Before starting treatment with ZOLADEX, pregnancy must be excluded. Safe use of ZOLADEX in pregnancy has not been established. ZOLADEX can cause fetal harm when administered to a pregnant woman. ZOLADEX has been found to cross the placenta following subcutaneous administration of 50 and 1000 µg/kg in rats and rabbits, respectively. Studies in both rats and rabbits at doses equal to or greater than 2 and 20 µg/kg/day, respectively (about 1/10 and 2 times the daily maximum recommended human dose, respectively, on a mg/m² basis), administered during the period of organogenesis, have confirmed that ZOLADEX will increase pregnancy loss, and is embryotoxic/fetotoxic (characterized by increased preimplantation loss, increased resorption and an increase in umbilical hernia in rats at a dose of ³ 10 µg/kg/day [about 1/2 the recommended human dose on a mg/m² basis]); effects were dose-related. In additional reproduction studies in rats, ZOLADEX was found to decrease fetus and pup survival.

There are no adequate and well-controlled studies in pregnant women using ZOLADEX. Women of childbearing potential should be advised to avoid becoming pregnant.

When used every 28 days, ZOLADEX usually inhibits ovulation and stops menstruation. Contraception is not ensured, however, by taking ZOLADEX. During treatment, pregnancy must be avoided by the use of nonhormonal methods of contraception. If ZOLADEX is used during pregnancy in a patient with advanced breast cancer or the patient becomes pregnant while receiving this drug, the patient must be apprised of the potential risk for loss of the pregnancy due to possible hormonal imbalance as a result of the expected pharmacological action of ZOLADEX treatment.

Following the last ZOLADEX injection, nonhormonal methods of contraception must be continued until the return of menses or for at least 12 weeks. (See CONTRAINDICATIONS.)

Prostate and Breast Cancer: Initially, ZOLADEX, like other LHRH agonists, causes transient increases in serum levels of testosterone in men with prostate cancer, and estrogen in women with breast cancer. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate or breast cancer, may occasionally develop during the first few weeks of ZOLADEX treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other LHRH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed in patients with prostate cancer. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted. For extreme cases in prostate cancer patients, an immediate orchiectomy should be considered.

As with other LHRH agonists or hormonal therapies (antiestrogens, estrogens, etc.), hypercalcemia has been reported in some prostate and breast cancer patients with bone metastases after starting treatment with ZOLADEX. If hypercalcemia does occur, appropriate treatment measures should be initiated.

General

Hypersensitivity, antibody formation and acute anaphylactic reactions have been reported with LHRH agonist analogues.

Of 115 women worldwide treated with ZOLADEX and tested for development of binding to goserelin following treatment with ZOLADEX, one patient showed low-titer binding to goserelin. On further testing of this patient's plasma obtained following treatment, her goserelin binding component was found not to be precipitated with rabbit antihuman immunoglobulin polyvalent sera. These findings suggest the possibility of antibody formation.

The pharmacologic action of ZOLADEX on the uterus and cervix may cause an increase in cervical resistance. Therefore, care should be taken when dilating the cervix for endometrial ablation.

Information for Patients

Males: The use of ZOLADEX in patients at particular risk of developing ureteral obstruction or spinal cord compression should be considered carefully and the patients monitored closely during the first month of therapy. Patients with ureteral obstruction or spinal cord compression should have appropriate treatment prior to initiation of ZOLADEX therapy.

Females: Patients must be made aware of the following information:

1. Since menstruation should stop with effective doses of ZOLADEX the patient should notify her physician if regular menstruation persists. Patients missing one or more successive doses of ZOLADEX may experience breakthrough menstrual bleeding.
2. ZOLADEX should not be prescribed if the patient is pregnant, breast feeding, lactating, has nondiagnosed abnormal vaginal bleeding, or is allergic to any of the components of ZOLADEX.
3. Use of ZOLADEX in pregnancy is contraindicated in women being treated for endometriosis or endometrial thinning. Therefore, a nonhormonal method of contraception should be used during treatment. Patients should be advised that if they miss one or more successive doses of ZOLADEX, breakthrough menstrual bleeding or ovulation may occur with the potential for conception. If a patient becomes pregnant during treatment for endometriosis or endometrial thinning, ZOLADEX treatment should be discontinued and the patient should be advised of the possible risks to the pregnancy and fetus. (See CONTRAINDICATIONS.)
   For patients being treated for advanced breast cancer, see

   WARNINGS

   .
4. Those adverse events occurring most frequently in clinical studies with ZOLADEX are associated with hypoestrogenism; of these the most frequently reported are hot flashes (flushes), headaches, vaginal dryness, emotional lability, change in libido, depression, sweating and change in breast size. Clinical studies in endometriosis suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to ZOLADEX may decrease the occurrence of vasomotor symptoms and vaginal dryness associated with hypoestrogenism without compromising the efficacy of ZOLADEX in relieving symptoms. The optimal drugs, dose and duration of treatment has not been established.
5. As with other LHRH agonist analogues, treatment with ZOLADEX induces a hypoestrogenic state which results in a loss of bone mineral density (BMD) over the course of treatment, some of which may not be reversible. In patients with a history of prior treatment that may have resulted in bone mineral density loss and/or in patients with major risk factors for decreased bone mineral density such as chronic alcohol abuse and/or tobacco abuse, significant family history of osteoporosis, or chronic use of drugs that can reduce bone density such as anticonvulsants or corticosteroids, ZOLADEX therapy may pose an additional risk. In these patients the risks and benefits must be weighed carefully before therapy with ZOLADEX is instituted. Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to ZOLADEX is effective in reducing the bone mineral loss which occurs with ZOLADEX alone. The optimal drugs, dose and duration of treatment has not been established.
6. Currently, there are no clinical data on the effects of retreatment or treatment of benign gynecological conditions with ZOLADEX for periods in excess of 6 months.
7. As with other hormonal interventions that disrupt the pituitary-gonadal axis, some patients may have delayed return to menses. The rare patient, however, may experience persistent amenorrhea.

Drug Interactions

No formal drug-drug interaction studies have been performed. No confirmed interactions have been reported between ZOLADEX and other drugs.

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 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 or endometrial thinning. See CONTRAINDICATIONS and

WARNINGS

Nursing Mothers

ZOLADEX has been shown to be excreted in the milk of lactating rats. It is not known if this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from ZOLADEX in nursing infants, mothers should discontinue nursing prior to taking the drug.

Pediatric Use

The safety and efficacy of ZOLADEX in pediatric patients have not been established.

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