Adrucil (Fluorouracil)

ADRUCIL®

Pharmacia & Upjohn

Fluorouracil

Antineoplastic

Action And Clinical Pharmacology: The mechanism of action of fluorouracil is mainly related to competitive inhibition of thymidylate synthetase, the enzyme catalyzing the methylation of deoxyuridylic acid to thymidylic acid. The consequent thymidine deficiency results in inhibition of deoxyribonucleic acid (DNA) synthesis, thus inducing cell death. Also, moderate inhibition of ribonucleic acid (RNA) and incorporation of fluorouracil into RNA have been observed. The predominant mechanism of antitumor action appears to be dependent, at least in part, on individual tumor intracellular metabolism.

The effects of DNA and RNA deprivation are most marked on those cells which grow rapidly and which take up fluorouracil at a more rapid pace. Inactive degradation products (e.g., CO2, urea, a-fluoro-b-alanine) result from the extensive catabolic metabolism of fluorouracil. Following i.v. injection, no intact drug can be detected in the plasma after 3 hours and 60 to 80% of the dose is excreted as respiratory CO2 in 8 to 12 hours. Within 6 hours approximately 15% of the total drug administered is excreted unchanged in the urine with over 90% of this excretion occurring in the first hour.

Indications And Clinical Uses: Used alone, is effective in the palliative management of carcinoma of the colon, rectum, breast, stomach and pancreas. Clinical studies support the efficacy of fluorouracil used with other chemotherapeutic agents in patients with carcinoma of the breast, stomach and pancreas. Listed below are tumor types and drugs used concurrently with fluorouracil.

Carcinoma of the Breast: Fluorouracil with cyclophosphamide and doxorubicin; fluorouracil with cyclophosphamide and epirubicin; fluorouracil with cyclophosphamide and doxorubicin, vincristine and prednisone.

Carcinoma of the Stomach: Fluorouracil with doxorubicin and mitomycin-C or fluorouracil with epirubicin.

Carcinoma of the Pancreas: Fluorouracil with doxorubicin and mitomycin-C; fluorouracil with mitomycin-C and streptozotocin.

A number of other solid tumors have also shown some responsiveness to fluorouracil alone or in combination with other drugs. These include the following:

Cancer of the Urinary Bladder: fluorouracil alone; fluorouracil with doxorubicin; fluorouracil with doxorubicin and cisplatin; fluorouracil with doxorubicin and cyclophosphamide; fluorouracil with methotrexate, cyclophosphamide and vincristine.

Cancer of the Prostate: fluorouracil alone; fluorouracil with doxorubicin and cyclophosphamide.

Cancer of the Head and Neck: fluorouracil with cisplatin.

Cancer of the Ovary: fluorouracil with hexamethylmelamine, cyclophosphamide and doxorubicin.

No studies performed to date have shown malignant melanoma, kidney carcinoma, the leukemias and lymphomas, soft tissue and bone sarcomas, bronchogenic carcinoma, brain tumors and metastases to the CNS to be significantly responsive to fluorouracil therapy.

Contra-Indications: Should not be started in patients in a poor nutritional state, with depressed bone marrow function, or with potentially serious infections.

Manufacturers’ Warnings In Clinical States: Use fluorouracil with extreme caution in poor risk patients with a history of high dose pelvic irradiation, previous use of alkylating agents, or who have widespread involvement of bone marrow by metastatic tumors, or impaired renal or hepatic function. Although severe toxicity and fatalities are more likely to occur in poor risk patients, these effects have occasionally been encountered in patients in relatively good condition. Severe hematologic toxicity, gastrointestinal hemorrhage, and even death may result from the use of fluorouracil despite meticulous selection of patients and careful dosage adjustment.

Pregnancy: Fluorouracil’s safe use has not been established with respect to adverse effects on fetal development. Therefore, the drug should not be used during pregnancy, particularly in the first trimester, unless in the judgment of the physician, the potential benefits to the patient outweigh the hazards.

Because the risk of mutagenesis has not been evaluated, such possible effects on males and females must be considered.

Precautions: Fluorouracil is a highly toxic drug with a narrow margin of safety and thus, special attention must be given to its toxicity. Patients should be advised of expected toxic effects especially oral manifestations. White blood counts with differential and platelet counts are recommended before each dose. Knowledge of WBC nadir is necessary for eventual subsequent dosage adjustments.

Discontinue fluorouracil administration promptly if any of the following signs of toxicity appear: stomatitis or esophagopharyngitis (at first visible sign); leukopenia.

Fluorouracil should be resumed only when the patient has recovered from the above signs.

Drug Interactions: Fluorouracil with leucovorin, the latter usually given 24 hours after sequential administration of methotrexate and fluorouracil may result in increased potency and toxicity.

Fluorouracil causes a change in the spectrophotometric spectrum of cytarabine, possibly reducing its effectiveness. Fluorouracil mixed with methotrexate alters the spectra of both agents. Fluorouracil is physically incompatible with doxorubicin, epirubicin and with diazepam; a precipitate forms when fluorouracil is mixed with these drugs. It is recommended that complete i.v. line flushing take place between injections of fluorouracil and cytarabine, methotrexate, doxorubicin, epirubicin or diazepam.

Adverse Reactions: Stomatitis and esophagopharyngitis (which may lead to sloughing and ulceration), diarrhea, anorexia and emesis are common.

Myelosuppression almost uniformly accompanies a course of adequate therapy with fluorouracil. Low WBC counts are usually first observed between the 9th and 14th day after the first course of treatment with the nadir occurring during the third week, although at times delayed for as long as 25 days. By the 30th day the count is usually within the normal range. Thrombocytopenia also may occur.

Alopecia and dermatitis are seen in a substantial number of cases and patients should be advised of this consequence of treatment. The alopecia is reversible. The dermatitis is often a pruritic maculopapular rash generally appearing on the extremities and less frequently on the trunk. It is usually reversible and responsive to symptomatic treatment. Palmar-plantar erythrodysesthesia has been reported in association with the continuous infusion of fluorouracil. Dry skin and fissuring have also been noted.

Photosensitivity, as manifested by erythema or increased skin pigmentation, may occasionally occur.

Also reported were photophobia, lacrimation, epistaxis, euphoria, acute cerebellar syndrome (which may persist following discontinuation of treatment), nail changes including banding or loss of nails and vein discoloration proximal to injection sites. Myocardial ischemia has also been reported.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Signs and symptoms of overdosage include stomatitis, diarrhea, fever, infection and petechiae with bleeding. No antidotes are available; management of overdosage consists of supportive therapy including fluid replacement, antibiotics and platelet transfusions. tag_DosageDosage

Dosage And Administration: The recommended route of administration is by i.v. injection, using care to avoid extravasation. No dilution of Adrucil is required. Although fluorouracil can be used orally, the product is not formulated for this clinical application.

It is recommended that all dosages be based on the patient’s actual weight. However, if the patient is obese or if there has been a spurious weight gain due to edema, ascites, or other forms of abnormal fluid retention, then the estimated lean body mass (dry weight) should be used.

Prior to treatment, it is recommended that each patient be carefully evaluated to accurately estimate the optimum initial fluorouracil dosage.

Initial Therapy: See Contraindications, Warnings and Precautions before prescribing. Patients should be hospitalized during the first course of therapy. Daily dosage generally should not exceed 800 mg. In good risk patients a dose of 12 mg/kg (500 mg/m is given daily for 5 days and repeated every 28 days. In poor risk patients a dose of 6 to 10 mg/kg (250 to 400 mg/m is given daily for 5 days and repeated every 28 days. When used in combination with other chemotherapeutic agents various schedules may be used including a single dose per course, a dose on day 1 and day 8 and daily for 4 or 5 days. The dose given varies, depending on the regimen used.

A sequence of 1 to 5 injections constitutes a “course of therapy”. Therapy should be discontinued promptly when any of the signs of toxicity listed under Precautions appear.

Maintenance Therapy: When toxicity has not been a problem, or after the toxic signs from the initial course of therapy have subsided, therapy should be continued using either of the following schedules:

A. Repeat dosage of the first course, beginning 28 days after the first day of the previous course of treatment.

B. Administer a maintenance dosage of 10 to 15 mg/kg/week. Reduced doses should be used for poor risk patients.

The dosage of drug to be used should take into account the patient’s reaction to the previous course of therapy and be adjusted accordingly. Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

Adrucil should not be mixed with i.v. additives or other chemotherapeutic agents.

Guidelines for Safe Handling and Disposal: Handling: Personnel involved in handling fluorouracil solutions or in the clean-up of spillage and disposal operations should wear protective clothing, gloves, and glasses. If the solution contacts the skin, the area should be washed with soap and water immediately. If the solution accidentally contacts the eyes, irrigate immediately with water or saline. Personnel regularly involved in the preparation and handling of antineoplastics should have blood examinations on a regular basis.

Disposal: All needles, syringes, vials and other materials which have come in contact with fluorouracil should be segregated in plastic bags, sealed and marked as hazardous waste. Incinerate at 1 000°C or higher. Sealed containers may explode if a tight seal exists. If incineration is not available, fluorouracil may be detoxified by adding sodium hypochlorite solution (household bleach). Dispose of detoxified fluorouracil solution in a safe manner. Nondisposable equipment should be rinsed in sodium hypochlorite solution and then washed in soap and water.

Spillage: Deactivate with sodium hypochlorite solution and rinse well with water.

Note: The use of pharmacy bulk vials is restricted to hospitals with a recognized i.v. admixture program. The pharmacy bulk vial is intended for single puncture, multiple dispensing and for i.v. use only.

Entry into the vial must be made with a suitable, sterile transfer or dispensing device. Multiple use of a syringe with needle is not recommended since it may cause leakage as well as it may increase the potential for microbial and particulate matter contamination.

In a suitable work area such as a laminar flow hood, swab the vial stopper with an antiseptic solution. Insert the device into the vial.

Withdraw contents of the vial into sterile syringes using strict aseptic techniques. Dispensing from the pharmacy bulk vial should be completed within 8 hours of the initial entry because of the potential for microbial contamination. Discard any unused portion. The contents of the syringes filled from the pharmacy bulk vial should be used within 24 hours at room temperature from the time of the initial entry into the pharmacy bulk vial.

Availability And Storage: Each mL of colorless to faint yellow aqueous solution, buffered with sodium hydroxide to pH 8.6 to 9.4, contains: fluorouracil 50 mg. Glass vials of 10 mL, cartons of 10. Pharmacy bulk vials of 50 mL, cartons of 1. Store at controlled temperature (15 to 30°C). Protect from freezing.

Note: Adrucil solution may turn a very pale yellowish color during storage. A highly colored solution is evidence of degradation and its use is not recommended. If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 60°C with vigorous shaking; allow to cool to body temperature before using.

ADRUCIL® Pharmacia & Upjohn Fluorouracil Antineoplastic

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