Gemcitabin & 5-fu Nahid - PowerPoint Presentation

Slide1

Gemcitabin & 5-fu

Slide2

Nahid

Aarabi

Fellow of pediatric hematology& oncology

Mofid

Hospital

1391/8/27

Slide3

References

Principle &practice of pediatric Oncology;

P.Pizzo

, sixth edition

The Complete Drug Reference; Martindale,35

th

edition

Cure4kids.org

Drug Interactions in the therapy of malignant

tumors(BAXTER Pub.)

Drugs.com

Slide4

Gemcitabin

Hydrochloride

(

Gemzar

)

Slide5

Gemcitabin

is an analogue of

cytarabine

, which inhibit DNA synthesis & induce

apoptosis

It is primarily active against cells in

S- phase

Is given for solid tumors including:

bladder

,

breast

,

lung

,

pancreas

. Also

being tried

in cancers of

cervix

&

ovary

Slide6

Pharmacokinetics

Slide7

After IV doses, is

rapidly

cleared from blood &

metabolised

by

cytidine

de-

aminase

in

liver

,

kidney

,

blood

& other tissue.

Clearance is 25%,

lower

in

women

than in men

Almost

all

of doses is excreted in

urine

, only 1% in

faeces

Slide8

Intracellular metabolism produces mono-,

di

-,

and

tri-phosphate

metabolites , the latter two

active

Half-life 42 – 94 minutes, depending on

age

&

gender

Slide9

In children:

- volume

distribution

is

greater

with

longer

infusion duration

- in children receiving a

30- minute infusion

, half- life is

14 minutes

. In children receiving a

6- hour infusion

, half-life is

62 minutes

.

Slide10

Uses and Administration

Slide11

In adults:

-

Ovarian Cancer

- Breast Cancer

-Non-Small Cell Lung Cancer

-Pancreatic Cancer

Slide12

In children:

as a

single

agent

not

have a clearly defined role in treatment of childhood

solid tumors

In

combination

with

vinorelbin

there is substantial antitumor activity in

recurrent

Hodgkin lymphoma

Slide13

In

combination

with

docetaxe

l

, there is modest antitumor activity in

refractory

sarcomas of bone

In children is

not active

in

recurrent

or

refractory

leukemias

Slide14

Dose : most commonly used dose of

Gemcitabine

is

1000

mg

/

m

2

at a

30-minute

infusion

weekly

* 3 weeks every 28 days

.

Is given by

infusion

over

30 to 60 minutes

Dose are

adjusted

according to

response

and

toxicity

Slide15

Concentration

of infusion solution should

not

exceed

equivalent

gemcitabine

40 mg/ ml

Slide16

Adverse Effects

Slide17

Myelosuppression

, nausea, vomiting,

flu-like

syndrome,

swelling

,

dyspnea

, alopecia, fatigue,

increased serum

transaminases

,

fever

, diarrhea,

mucositis

, rash

Rarely : hypotension, severe pulmonary toxicity,

somnolence

,

thrombocytopenic

purpura

,

Haemolytic

– uremic syndrome

Slide18

Patients should not drive or operate

machinary

Gemcitabine

should be stopped at the first signs of

microangiopathic

hemolytic anemia

Life –threatening

esophagitis

and

pneumonitis

has been seen in patients given radical

radiotherapy to thorax

Slide19

Dosage Forms :

Gemcitabine

for Injection is a white to off-white

lyophilized powder

available in sterile

single

-

use

vials containing

200 mg

or

1 g

Gemcitabine

.

Slide20

Slide21

Slide22

preparation

Slide23

Recommended

diluent

for reconstitution of

Gemcitabine

is

0.9% Sodium Chloride

Injection

without preservatives

, upon reconstitution is

40 mg/

mL

Reconstitution at concentrations greater than 40 mg/

mL

may result in incomplete dissolution, and should be avoided.

Slide24

Prior to administration the appropriate amount of drug must be

diluted

with

0.9% Sodium Chloride

Injection. Final concentrations may be as low as

1 mg/

mL

Prolongation of the infusion time

beyond 60 minute

s

and

more frequent than weekly

dosing have been shown to

increase toxicity

Slide25

If

particulate matter

or

discoloration

is found, do

not administer

Slide26

Gemcitabine

solutions

are stable for

24 hours

at controlled room temperature

20° to 25°C

(68° to 77°F) . Discard unused portion . Solutions of reconstituted

Gemcitabine

should

not be refrigerated

, as crystallization may occur

Slide27

Dose modification

Slide28

Dosage

Reduction Guidelines

Absolute granulocyte count

( *1,000,000/L)

Platelet count

( *1,000,000/L

)

% of full dose

>

1000

And

>100,000

100

500 - 999

or

50,000 – 99,999

75

<500

or

<50,000

Hold

Slide29

precautions

Slide30

Radiation Therapy:

Data suggest that

Gemcitabine

can be started

after the acute effects of radiation have resolved

or

at least one week after

radiation.

Slide31

Patients receiving

Gemcitabine

should be monitored

prior

to

each dose

with a complete blood count

(CBC),

including

differentia

l and

platelet count.

Laboratory evaluation of

renal

and

hepatic

function should be performed prior to initiation of therapy

Slide32

Gemcitabine

should be used with

caution

in patients with preexisting

renal impairment

or

hepatic insufficiency

as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations.

Slide33

Administration of

Gemcitabine

in patients with

concurrent

liver metastases

or a

preexisting

medical history of

hepatitis

,

alcoholism

, or

liver cirrhosis

may lead to

exacerbation

of the

underlying hepatic insufficiency

Slide34

Drug Interactions

Slide35

No specific drug interaction studies have been conducted

Slide36

Fluorouracil

( 5- Fu)

Slide37

Analogue of

pyrimidine

uracil

, acts as an

antimetabolitis

. The metabolism of fluorouracil in the anabolic pathway blocks the

methylation

reaction of

deoxyuridylic

acid

to

thymidylic

acid

. In this manner, fluorouracil interferes with the

synthesis of DNA

and, to a

lesser

extent, inhibits the formation of

RNA

.

Slide38

Pharmacokinetics

Slide39

Bioavailability of oral fluorouracil is highly variable

Little is absorbed when is applied to healthy skin

Subcutaneously

administered 5-FU is well tolerated & has nearly complete bioavailability

Slide40

Bioavailable

fluorouracil

prodrugs

, such as

eniluraci

l

&

tegafur-uracil

have been developed for

oral

administration that are converted to 5-FU after absorption& provide more

prolonged drug exposure

, similar to a prolonged intravenous infusion

Slide41

After

IV injection

, is

cleared rapidly

from plasma, with a mean

half-life

about

16

minutes

( 6-20 minutes), is distributed throughout body tissues & fluids , crossing the blood-brain barrier & appear in

CSF

&

disappears

from plasma within

3 hours

Slide42

Less than

10%

of drug is excreted unchanged in

urine

Remainder is

inactivated

primarily in

liver

&

catabolised

via

dihydropyrimidine

dehydrogenase

( DPD) , similarly to endogenous

uracil

A

large amount

is excreted as respiratory

carbon dioxide

; urea & other metabolites also produced

Slide43

During continuous IV infusion , plasma 5-fu

concentrations

were

highest in late morning

&

lowest shortly before midnight

( related to activity of catabolic enzyme , DPD, in peripheral mononuclear cells ).

Slide44

Trade Names

Slide45

Adrucil

:

Injection, solution 50 mg/

mL

Carac

:

Cream 0.5%

Efudex

:

Cream 5%

Fluorouracil : -

Injection, solution 50 mg/

mL

- Cream 5%

- Solution 2%

- Solution 5%

Fluoroplex

:

Cream 1%

Slide46

Uses & Administration

Slide47

In adults:

Parenteral

:

Palliative management of

colon

,

rectum

,

breas

t,

gastric

, and

pancreatic carcinoma.

Topical

Carac

,

Efudex

,

Fluoroplex

:

Multiple actinic or solar

keratoses

.

Carac

is only indicated for the

face

and

anterior scalp areas.

Slide48

Efudex

5%:

Superficial basal cell carcinoma.

Unlabeled Uses:

Condylomata

acuminata

(topical).

Slide49

In children:

parentral

:

Germ cell tumors

Hepatic tumors

Dosage :

- bolus injection: 500 mg/m2/ day for 5 days

- continuous infusion over 24 hours: 800 – 1200 mg/m2

Slide50

Adverse Reactions

Slide51

Myelosuppression

,

stomatitis

, diarrhea,

palmar

-plantar

dysesthesia

(

hand-foot syndrome

),

reversible neurologic toxicity

: somnolence,

cerebellar

ataxia, headache, ocular toxicity consisting of conjunctivitis &

ectropion

Slide52

Drug Interactions

Slide53

Cimetidine

May increase serum concentrations of fluorouracil and potentially

increase toxicity.

Hydantoins

(

eg

,

phenytoin

)

Hydantoin

plasma levels may be elevated,

increasing

the risk of

toxicity.

Slide54

Leucovorin

Leucovorin

may enhance

GI toxicity

of fluorouracil.

Fatalities

have occurred because of severe toxic

enterocolitis

.

Thiazide

diuretics (

eg

,

chlorothiazide

)

Fluorouracil-induced

leukopenia

may be prolonged.

Slide55

Warfarin

Anticoagulant

effect

of

warfarin

may be

increased.

Slide56

Contraindications

Slide57

Hypersensitivity to any component of the product

Parenteral

:

Depressed bone marrow function;

poor nutritional status

; potentially serious infections.

Topical

:

Pregnancy;

dihydropyrimidine

dehydrogenase

enzyme deficiency

(except for 1% cream).

Slide58

preparation

Slide59

by

IV

infusion: usual doses (15 mg/kg daily to maximum of 1

gr

daily) being infused in

500 ml

of

sodium chloride 0.9%

or

glucose 5%

over

4 hours

by mouth : a dose of 15 mg/kg , maximum 1

gr

in one day, has been given weekly for maintenance