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Zoladex (Goserelin Acetate) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

Drug/Laboratory Test Interactions:

Administration of ZOLADEX in therapeutic doses results in suppression of the pituitary-gonadal system. Because of this suppression, diagnostic tests of pituitary-gonadotropic and gonadal functions conducted during treatment and until the resumption of menses may show results which are misleading. Normal function is usually restored within 12 weeks after treatment is discontinued.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Subcutaneous implant of ZOLADEX in male and female rats once every 4 weeks for 1 year and recovery for 23 weeks at doses of about 80 and 150 μg/kg (males) and 50 and 100 μg/kg (females) daily (about 3 to 9 times the recommended human dose on a mg/m2 basis) resulted in an increased incidence of pituitary adenomas. An increased incidence of pituitary adenomas was also observed following subcutaneous implant of ZOLADEX in rats at similar dose levels for a period of 72 weeks in males and 101 weeks in females. The relevance of the rat pituitary adenomas to humans has not been established. Subcutaneous implants of ZOLADEX every 3 weeks for 2 years delivered to mice at doses of up to 2400 μg/kg/day (about 70 times the recommended human dose on a mg/m2 basis) resulted in an increased incidence of histiocytic sarcoma of the vertebral column and femur.

Mutagenicity tests using bacterial and mammalian systems for point mutations and cytogenetic effects have provided no evidence for mutagenic potential.

Administration of goserelin led to changes that were consistent with gonadal suppression in both male and female rats as a result of its endocrine action. In male rats administered 500-1000 μg/kg/day (about 30-60 times the recommended human dose on a mg/m2 basis), a decrease in weight and atrophic histological changes were observed in the testes, epididymis, seminal vesicle and prostate gland with complete suppression of spermatogenesis. In female rats administered 50-1000 μg/kg/day (about 3-60 times the recommended daily human dose on a mg/m2 basis), suppression of ovarian function led to decreased size and weight of ovaries and secondary sex organs; follicular development was arrested at the antral stage and the corpora lutea were reduced in size and number. Except for the testes, almost complete histologic reversal of these effects in males and females was observed several weeks after dosing was stopped; however, fertility and general reproductive performance were reduced in those that became pregnant after goserelin was discontinued. Fertile matings occurred within 2 weeks after cessation of dosing, even though total recovery of reproductive function may not have occurred before mating took place; and, the ovulation rate, the corresponding implantation rate, and number of live fetuses were reduced.

Based on histological examination, drug effects on reproductive organs were reversible in male and female dogs administered 107-214 μg/kg/day ZOLADEX (about 20-40 times the recommended daily human dose on a mg/m2 basis) when drug treatment was stopped after continuous administration for 1 year.

Pregnancy:

Pregnancy Category X:

For treatment of endometriosis and endometrial thinning. See CONTRAINDICATIONS and WARNINGS sections. Pregnancy Category D for treatment of advanced breast cancer in pre- and perimenopausal women. See WARNINGS section.

OVERDOSAGE

The pharmacologic properties of ZOLADEX and its mode of administration make accidental or intentional overdosage unlikely. There is no experience of overdosage from clinical trials. Animal studies indicate that no increased pharmacologic effect occurred at higher doses or more frequent administration. Subcutaneous doses of the drug as high as 1 mg/kg/day in rats and dogs did not produce any nonendocrine related sequelae; this dose is greater than 400 times that proposed for human use. If overdosage occurs, it should be managed symptomatically.

CONTRAINDICATIONS

A report of an anaphylactic reaction to synthetic GnRH (Factrel) has been reported in the medical literature. ZOLADEX is contraindicated in those patients who have a known hypersensitivity to LHRH, LHRH agonist analogues or any of the components in ZOLADEX.

ZOLADEX is contraindicated in women being treated for endometriosis or endometrial thinning who are or may become pregnant while receiving the drug. ZOLADEX can cause fetal harm when administered to a pregnant woman. Effects on reproductive function, as a result of antigonadotrophic properties of the drug, are expected to occur on chronic administration.

Effective nonhormonal contraception must be used by all premenopausal women during ZOLADEX therapy and for 12 weeks following discontinuation of therapy. There are no adequate and well-controlled studies in pregnant women using ZOLADEX. If this drug is used during pregnancy, or the patient being treated for endometriosis or endometrial thinning becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant.

For a description of findings in animal reproductive toxicity studies, see WARNINGS.

ZOLADEX is contraindicated in women who are breast feeding (see Nursing Mothers section).

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