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Gemcitabin & 5-fu. Nahid Aarabi Fellow of pediatric hematology& oncology Mofid Hospital 1391/8/27. References. Principle &practice of pediatric Oncology; P.Pizzo , sixth edition The Complete Drug Reference; Martindale,35 th edition Cure4kids.org

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slide2

NahidAarabi

Fellow of pediatric hematology& oncology

Mofid Hospital

1391/8/27

references
References
  • Principle &practice of pediatric Oncology;

P.Pizzo, sixth edition

                  • The Complete Drug Reference; Martindale,35th edition
                  • Cure4kids.org
                  • Drug Interactions in the therapy of malignant

tumors(BAXTER Pub.)

                  • Drugs.com
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
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 isgreaterwith longerinfusion 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.

slide11

In adults:

-Ovarian Cancer

- Breast Cancer

-Non-Small Cell Lung Cancer

-Pancreatic Cancer

slide12

In children:

as asingle agentnothave a clearly defined role in treatment of childhood solid tumors

  • In combination with vinorelbin there is substantial antitumor activity in recurrentHodgkin lymphoma
slide13

In combination with docetaxel, there is modest antitumor activity in refractorysarcomas of bone

  • In children is not active in recurrent or refractory leukemias
slide14

Dose : most commonly used dose of Gemcitabine is 1000 mg/ m2 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
slide17

Myelosuppression, nausea, vomiting, flu-like syndrome,swelling, dyspnea, alopecia, fatigue, increased serum transaminases, fever, diarrhea, mucositis, rash

Rarely : hypotension, severe pulmonary toxicity, somnolence, thrombocytopenicpurpura, 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 gGemcitabine.

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 minutes and more frequent than weekly dosing have been shown to increase toxicity
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

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 differential 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 concurrentliver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency

slide36

Fluorouracil

( 5- Fu)

slide37

Analogue of pyrimidineuracil, acts as an antimetabolitis. The metabolism of fluorouracil in the anabolic pathway blocks the methylationreaction 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.

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 eniluracil &tegafur-uracilhave 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 16minutes ( 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 dihydropyrimidinedehydrogenase( 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 ).

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%

slide47

In adults:

Parenteral: Palliative management of colon, rectum, breast, gastric, and pancreatic carcinoma.

TopicalCarac , 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: Condylomataacuminata (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

slide51

Myelosuppression, stomatitis, diarrhea, palmar-plantar dysesthesia(hand-foot syndrome),

reversible neurologic toxicity: somnolence, cerebellar ataxia, headache, ocular toxicity consisting of conjunctivitis & ectropion

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-inducedleukopeniamay be prolonged.

slide55

Warfarin

Anticoagulanteffect of warfarin may be increased.

slide57

Hypersensitivity to any component of the product

  • Parenteral :

Depressed bone marrow function; poor nutritional status; potentially serious infections.

  • Topical :

Pregnancy; dihydropyrimidinedehydrogenase enzyme deficiency (except for 1% cream).

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