Zoladex

Description

ZOLADEX (goserelin implant) is a GnRH agonist. Goserelin acetate is chemically described as an acetate salt of D-Ser(Bu t)6,Azgly10. Its chemical structure is pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 acetate C59H84N18O14·(C2H4O2)x where x = 1 to 2.4. Goserelin acetate appears as an off-white powder with a molecular weight of 1269 Daltons (free base). It is freely soluble in glacial acetic acid and soluble in water, 0.1M hydrochloric acid, 0.1M sodium hydroxide, dimethylformamide, and dimethyl sulfoxide, while being practically insoluble in acetone, chloroform, and ether.

ZOLADEX is supplied as a sterile, biodegradable product containing 3.8 mg goserelin acetate, equivalent to 3.6 mg of goserelin. It is designed for subcutaneous injection with continuous release over a 28-day period. Goserelin acetate, which may contain up to 12% goserelin-related substances, is dispersed in a matrix of D,L-lactic and glycolic acids copolymer. The total implant weight is 18.0 mg, containing less than 2.5% total acetic acid. ZOLADEX is presented as a sterile, white to cream colored 1-mm diameter cylinder, preloaded in a special single-use syringe with a 16-gauge x 36 +/- 0.5 mm siliconized needle.

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 and for the management of endometriosis. Additionally, this drug serves 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.

There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

ZOLADEX 3.6 mg is to be administered subcutaneously every 28 days. For the management of endometriosis, the recommended duration of administration is 6 months for women aged 18 years and older.

Healthcare professionals should ensure that the injection site is clean and that the medication is administered using proper aseptic techniques. It is important to monitor the patient’s response to therapy and adjust the treatment plan as necessary based on clinical evaluation.

Contraindications

Use of this product is contraindicated in patients with hypersensitivity to any of its components. Additionally, it is contraindicated in pregnancy, except when utilized for the treatment of advanced breast cancer, due to potential risks to the fetus.

Warnings and Precautions

Women of childbearing potential must have pregnancy excluded prior to the use of ZOLADEX for benign gynecological conditions. It is imperative that these women avoid becoming pregnant during treatment.

The tumor flare phenomenon may occur during the initial weeks of ZOLADEX treatment, leading to a transient worsening of tumor symptoms, which can include ureteral obstruction and spinal cord compression. Patients at risk for complications from tumor flare should be closely monitored.

In men receiving GnRH analogs, hyperglycemia and an increased risk of developing diabetes have been reported. Therefore, it is essential to monitor blood glucose levels and manage them according to current clinical practice guidelines.

There is an increased risk of myocardial infarction, sudden cardiac death, and stroke associated with the use of GnRH analogs in men. Regular monitoring for cardiovascular disease is recommended, with management in accordance with current clinical practice.

Patients with bone metastases treated with ZOLADEX may experience hypercalcemia. Monitoring and appropriate management of hypercalcemia are necessary.

Systemic hypersensitivity reactions have been reported in patients receiving goserelin/ZOLADEX implants. Additionally, ZOLADEX can lead to severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome and toxic epidermal necrolysis. If signs or symptoms of SCARs develop, ZOLADEX should be interrupted, and it must be permanently discontinued if SCARs are confirmed.

Caution is advised when dilating the cervix for endometrial ablation, as an increase in cervical resistance may occur. Furthermore, androgen deprivation therapy has the potential to prolong the QT interval; thus, the risks and benefits should be carefully considered.

Injection site injuries and vascular injuries have been reported during the administration of ZOLADEX. Healthcare professionals should be vigilant in monitoring for these complications.

Depression may occur or worsen in women receiving GnRH agonists, necessitating appropriate monitoring and management.

Healthcare providers are encouraged to implement the recommended laboratory tests, including monitoring blood glucose levels, cardiovascular health, and hypercalcemia, to ensure patient safety during treatment with ZOLADEX.

Side Effects

Patients receiving treatment with ZOLADEX may experience a range of adverse reactions, which can be categorized into common and serious reactions.

Common adverse reactions reported in clinical trials include hot flashes, sexual dysfunction, and lower urinary tract symptoms in men, with an incidence greater than 10%. In women, common reactions include hot flushes, headache, sweating, acne, emotional lability, depression, decreased libido, vaginitis, breast atrophy, seborrhea, and peripheral edema, with an incidence exceeding 20%.

Serious adverse reactions include the tumor flare phenomenon, which may manifest as a transient worsening of tumor symptoms during the initial weeks of treatment. This can include complications such as ureteral obstruction and spinal cord compression.

Additional adverse reactions of clinical significance include hyperglycemia and an increased risk of developing diabetes, particularly in men receiving GnRH analogs. There is also an increased risk of cardiovascular diseases, including myocardial infarction, sudden cardiac death, and stroke associated with the use of GnRH analogs in men. Hypercalcemia has been observed in patients with bone metastases treated with ZOLADEX.

Systemic hypersensitivity reactions have been reported in patients receiving goserelin/ZOLADEX implants. Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome and toxic epidermal necrolysis, may occur; ZOLADEX should be interrupted if signs or symptoms of SCARs develop, and permanently discontinued if SCARs are confirmed.

Patients may also experience an increase in cervical resistance, necessitating caution during cervical dilation for endometrial ablation. Additionally, androgen deprivation therapy may prolong the QT interval, warranting careful consideration of the associated risks and benefits. Injection site injuries and vascular injuries have been reported during the administration of ZOLADEX.

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

Drug Interactions

Administration of ZOLADEX may interfere with the results of diagnostic tests assessing pituitary-gonadotropic and gonadal functions. This interference can persist during treatment and until the resumption of menses. It is important to note that normal physiological function generally returns within approximately 12 weeks following the discontinuation of ZOLADEX.

Healthcare professionals should consider this potential for misleading test results when interpreting diagnostic assessments during and shortly after treatment with ZOLADEX. No specific dosage adjustments or additional monitoring parameters are indicated based on the available data.

Packaging & NDC

The table below lists all NDC Code configurations of Zoladex (goserelin), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution, and healthcare professionals are advised to consider the lack of data when prescribing to this population.

Geriatric Use

Elderly patients do not require any dosage adjustment when receiving ZOLADEX. However, it is important to note that ZOLADEX has not been studied in women over the age of 65 years. Therefore, healthcare providers should exercise caution when considering the use of ZOLADEX in this population, as the safety and efficacy in elderly female patients remain undetermined. Regular monitoring and assessment of treatment response and tolerability are recommended for geriatric patients receiving this medication.

Pregnancy

ZOLADEX is contraindicated during pregnancy unless it is being used for the 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 has the potential to cause fetal harm when administered to a pregnant woman. If ZOLADEX is used during pregnancy, the patient should be informed of the potential risks to the fetus.

Clinical data indicate an increased risk for pregnancy loss associated with the hormonal changes expected from ZOLADEX treatment. Animal studies have demonstrated that ZOLADEX crosses the placenta in rats and rabbits following subcutaneous administration. Administration of goserelin to pregnant rats and rabbits during organogenesis resulted in increased preimplantation loss and higher rates of resorption. Furthermore, when pregnant rats received goserelin throughout gestation and lactation, there was a dose-related increase in the incidence of umbilical hernia in the offspring. Additional reproduction studies in rats revealed that goserelin decreased both fetus and pup survival.

The actual doses in animal studies that resulted in adverse outcomes were ≥ 2 mcg/kg/day for pregnancy loss and > 10 mcg/kg/day for umbilical hernia in offspring in rats, and > 20 mcg/kg/day in rabbits. Given these findings, healthcare professionals should exercise caution when considering the use of ZOLADEX in women of childbearing potential and ensure appropriate counseling regarding the risks associated with its use during pregnancy.

Lactation

It is not known if goserelin is excreted in human milk. However, goserelin has been shown to be excreted in the milk of lactating rats. Given that many drugs can be excreted in human milk and considering the potential for serious adverse reactions in breastfed infants from ZOLADEX, lactating mothers should make a decision to either discontinue nursing or discontinue the drug. This decision should take into account the importance of the drug to the mother.

Renal Impairment

There is no specific information regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

The pharmacologic properties of ZOLADEX, along with its mode of administration, render both accidental and intentional overdosage unlikely. Clinical trials have not reported any instances of overdosage, indicating a robust safety profile in this regard.

Animal studies have demonstrated that administering subcutaneous doses as high as 1 mg/kg/day in rats and dogs did not result in any nonendocrine related sequelae. This dosage is significantly higher—up to 250 times the estimated human daily dose based on body surface area—yet no increased pharmacologic effect was observed with higher doses or more frequent administration.

In the rare event that overdosage occurs, it should be managed symptomatically. Healthcare professionals are advised to monitor the patient closely and provide supportive care as needed.

Nonclinical Toxicology

No teratogenic effects were observed in nonclinical studies. However, non-teratogenic effects were noted following administration of goserelin, which 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, there was a decrease in weight and atrophic histological changes in the testes, epididymis, seminal vesicle, and prostate gland, accompanied by complete suppression of spermatogenesis. Female rats administered 50-1000 mcg/kg/day exhibited suppression of ovarian function, leading to decreased size and weight of ovaries and secondary sex organs. Follicular development was arrested at the antral stage, and the size and number of corpora lutea were reduced.

Following cessation of goserelin treatment, almost complete histological reversal of these effects was observed in males and females several weeks later. However, fertility and general reproductive performance were diminished in those that became pregnant after discontinuation of goserelin. Fertile matings occurred within two weeks post-treatment, although total recovery of reproductive function may not have been achieved prior to mating. The ovulation rate, implantation rate, and number of live fetuses were reduced. Histological examinations indicated that the drug effects on reproductive organs were reversible in male and female dogs administered 107-214 mcg/kg/day of goserelin after continuous treatment for one year.

Subcutaneous implantation of goserelin in male and female rats every four weeks for one 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 following subcutaneous implantation of goserelin in rats at comparable dose levels for 72 weeks in males and 101 weeks in females. The relevance of these findings in rats to humans has not been established.

Additionally, subcutaneous implants of goserelin administered every three weeks for two years to mice at doses up to 2400 mcg/kg/day resulted in 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. Mutagenicity tests conducted using bacterial and mammalian systems for point mutations and cytogenetic effects did not provide evidence of mutagenic potential.

Postmarketing Experience

Following the administration of ZOLADEX, injection site injury has been reported. Patients are advised to seek immediate medical attention if they experience any of the following symptoms: abdominal pain, abdominal distension, dyspnea, dizziness, hypotension, or any altered levels of consciousness.

Patient Counseling

Patients should be informed about the potential for severe cutaneous adverse reactions (SCARs) associated with ZOLADEX, which may include life-threatening conditions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). It is crucial for patients to contact their healthcare provider or seek immediate medical attention if they experience any signs or symptoms indicative of SCARs, such as a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy.

Patients should also be made aware that the use of GnRH agonists, including ZOLADEX, has been associated with diabetes or loss of glycemic control in individuals with pre-existing diabetes. Therefore, healthcare providers should consider periodic monitoring of blood glucose and/or glycosylated hemoglobin (HbA1c) in patients receiving ZOLADEX.

There is a reported small increased risk of myocardial infarction, sudden cardiac death, and stroke in men using GnRH agonists. Patients receiving ZOLADEX should be monitored for any symptoms or signs suggestive of cardiovascular disease and managed according to current clinical guidelines.

Injection site injuries have been noted following ZOLADEX administration. Patients should be advised to contact their healthcare provider immediately if they experience symptoms such as abdominal pain, abdominal distension, dyspnea, dizziness, hypotension, or any altered levels of consciousness.

For women, menstruation is expected to cease with effective doses of ZOLADEX. Patients should notify their physician if regular menstruation continues. Additionally, missing one or more successive doses of ZOLADEX may lead to breakthrough menstrual bleeding.

ZOLADEX is contraindicated in pregnant or breastfeeding women, except for the palliative treatment of advanced breast cancer, due to the potential harm to the fetus and increased risk of pregnancy loss. Women should not initiate ZOLADEX treatment if they have undiagnosed abnormal vaginal bleeding or a known allergy to any components of ZOLADEX.

Premenopausal women using ZOLADEX must utilize nonhormonal contraception during treatment and for 12 weeks following the conclusion of treatment. If a patient becomes pregnant while using ZOLADEX for endometriosis or endometrial thinning, treatment should be discontinued, and the patient should be informed of the potential risks to the pregnancy and fetus, including an increased risk of pregnancy loss.

Patients should also be made aware that depression may occur or worsen during treatment with GnRH agonists, including ZOLADEX, particularly in those with a history of depression. It is important for patients to report any concerning thoughts or behaviors to their healthcare providers promptly.

Storage and Handling

The product is supplied in a sealed, light- and moisture-proof aluminum foil laminate pouch, which contains 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 handling and storage conditions are crucial to preserve the integrity and effectiveness of the product.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Zoladex as submitted by TerSera Therapeutics LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)