > 75,000 100

1000 – < 1,200 or 50,000–75,000 75

700 – < 1000 and ≥50,000 50

< 700 or < 50,000 Omit dose *

* Omitted treatment 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 1500 (x10 6 /l)

and the platelet count reaches 100,000 (x10 6 /l).

Dose modification of gemcitabine within a cycle

for ovarian cancer, given in combination with

carboplatin

Absolute

granulocyte

count (x10 6 /l) Platelet count

(x10 6 /l) % of standard

dose of

gemcitabine

> 1,500 and ≥100,000 100

1000–1,500 or 75,000–100,000 50

< 1000 or < 75,000 Omit dose *

*Omitted treatment 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 1500 (x10 6 /l)

and the platelet count reaches 100,000 (x10 6 /l).

Dose modification due to hematological 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

hematological toxicities:

1.Absolute granulocyte count < 500 x 10 6 /l for more than

5 days

2.Absolute granulocyte count < 100 x 10 6 /l for more than

3 days

3. Febrileneutropenia

4.Platelets < 25,000 x10 6 /l

5.Delay of next treatment cycle by more than 1 week due

to toxicity

Method of administration

Gemcitabine”Ebewe”is tolerated well during infusion and

may be administered in outpatient settings. 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 “Instructions

for Use/Handling”.

Special populations

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 “Special Warnings and

Precautions for Use” & “Pharmacokinetic Properties”).

Elderly population (> 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 the elderly

(see section “Pharmacokinetic Properties”).

Pediatric population (<18 years):Gemcitabine is not

recommended for use in children under 18 years of age due

to insufficient data on safety and efficacy.

Contraindications

Hypersensitivity to the active substance or to any of the

excipients.

Breast-feeding (see section “Pregnancy and Lactation”).

Special Warnings and Precautions for Use

Prolongation of the infusion time and increased dosing

frequency have been shown to increase toxicity.

Hematological toxicity:Gemcitabine can suppress

bone marrow function as manifested by leucopenia,

thrombocytopenia and anemia.

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 “Posology and Method of Administration”). 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 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.

Laboratory evaluation of renal and hepatic function (including

virological tests) should be performed periodically.

Gemcitabine should be used with caution in patients with

hepatic insufficiency or with impaired renal function as there

is insufficient information from clinical studies to allow clear

dose recommendation for this patient population (see section

“Posology and Method of Administration”).

Concomitant radiotherapy:Concomitant radiotherapy

(given together or≤7 days apart): Toxicity has been reported

forms of Interaction” 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 “Interactions with

other Medicaments and other forms of Interaction”).

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.

Pulmonary:Pulmonary effects, sometimes severe (such

as pulmonary edema, interstitial pneumonitis or adult

respiratory distress syndrome (ARDS) have been reported in

association with gemcitabine therapy. The etiology of these

effects is unknown. If such effects develop consideration

should be made to discontinue gemcitabine therapy. Early

use of supportive caremeasures may help ameliorate the

condition.

Renal:Clinical findings consistent with the hemolytic uremic

syndrome (HUS) wererarely reported in patients receiving

gemcitabine (see section “Undesirable Effects”). Gemcitabine

should be discontinued at the first signs of any evidence of

microangiopathic hemolytic anemia, such as rapidly falling

hemoglobin 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 “Preclinical

Safety Data”). Therefore, men being treated with gemcitabine

are advised not to father a child during and up to 6

months after treatment and see further advice regarding

cryoconservation of sperm prior to treatment because of

the possibility of infertility due to therapy with gemcitabine

(see section “Pregnancy and Lactation”).

Sodium:

Powder for solution for infusion:Vials contain gemcitabine

hydrochloride equivalent to 200 mg gemcitabine and

1000 mg.

Each 200 mg vial contains 3.9 mg (< 1mmol) sodium.

Each 1000 mg vial contains 19.6 mg (< 1mmol) sodium.

These should be taken into consideration in patients

on a controlled sodium diet.

Interactions with other Medicaments and other

forms of Interaction

No specific interaction studies have been performed (see

section “Pharmacokinetic Properties”).

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 radiosensitizing activity. In a single trial, where gemcitabine

at a dose of 1,000 mg/m² 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 esophagitis and pneumonitis was

observed, particularly in patients receiving large volumes

of radiotherapy (median treatment volumes 4,795 cm 3 ).

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 66Gy were applied concomitantly with an administration

of gemcitabine (600 mg/m², four times) and cisplatin

(80 mg/m² twice) during 6 weeks. The optimum regimen for

safe administration of gemcitabine with therapeutic doses of

radiation has not yet been determined in all tumor 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” phenomena. 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.

esophagitis, 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 risk of systemic, possibly fatal,

disease, particularly in immunosuppressed patients.

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 “Preclinical Safety

Data”). 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 to the nursing

child can not be excluded. Breast-feeding must be discontinued

during gemcitabine therapy.

Fertility:In fertility studies gemcitabine caused

hypospermatogenesis in male mice (see section “Preclinical

Safety Data”). Therefore, males being treated with gemcitabine

are advised to avoid conception during and up to 6 months

after cessation of treatment and seek further advice regarding

cryoconservation of sperm prior to treatment because of the

possibility of infertility due to therapy with gemcitabine.

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.

Undesirable Effects

The most commonly reported adverse drug reactions associated

with Gemcitabine “Ebewe” include: nausea with or without

vomiting, raised liver transaminases (AST/ALT) and alkaline

phosphatase, reported in approximately 60% of patients;

proteinuria and hematuria reported in approximately 50%

of patients; dyspnea 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 “Special Warnings and Precautions for

Use”). Dose-limiting adverse reactions are reductions in

thrombocyte, leucocyte and granulocyte counts (see section

“Posology and Method of Administration”).

Clinical trial data:

Frequencies are defined as: Very common (≥1/10), Common

(≥1/100 to < 1/10), Uncommon (≥1/1000 to < 1/100), Rare

(≥1/10000 to < 1/1000), Very Rare (< 1/10000).

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 severity.

System organ class Frequency grouping

Blood and lymphatic

system disorder Verycommon

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 “Posology and Method of

Administration”).

Thrombocytopenia

Anemia

Common

Febrile neutropenia

Veryrare

Thrombocytosis

Immune system

disorders Veryrare

Anaphylactoid reaction

Metabolism and

nutrition disorders Common

Anorexia

Nervous system

disorders Common

Headache

Insomnia

Somnolence

Cardiac disorders Rare

Myocardial infarct

Vascular disorders Rare

Hypotension

Respiratory, thoracic

and mediastinal

disorders Verycommon

Dyspnea – usually mild, resolves

rapidly without treatment

Common

Cough

Rhinitis

Uncommon

Interstitial pneumonitis (see

section “Special Warnings and

Precautions for Use”)

Bronchospasm – usually mild and

transient but may require parenteral

treatment

Gastrointestinal

disorders Verycommon

Vomiting

Nausea

Common

Diarrhea

Stomatitis and ulceration of oral

mucosa

Constipation

Hepatobiliary disorders Verycommon

Elevation of liver transaminases

(AST and ALT) and alkaline

phosphatase

Common

Increased bilirubin

Rare

Increased gamma-glutamyl

transferase (GGT)

Skin and subcutaneous

tissue disorders Verycommon

Allergic skin rash frequently

associated with pruritus

Alopecia

Common

Itching

Sweating

Rare

Ulceration

Vesicle and sore formation

Scaling

Veryrare

Severe skin reactions, including

desquamation and bullous skin

eruptions

Musculoskeletal and

connective tissue

disorder Common

Back Pain

Myalgia

Renal and urinary

disorders Verycommon

Hematuria

Mild proteinuria

General disorders and

administration site

conditions Verycommon

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.

Edema/peripheral edema-

including facial edema.

Edema is usually reversible after

stopping treatment.

Common

Fever

Asthenia

Chills

Rare

Injection site reactions mainly mild

in nature

Injury, poisoning

and procedural

complications Radiation toxicity (see section

“Interactions with other

Medicaments and other forms of

Interaction”).

Postmarketing experience (spontaneous reports)

frequency not known (can not be estimated from the

available data)

Nervous system disorders

Cerebrovascular accident

Cardiac disorders

Arrhythmias, predominantly supraventricular in nature

Heart failure

Vascular disorders

Clinical signs of peripheral vasculitis and gangrene

Respiratory, thoracic and mediastinal disorders

Pulmonary edema

Adult respiratory distress syndrome (see section “Special

Warnings and Precautions for Use”).

Gastrointestinal disorders

Ischemic colitis

Hepatobiliary disorders

Serious hepatoxicity, including liver failure and death

Skin and subcutaneous tissue disorders

Severe skin reactions, including desquamation and bullous skin

eruptions, Lyell’s Syndrome, Steven-Johnson Syndrome

Renal and urinary disorders

Renal failure(see section “Special Warnings and Precautions

for Use”)

Hemolytic uremic syndrome (see section “Special Warnings

and Precautions for Use”)

Injury, poisoning and procedural complications

Radiation recall

Combination use in breast cancer

The frequency of Grade 3 and 4 hematological 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 hemorrhagic events. Fatigue and febrile

neutropenia occur more frequently when gemcitabine is used

in combination with paclitaxel. Fatigue which is not associated

with anemia, usually resolves after the first cycle.

Grade 3 and 4 adverse events

paclitaxel vs. gemcitabine & paclitaxel

Number (% of patients)

Paclitaxel

arm

(N=259) Gemcitabine and

paclitaxel arm

(N=262)

Grade3 Grade4Grade 3 Grade 4

Hematological

Anemia 5(1.9) 1 (0.4)15 (5.7) 3 (1.1)

Thrombocytopenia 0 0 14 (5.3) 1 (0.4)

Neutropenia 11 (4.2)17 (6.6)*82 (31.3)45(17.2)*

Non-hematological

Febrile

neutropenia 3 (1.2) 0 12 (4.6) 1 (0.4)

Fatigue 3 (1.2)1(0.4) 15(5.7) 2(0.8)

Diarrhoea 5 (1.9)0 8 (3.1) 0

Motor neuropathy 2 (0.8) 0 6(2.3) 1 (0.4)

Sensory

neuropathy 9 (3.5) 0 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 vs. gemcitabine & cisplatin

Number (% of patients)

MVAC

(methotrexate,

vinblastine,

adryamicin and

cisplatin arm)

(N=196) Gemcitabine and

cisplatin arm

(N=200)

Grade 3Grade 4 Grade 3 Grade 4

Hematological

Anemia 30 (16) 4(2) 47(24) 7(4)

Thrombocytopenia 15 (8)25 (13) 57 (29) 57 (29)

Non-hematological

Nausea and

vomiting 37(19) 3(2) 44(22) 0

Diarrhea 15 ( 8) 1 (1) 6 (3) 0

Infection 19 (10) 10(5) 4(2) 1(1)

Stomatitis 34 (18) 8 (4) 2 (1) 0

Combination use in ovarian cancer

Grade 3 and 4 adverse events

carboplatin vs. gemcitabine & carboplatin

Number (% of patients)

Carboplatin arm

(N=174) Gemcitabine and

carboplatin

(N=175)

Grade 3Grade 4 Grade 3 Grade 4

Hematological

Anemia 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)

Thrombocytopenia18 (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-hematological

Hemorrhage 00 3 (1.8) 0

Febrile

neutropenia 00 2 (1.1) 0

Infection without

neutropenia 0 0 0 0

Sensory neuropathy was also more frequent in the combination

arm than with single agent carboplatin.

Overdose

There is no known antidote for overdose of gemcitabine. Doses

as high as 5700 mg/m² have been administered by intravenous

infusion over 30 minutes every 2 weeks with clinically

acceptable toxicity. In the event of suspected overdose, the

patient blood counts should be monitored and the patient

should receive supportive therapy, as necessary.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic Properties

Pharmacotherapeutic group:Pyrimidine analogues:

ATC code LO1BCO5

Cytotoxic activity in cell cultures:Gemcitabine shows

significant cytotoxic effects against a variety of cultured

murine and human tumor 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 G

/S

phase boundary.In vitro, the cytotoxic effect of gemcitabine

is dependent on both concentration and time.

Antitumoral activity in preclinical models

In animal tumor models, antitumoral activity of gemcitabine is

schedule-dependant. When gemcitabine is administered daily,

high mortality among the animals but minimal antitumoral

activity is observed. If, however, gemcitabine is given every

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

doses with substantial antitumoral activity against a broad

spectrum of mouse tumors.

Mechanism of action

Cellular metabolism and mechanism of action: Gemcitabine

(dFdC), which is a pyrimidine antimetabolite, is metabolized

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 completes 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.

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/

adryamicin/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 randomized 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

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% response, 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 randomized phase III study of 135 patients with

stage IIIB or IV NSCLC, a combination of gemcitabine and

cisplatin showed a statistically 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 randomized 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, 47.2% in the GCb arm versus

30.9 in the Cb (p=0.0016), and median survival, 18 months

GCb versus 17.3 Cb (p=0.73) favored the GCb arm.

Breast cancer:In a randomized 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. 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).

Pharmacokinetic Properties

The pharmacokinetics of gemcitabine has 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, approx.

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/m² 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 1000 mg/m²/30 minutes are greater than 5 µg/ml for

approximately 30 minutes after the end of the infusion and

Distribution

The volume of distribution of the central compartment was

12.4 l/m² for women and 17.5 l/m² for men (inter-individual

variability was 91.9%). The volume of distribution of the

peripheral compartment was 47.4 l/m².

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.

Metabolism

Gemcitabine is rapidly metabolized 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/m² to 92.2 l/hr/

m² 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/ m²

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 2–7 l/hr/m².

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 feces.

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/m²/30 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 saturated

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/m²): 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/m² (range 11–22 l/m²).

Mean steady-state volume distribution (Vss): 150 l/m²

(range 96–228 l/m²).

Tissue distribution: Extensive.

Mean apparent clearance: 2.5 l/hr/m² (range 1–4 l/hr/m²).

Urinary excretion: All.

Gemcitabine and paclitaxel combination therapy

Gemcitabine 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.

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-dependant hematopoietic suppression which was

reversible.

Gemcitabine is mutagenic in anin vitromutation test and an

in vivobone 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.

PHARMACEUTICAL PARTICULARS

List of Excipients

Powder for solution for infusion

Mannitol (E421), Sodium acetate (E262), Sodium hydroxide

(E524) for pH adjustment, Water for injection.

Incompatibilities

Should not be mixed with other medicinal products

except those mentioned in section “Instructions for use/

Handling”.

Shelf Life

Powder for solution for infusion - 30 months.

Shelf life after dilution:Chemical and physical in-use

stability has been demonstrated for 24 h at 25°C.

From a microbiological point of view, the solution should

be administered immediately after dilution. 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 h at room temperature. unless reconstitution

and further dilution has taken place in controlled and validated

aseptic conditions.

Special Precautions for Storage

Powder for solution for infusion

Do not refrigerate or freeze. For storage conditions of the

diluted medicinal product see section “Shelf Life”.

Nature and contents of container

Powder for solution for infusion

Clear colorless type I glass vials 10 ml and 50 ml.

Instructions for Use/Handling.

Powder for solution for infusion

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.

1.Parenteral drugs should be inspected visually for particulate

matter and discoloration, prior to administration, whenever

solution and container permit.

2.Use aseptic technique during the reconstitution and any

further dilution of gemcitabine for IV infusion.

3.Toreconstitute, add 5 ml of sterile sodium chloride

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

to the 200 mg vial or 25 ml sterile sodium chloride

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

to the 1000 mg vial. The total volume after reconstitution

is 5.26 ml (200 mg vial) or 26.3 ml (1000 mg vial)

respectively. This results in a concentration of gemcitabine

of 38 mg/ml, which includes accounting for the

displacement volume of the lyophilised powder. Shake

to dissolve.

4.Further dilution with sterile sodium chloride 9 mg/ml

(0.9%) solution for injection without preservative can

be done. Reconstituted solution is a clear, colorless to

light straw-colored solution.

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.

Any unused drug or waste material should be disposed of

in accordance with local requirements.

Presentations

Powder for solution for infusion:Vials contain gemcitabine

hydrochloride equivalent to

Gemcitabine “Ebewe” 200 mg- 1vial

Gemcitabine “Ebewe” 1000 mg- 1 vial

MANUFACTURER

EBEWE Pharma Ges.m.b.H., A-4866 Unterach, Austria

LICENSE HOLDER

Pharmalogic LTD, P.O.B. 3838, Petah-Tikva 49130

The format of this leaflet was determined by the

Ministry of Health and its content was checked and

approved in April 2010

GEMC POWD PHY SH 250410_Size1