Goserelin acetate

Uses and Indications

This drug is indicated for use in combination with flutamide for the management of locally confined carcinoma of the prostate. It is also indicated for the palliative treatment of advanced carcinoma of the prostate.

In addition, this drug is indicated for the management of endometriosis and as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding. Furthermore, it is indicated for the palliative treatment of advanced breast cancer in pre- and perimenopausal women.

Limitations of Use

No teratogenic or nonteratogenic effects have been mentioned.

Dosage and Administration

Zoladex is available as a subcutaneous implant in two formulations: 3.6 mg and 10.8 mg.

For the 3.6 mg formulation, it is recommended that Zoladex be administered subcutaneously every 28 days. The duration of administration for the management of endometriosis is typically 6 months for women aged 18 years and older.

For the 10.8 mg formulation, Zoladex should be administered subcutaneously every 12 weeks. The injection site should be the anterior abdominal wall, specifically below the navel line.

Healthcare professionals should ensure proper administration techniques are followed to optimize therapeutic outcomes.

Contraindications

Use of Zoladex is contraindicated in patients with hypersensitivity to the active substance or any of its excipients. Additionally, it is contraindicated in pregnancy, except when used for the treatment of advanced breast cancer.

Warnings and Precautions

Women of childbearing potential must have pregnancy excluded prior to the use of Zoladex for benign gynecological conditions, and they should avoid pregnancy during treatment.

Serious Warnings

Tumor Flare Phenomenon: Transient worsening of tumor symptoms may occur during the first few weeks of treatment with Zoladex, potentially leading to ureteral obstruction and spinal cord compression. Patients at risk for complications of tumor flare should be closely monitored.

Hyperglycemia and Diabetes: There is a reported risk of hyperglycemia and an increased likelihood of developing diabetes in men receiving GnRH analogs. Blood glucose levels should be monitored and managed according to current clinical practice.

Cardiovascular Diseases: The use of GnRH analogs in men has been associated with an increased risk of myocardial infarction, sudden cardiac death, and stroke. Monitoring for cardiovascular disease is essential, and management should follow current clinical guidelines.

Hypercalcemia: Patients with bone metastases treated with Zoladex may experience hypercalcemia. Appropriate monitoring and management are required.

Hypersensitivity: Systemic hypersensitivity reactions have been reported in patients receiving goserelin/Zoladex implants.

Severe Cutaneous Adverse Reactions: Zoladex can lead to severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome and toxic epidermal necrolysis. Treatment should be interrupted if signs or symptoms of SCARs develop, and Zoladex should be permanently discontinued if SCARs are confirmed.

Cervical Resistance: An increase in cervical resistance may occur; caution is advised when dilating the cervix for endometrial ablation.

Effect on QT/QTc Interval: Androgen deprivation therapy may prolong the QT interval. The risks and benefits should be carefully considered.

Injection Site Injury: Injection site injury and vascular injury have been reported during the administration of Zoladex.

Depression: Depression may occur or worsen in women receiving GnRH agonists. Monitoring and appropriate management are recommended.

Monitoring Requirements

• Blood glucose levels should be monitored and managed according to current clinical practice.

• Patients should be monitored for cardiovascular disease and managed according to current clinical practice.

• Hypercalcemia should be monitored and managed appropriately.

Emergency Instructions

Patients should interrupt Zoladex if signs or symptoms of severe cutaneous adverse reactions develop and should permanently discontinue the treatment if SCARs are confirmed.

Side Effects

Patients receiving Zoladex (goserelin) implants may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

Common Adverse Reactions

• Women: Hot flushes, headache, sweating, acne, emotional lability, depression, decreased libido, vaginitis, breast atrophy, seborrhea, peripheral edema (reported in >20% of patients).

• Men: Hot flashes, sexual dysfunction, decreased erections, lower urinary tract symptoms (reported in >10% of patients).

Serious Adverse Reactions

• Tumor Flare Phenomenon: Transient worsening of tumor symptoms may occur during the first few weeks of treatment, potentially leading to ureteral obstruction and spinal cord compression. Patients at risk for complications of tumor flare should be closely monitored.

• Hypersensitivity: Systemic hypersensitivity reactions have been reported in patients receiving goserelin implants.

• Hyperglycemia and Diabetes: An increased risk of hyperglycemia and diabetes has been observed in men receiving GnRH analogs. Blood glucose levels should be monitored and managed according to current clinical practice.

• Cardiovascular Diseases: There is an increased risk of myocardial infarction, sudden cardiac death, and stroke associated with the use of GnRH analogs in men. Patients should be monitored for cardiovascular disease and managed accordingly.

• Severe Cutaneous Adverse Reactions: Zoladex can lead to severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome and toxic epidermal necrolysis. Treatment should be interrupted if signs or symptoms of SCARs develop, and Zoladex should be permanently discontinued if SCARs are confirmed.

• Effect on QT/QTc Interval: Androgen deprivation therapy may prolong the QT interval; the risks and benefits should be carefully considered.

• Injection Site Injury: Injection site injuries and vascular injuries have been reported during the administration of Zoladex.

Additional Considerations

• Cervical Resistance: An increase in cervical resistance may occur, necessitating caution during cervical dilation for endometrial ablation.

• Depression: Depression may occur or worsen in women receiving GnRH agonists; appropriate monitoring and management are recommended.

• Pregnancy: Zoladex may cause fetal harm when administered to a pregnant woman, as indicated by findings of increased pregnancy loss in animal studies. Patients should be informed of the potential risks to the fetus if the drug is used during pregnancy or if they become pregnant while on treatment.

Drug Interactions

Administration of Zoladex (implant) does not have specific drug interaction information provided. However, it is important to note that the use of Zoladex in therapeutic doses results in the suppression of the pituitary-gonadal system. This suppression may lead to misleading results in diagnostic tests assessing pituitary-gonadotropic and gonadal functions during treatment and until menses resume. Typically, normal function is expected to return within 12 weeks after discontinuation of the treatment.

Pediatric Use

Safety and effectiveness of Zoladex (implant) in pediatric patients have not been established.

Geriatric Use

Zoladex can be administered to geriatric patients without any dosage adjustments, including male patients. However, it is important to note that Zoladex has not been studied in women over the age of 65. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing this medication to elderly patients, particularly women in this age group. Regular monitoring may be warranted to ensure safety and efficacy in this population.

Pregnancy

Zoladex is contraindicated during pregnancy unless it is being used for palliative treatment of advanced breast cancer. There are no adequate and well-controlled studies in pregnant women using Zoladex. Based on its mechanism of action and findings from animal studies, Zoladex may cause fetal harm when administered to a pregnant patient. The expected hormone changes associated with Zoladex treatment increase the risk for pregnancy loss. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, the patient should be informed of the potential hazards to the fetus.

Zoladex crosses the placenta in animal models, specifically in rats and rabbits, following subcutaneous administration. Studies have shown that administration of goserelin to pregnant rats and rabbits during organogenesis resulted in increased preimplantation loss and higher rates of resorptions. Additionally, when pregnant rats received goserelin throughout gestation and lactation, there was a dose-related increase in umbilical hernia in offspring. Further reproduction studies in rats indicated a decrease in fetus and pup survival.

The actual doses associated with these adverse outcomes in animal studies were ≥ 2 mcg/kg/day for pregnancy loss and ≥ 10 mcg/kg/day for umbilical hernia in offspring in rats, while in rabbits, the threshold was > 20 mcg/kg/day. Given these findings, healthcare providers should exercise caution and consider the risks when prescribing Zoladex to pregnant patients.

Lactation

It is not known if goserelin, the active ingredient in Zoladex, is excreted in human milk. However, studies indicate that goserelin is excreted in the milk of lactating rats. Given that many medications can be present in human breast milk and the potential for serious adverse reactions in breastfed infants, healthcare providers should carefully consider the risks and benefits when advising lactating mothers. A decision should be made to either discontinue breastfeeding or discontinue the use of Zoladex, taking into account the importance of the medication to the mother’s health.

Renal Impairment

Patients with renal impairment have no specific dosage adjustments, monitoring requirements, or safety considerations outlined for the use of Zoladex (implant). The available data does not provide guidance on the management of patients with reduced kidney function, indicating that further clinical judgment may be necessary when considering treatment in this population.

Hepatic Impairment

Patients with hepatic impairment have no specific dosage adjustments, special monitoring requirements, or precautions outlined for the use of Zoladex (implant). The available data does not provide guidance on the management of this medication in individuals with liver problems. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing Zoladex to patients with hepatic impairment.

Overdosage

The pharmacologic properties of Zoladex and its mode of administration render accidental or intentional overdosage unlikely. Clinical trials have not reported any instances of overdosage, and animal studies have demonstrated that higher doses or more frequent administration do not result in increased pharmacologic effects. Specifically, subcutaneous doses as high as 1 mg/kg/day in rats and dogs did not lead to any nonendocrine related sequelae, a dose that is up to 250 times the estimated human daily dose based on body surface area.

In the event of overdosage, management should be symptomatic. Monitoring for any potential adverse effects is recommended, although the likelihood of significant complications appears minimal based on available data.

Nonclinical Toxicology

Teratogenic Effects

No teratogenic effects were observed in the studies conducted with goserelin.

Non-Teratogenic Effects

Administration of goserelin resulted in changes consistent with gonadal suppression in both male and female rats due to its endocrine action. In male rats receiving doses of 500-1000 mcg/kg/day, a decrease in weight and atrophic histological changes were noted in the testes, epididymis, seminal vesicle, and prostate gland, leading to complete suppression of spermatogenesis. In female rats administered 50-1000 mcg/kg/day, ovarian function was suppressed, resulting in 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.

Histological examination indicated that, except for the testes, almost complete reversal of these effects occurred several weeks after discontinuation of dosing. However, fertility and general reproductive performance were diminished in those that became pregnant following the cessation of goserelin treatment. Fertile matings were observed within 2 weeks after stopping the drug, although total recovery of reproductive function may not have been achieved prior to mating; consequently, the ovulation rate, implantation rate, and number of live fetuses were reduced.

Carcinogenesis

Subcutaneous implantation of goserelin in male and female rats once every 4 weeks for 1 year, followed by a recovery period of 23 weeks at doses of approximately 80 and 150 mcg/kg (males) and 50 and 100 mcg/kg (females), resulted in an increased incidence of pituitary adenomas. A similar increased incidence of pituitary adenomas was observed in rats receiving subcutaneous implants at comparable dose levels for 72 weeks in males and 101 weeks in females. The relevance of these findings to humans has not been established.

Additionally, subcutaneous implants of goserelin administered every 3 weeks for 2 years to mice at doses up to 2400 mcg/kg/day led to an increased incidence of histiocytic sarcoma of the vertebral column and femur. Human dose/exposure multiples could not be calculated from the available animal data.

Mutagenesis

Mutagenicity tests conducted using bacterial and mammalian systems for point mutations and cytogenetic effects have provided no evidence of mutagenic potential associated with goserelin.

Impairment of Fertility

Based on histological examination, the effects of goserelin on reproductive organs were reversible in male and female dogs administered doses of 107-214 mcg/kg/day when treatment was stopped after continuous administration for 1 year.

Storage and Handling

The product is supplied as an implant in a sealed, light- and moisture-proof aluminum foil laminate pouch, which includes a desiccant capsule to maintain sterility.

It is essential to store the product at room temperature, ensuring that the temperature does not exceed 25°C (77°F). Proper storage conditions are crucial to maintain the integrity and effectiveness of the implant.