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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

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Fellow of pediatric hematology& oncology

Mofid Hospital


  • Principle &practice of pediatric Oncology;

P.Pizzo, sixth edition

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

tumors(BAXTER Pub.)


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

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

Intracellular metabolism produces mono-, di-, and tri-phosphate metabolites , the latter two active

  • Half-life 42 – 94 minutes, depending on age & gender

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.


In adults:

-Ovarian Cancer

- Breast Cancer

-Non-Small Cell Lung Cancer

-Pancreatic Cancer


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

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

  • In children is not active in recurrent or refractory leukemias

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

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


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

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.


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.

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

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


Radiation Therapy: Data suggest that Gemcitabine can be started after the acute effects of radiation have resolved or at least one week after radiation.


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

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.


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



( 5- Fu)


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.


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

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


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


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

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 ).


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%


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.


Efudex 5%: Superficial basal cell carcinoma.

Unlabeled Uses: Condylomataacuminata (topical).


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


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

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



May increase serum concentrations of fluorouracil and potentially increase toxicity.

  • Hydantoins (eg, phenytoin)

Hydantoin plasma levels may be elevated, increasing the risk of toxicity.



Leucovorin may enhance GI toxicity of fluorouracil. Fatalities have occurred because of severe toxic enterocolitis.

  • Thiazide diuretics (eg, chlorothiazide)

Fluorouracil-inducedleukopeniamay be prolonged.



Anticoagulanteffect of warfarin may be increased.


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).


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