Adrucil (Fluorouracil) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of fluorouracil have not been conducted. However, there was no evidence of carcinogenicity in small groups of rats given fluorouracil orally at doses of 0.01, 0.3, 1 or 3 mg per rat 5 days per week for 52 weeks, followed by a six-month observation period. Also, in other studies, 33 mg/kg of fluorouracil was administered intravenously to male rats once a week for 52 weeks followed by observation for the remainder of their lifetimes with no evidence of carcinogenicity. Female mice were given 1 mg of fluorouracil intravenously once a week for 16 weeks with no effect on the incidence of lung adenomas. On the basis of the available data, no evaluation can be made of the carcinogenic risk of fluorouracil to humans.

Mutagenesis

Oncogenic transformation of fibroblasts from mouse embryo has been induced in vitro by fluorouracil, but the relationship between oncogenicity and mutagenicity is not clear. Fluorouracil has been shown to be mutagenic to several strains of Salmonella typhimurium, including TA 1535, TA 1537 and TA 1538, and to Saccharomyces cerevisiae, although no evidence of mutagenicity was found with Salmonella typhimurium strains TA 92, TA 98 and TA 100. In addition, a positive effect was observed in the micronucleus test on bone marrow cells of the mouse, and fluorouracil at very high concentrations produced chromosomal breaks in hamster fibroblasts in vitro.

Impairment of Fertility

Fluorouracil has not been adequately studied in animals to permit an evaluation of its effects on fertility and general reproductive performance. However, doses of 125 or 250 mg/kg, administered intraperitoneally, have been shown to induce chromosomal aberrations and changes in chromosomal organization of spermatogonia in rats. Spermatogonial differentiation was also inhibited by fluorouracil, resulting in transient infertility. However, in studies with a strain of mouse which is sensitive to the induction of sperm head abnormalities after exposure to a range of chemical mutagens and carcinogens, fluorouracil did not produce any abnormalities at oral doses of up to 80 mg/kg/day. In female rats, fluorouracil, administered intraperitoneally at weekly doses of 25 or 50 mg/kg for 3 weeks during the pre-ovulatory phases of oogenesis, significantly reduced the incidence of fertile matings, delayed the development of pre- and post-implantation embryos, increased the incidence of pre-implantation lethality and induced chromosomal anomalies in these embryos. In a limited study in rabbits, a single 25 mg/kg dose of fluorouracil or 5 daily doses of 5 mg/kg had no effect on ovulation, appeared not to affect implantation and had only a limited effect in producing zygote destruction. Compounds such as fluorouracil, which interfere with DNA, RNA and protein synthesis, might be expected to have adverse effects on gametogenesis.

OVERDOSAGE

The possibility of overdosage with fluorouracil is unlikely in view of the mode of administration. Nevertheless, the anticipated manifestations would be nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, bone marrow depression (including thrombocytopenia, leukopenia and agranulocytosis). No specific antidotal therapy exists. Patients who have been exposed to an overdose of fluorouracil should be monitored hematologically for at least four weeks. Should abnormalities appear, appropriate therapy should be utilized.

The acute intravenous toxicity of fluorouracil is as follows:

Species	LD50 (mg/kg ±S.E.)
Mouse	340	± 17
Rat	165	± 26
Rabbit	27	± 5.1
Dog	31.5	± 3.8

CONTRAINDICATIONS

ADRUCIL Injection therapy is contraindicated for patients in a poor nutritional state, those with depressed bone marrow function, those with potentially serious infections or those with a known hypersensitivity to ADRUCIL.

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Washington, DC, U.S. Government Printing Office (NIH Publication No. 83-2621).
2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA Mar 15, 1985; 253:1590—1592.
3. National Study Commission on Cytotoxic Exposure: Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Director of Pharmacy Services, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02902.
4. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Aust. Apr 30, 1983; 1:426—428.
5. Jones RB, Frank R, Mass T: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA. Sept–Oct 1983; 33:258—263.
6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic Drugs in Hospitals. Am J Hosp Pharm. Jan 1985; 42:131—137.
7. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. Am J Hosp Pharm. 1986; 43:1193—1204.

Manufactured By:
Teva Parenteral Medicines, Inc.
Irvine, CA 92618
Issued: July 2007