Fluorouracilo Accord

Uses

5-Fluorouracilo Accord is used alone or in combination for carcinoma of the colon or rectum, carcinoma of the stomach and exocrine pancreas, carcinoma of the liver, carcinoma of the breast (an especially aggressive form of breast cancer), carcinoma of the bladder, carcinoma of the lung, epithelial ovarian carcinoma andcervical carcinoma.

Fluorouracilo Accord is also used to associated treatment for these conditions: Actinic Keratosis (AK), Breast Cancer, Malignant Neoplasm of Colon, Malignant Neoplasm of Pancreas, Malignant Neoplasm of Stomach, Rectal Carcinoma, Superficial Basal Cell Carcinoma, Warts, Hyperkeratotic actinic keratosis

How Fluorouracilo Accord works

The precise mechanism of action has not been fully determined, but the main mechanism of fluorouracil is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5–10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex. This results in the inhibition of the formation of thymidylate from uracil, which leads to the inhibition of DNA and RNA synthesis and cell death. Fluorouracilo Accord can also be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis.

Dosage

Fluorouracilo Accord dosage

Various protocols exist-

• 500 mg/m2 IV on Days 1-5, OR
• 450-600 mg/m2 IV weekly, OR
• 200-400 mg/m2 IV continuous infusion qD
• Not to exceed 800 mg/day

The commonest schedules being 500 mg/m2 daily for 5 days repeated at 4-weekly intervals.

Intravenous 5-FU can be delivered by rapid intravenous bolus injection or slow infusion. The vial contents can rapidly be injected directly into a peripheral vein. Slow intravenous infusion requires the drug to be diluted in 500 mL of dextrose 5% solution, then infused over 2-3 hours on 5 successive days.

Side Effects

Mild to moderate cardiac effects, hepatic effects, hematological effects, neurological effects, allergic reaction, decreased bone marrow function, hand-foot syndrome, severe vomiting, diarrhoea, frequent bowel movements or watery stools, sores in the mouth or throat may occur.

Toxicity

LD₅₀=230mg/kg (orally in mice)

Precaution

Dose should be reduced in patients with compromised liver function. For intra-arterial infusion, 5000 U of L.M. heparin should be added to 1 L of 5% dextrose in water together with the daily dose of fluorouracil. Ulcer-like pain or other significant gastrointestinal symptoms are indications to discontinue intra-arterial therapy, as hemorrhage or perforation may occur. Precipitation may occur when leucovorin and fluorouracil are mixed in the same bag.

Interaction

Pre-treatment with cimetidine for 4 weeks lead to increased plasma concentrations of fluorouracil following intravenous and oral administration. The effect was probably due to a combination of hepatic enzyme inhibition and reduced hepatic blood flow.

Its use should be avoided in patients receiving drugs known to modulate dihydropyrimidine dehydrogenase (such as the antiviral drug sorivudine). It may also increase the INR and prothrombin times in patients on warfarin. Fluoruracil's efficacy is decreased when used alongside allopurinol which can be used to decrease fluoruracil induced stomatitis through use of allopurinol mouthwash.

Food Interaction

Fluorouracilo Accord multivitamins interaction

[Major] MONITOR CLOSELY: Coadministration with folate therapy may potentiate the pharmacologic effects of 5-fluorouracil (5-FU).

The exact mechanism of interaction is unknown.

Although enhancement of 5-FU cytotoxicity may be used to advantage in some cancer patients, increased toxicity should also be considered.

Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.

In a clinical study consisting of 148 patients with advanced untreated colorectal cancer, weekly administration of 5-FU (600 mg

However, the combination was also more toxic than 5-FU alone, as evidenced by a higher incidence of grade 3 to 4 diarrhea (19.5% versus 8.5%) and conjunctivitis (26.5% versus 5.6%), as well as one recorded toxic death versus none.

No differences in median survival and time to progression were observed between the two groups.

Similar results were observed in another study with capecitabine, a prodrug of 5-FU.

The interaction has also been reported with folic acid.

A published case report describes two patients who were hospitalized for presumed 5-FU toxicity (anorexia, severe mouth ulceration, bloody diarrhea, vaginal bleeding) during concomitant treatment with a multivitamin containing folic acid (0.5 mg in one and 5 mg in the other).

Both patients tolerated subsequent courses of 5-FU at the previous dosage following discontinuation of the multivitamin.

Another published report describes a breast cancer patient who died during treatment with capecitabine (2500 mg

The patient developed diarrhea, vomiting, and hand-foot syndrome eight days after starting capecitabine therapy.

Her condition improved briefly following discontinuation of capecitabine and then folic acid, but she subsequently developed necrotic colitis and died from septic shock and vascular collapse.

Caution is advised if 5-FU or any of its prodrugs (e.g., capecitabine, tegafur) are prescribed in combination with leucovorin.

A lower dosage of 5-FU or the prodrug may be required.

Therapy with leucovorin and fluorouracil should not be initiated or continued in patients with symptoms of gastrointestinal toxicity until such symptoms have resolved.

Closely monitor patients with diarrhea until it resolves.

Monitor for other potential toxicities of 5-FU such as neutropenia, thrombocytopenia, stomatitis, cutaneous reactions, and neuropathy.

Patients should be instructed to avoid taking folic acid supplementation or multivitamin preparations containing folic acid without first speaking with their physician.

Fluorouracilo Accord Drug Interaction

Unknown: aspirin, aspirin, bevacizumab, bevacizumab, diphenhydramine, diphenhydramine, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, polyethylene glycol 3350, polyethylene glycol 3350, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol, ondansetron, ondansetron

Fluorouracilo Accord Disease Interaction

Major: myelosuppression, dihydropyrimidine dehydrogenase deficiency, infections, stomatitisModerate: bleeding, coronary artery disease

Elimination Route

28-100%

Half Life

10-20 minutes

Elimination Route

Seven percent to 20% of the parent drug is excreted unchanged in the urine in 6 hours; of this over 90% is excreted in the first hour. The remaining percentage of the administered dose is metabolized, primarily in the liver.

Pregnancy & Breastfeeding use

Pregnancy category D. There are no data on the excretion of fluorouracil into human milk. Because fluorouracil inhibits DNA, RNA and protein synthesis, mothers should not nurse while receiving this drug.

Contraindication

It is contraindicated in patients that are severely debilitated or in patients with bone marrow suppression due to either radiotherapy or chemotherapy. It is likewise contraindicated in pregnant or breastfeeding women. It should also be avoided in patients that do not have malignant illnesses.

Acute Overdose

There is very little difference between the minimum effective dose and maximum tolerated dose of 5-FU, and the drug exhibits marked individual pharmacokinetic variability. Therefore, an identical dose of 5-FU may result in a therapeutic response with acceptable toxicity in some patients and unacceptable and possibly life-threatening toxicity in others. Both overdosing and underdosing are of concern with 5-FU, although several studies have shown that the majority of colorectal cancer patients treated with 5-FU are underdosed based on today's dosing standard, body surface area (BSA). The limitations of BSA-based dosing prevent oncologists from being able to accurately titer the dosage of 5-FU for the majority of individual patients, which results in sub-optimal treatment efficacy or excessive toxicity.

Numerous studies have found significant relationships between concentrations of 5-FU in blood plasma and both desirable or undesirable effects on patients. Studies have also shown that dosing based on the concentration of 5-FU in plasma can greatly increase desirable outcomes while minimizing negative side effects of 5-FU therapy. One such test that has been shown to successfully monitor 5-FU plasma levels and which "may contribute to improved efficacy and safety of commonly used 5-FU-based chemotherapies" is the My 5-FU test.

Storage Condition

Product should be stored below 25℃, without freezing and protected from light.

Innovators Monograph

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