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 10.8 mg implant contains 11.3 mg goserelin acetate, which is equivalent to 10.8 mg of goserelin. The formulation is designed for subcutaneous implantation with continuous release over a 12-week period. Goserelin acetate is dispersed in a matrix of D,L-lactic and glycolic acids copolymer, with a total implant weight of 36.0 mg, containing less than 2% total acetic acid. The implant is presented as a sterile, white to cream colored 1.5 mm diameter cylinder, preloaded in a special single-use syringe with a 14-gauge x 36 +/- 0.5 mm siliconized needle. ZOLADEX is also available as a sterile, biodegradable product containing goserelin acetate equivalent to 3.6 mg of goserelin, designed for administration every 28 days.

Uses and Indications

ZOLADEX is indicated for use in combination with flutamide for the management of locally confined carcinoma of the prostate. Additionally, ZOLADEX is indicated for use as a palliative treatment of advanced carcinoma of the prostate.

There are no teratogenic or nonteratogenic effects associated with ZOLADEX.

Dosage and Administration

ZOLADEX is to be administered subcutaneously at a dose of 10.8 mg every 12 weeks. The injection should be given into the anterior abdominal wall, specifically below the navel line.

Healthcare professionals should ensure that the injection site is clean and free from any infection prior to administration. Proper aseptic technique should be employed to minimize the risk of contamination.

Contraindications

Use of this product is contraindicated in patients with hypersensitivity to any of its components. Additionally, it is contraindicated during pregnancy due to potential risks to the developing fetus.

Warnings and Precautions

Transient worsening of tumor symptoms, known as the tumor flare phenomenon, may occur during the initial weeks of treatment with ZOLADEX. This phenomenon can manifest as ureteral obstruction and spinal cord compression. It is essential to monitor patients who are at risk for complications associated with tumor flare to ensure timely intervention.

Systemic hypersensitivity reactions have been documented in patients receiving goserelin implants. Healthcare professionals should remain vigilant for signs of hypersensitivity and be prepared to manage such reactions appropriately.

Patients receiving GnRH analogs, including ZOLADEX, may experience hyperglycemia and an increased risk of developing diabetes. Regular monitoring of blood glucose levels is recommended, and management should align with current clinical practice guidelines to mitigate these risks.

There is an observed increased risk of cardiovascular events, including myocardial infarction, sudden cardiac death, and stroke, in men treated with GnRH analogs. It is crucial to monitor patients for cardiovascular disease and manage any identified risks according to established clinical practices.

ZOLADEX has the potential to cause severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If any signs or symptoms indicative of SCARs develop, ZOLADEX should be interrupted. Should SCARs be confirmed, permanent discontinuation of ZOLADEX is warranted.

Androgen deprivation therapy may lead to prolongation of the QT interval. Healthcare providers should carefully consider the associated risks and benefits when prescribing this treatment.

Injection site injuries and vascular injuries have been reported during the administration of ZOLADEX. Proper technique and monitoring during and after injection are advised to minimize the risk of such complications.

Side Effects

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

Common adverse reactions reported include hot flashes, sexual dysfunction, decreased erections, and lower urinary tract symptoms. These effects are frequently observed among participants in clinical trials and may impact the quality of life for those undergoing treatment.

Serious adverse reactions associated with ZOLADEX warrant careful monitoring and management. The tumor flare phenomenon may occur, characterized by a transient worsening of tumor symptoms during the initial weeks of treatment. This can include complications such as ureteral obstruction and spinal cord compression, particularly in patients at risk.

Systemic hypersensitivity reactions have been documented in patients receiving goserelin implants, necessitating vigilance for signs of hypersensitivity. Additionally, hyperglycemia and an increased risk of developing diabetes have been reported in men treated with GnRH analogs, highlighting the importance of monitoring blood glucose levels and managing them according to established clinical guidelines.

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. Patients should be monitored for cardiovascular health and managed accordingly.

Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur with ZOLADEX. If signs or symptoms of SCARs develop, treatment should be interrupted, and ZOLADEX should be permanently discontinued if SCARs are confirmed.

Furthermore, androgen deprivation therapy with ZOLADEX may prolong the QT interval, necessitating consideration of the associated risks and benefits. Injection site injuries and vascular injuries have also been reported during administration of the drug.

It is important to note that 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 in therapeutic doses leads to suppression of the pituitary-gonadal system. This suppression may result in misleading results in diagnostic tests assessing pituitary-gonadotropic and gonadal functions during the course of treatment.

Healthcare professionals should be aware of this potential effect when interpreting diagnostic tests and consider the timing of such tests in relation to ZOLADEX administration. No specific dosage adjustments or additional monitoring recommendations are provided; however, clinicians should exercise caution and evaluate the clinical context when interpreting test results during treatment with ZOLADEX.

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 until further data is available.

Geriatric Use

Elderly patients do not require any dosage adjustment when administered ZOLADEX 10.8 mg. However, it is important for healthcare providers to consider the overall health status and comorbidities of geriatric patients, as these factors may influence treatment outcomes and safety. Regular monitoring for potential adverse effects is recommended to ensure the well-being of this population.

Pregnancy

Based on the mechanism of action in humans and findings from animal studies, ZOLADEX may cause fetal harm when administered to pregnant patients. The expected hormonal changes associated with ZOLADEX treatment increase the risk of pregnancy loss. If ZOLADEX is used during pregnancy, or if a patient becomes pregnant while taking this medication, the patient should be informed of the potential risks to the fetus see Contraindications (4.2).

ZOLADEX has been shown to cross the placenta in animal studies involving rats and rabbits following subcutaneous administration. In these studies, 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 reproductive studies in rats indicated that goserelin decreased both fetus and pup survival. It is important to note that human dose/exposure multiples could not be calculated from the available animal data. Actual doses in animal studies 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.

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. Due to 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, considering the importance of the drug to the mother.

Renal Impairment

There is no specific information available 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 these patients to ensure safety and efficacy.

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 favorable safety profile in this regard.

Animal studies have demonstrated that higher doses or more frequent administration of ZOLADEX do not result in an increased pharmacologic effect. Specifically, subcutaneous doses as high as 1 mg/kg/day in rats and dogs, which equates to up to 250 times the estimated human daily dose based on body surface area, did not lead to any nonendocrine related sequelae.

In the event of an overdosage, management should be conducted symptomatically. Healthcare professionals are advised to monitor the patient closely and provide supportive care as necessary.

Nonclinical Toxicology

Administration of goserelin has been associated with non-teratogenic effects, primarily due to its endocrine action leading to gonadal suppression in both male and female rats. In male rats receiving doses of 500-1000 mcg/kg/day, notable decreases in weight and atrophic histological changes were observed in the testes, epididymis, seminal vesicle, and prostate gland, culminating in complete suppression of spermatogenesis. Female rats administered doses ranging from 50-1000 mcg/kg/day exhibited suppression of ovarian function, characterized by reduced size and weight of ovaries and secondary sex organs, with follicular development arrested at the antral stage and a decrease in the size and number of corpora lutea.

Following cessation of goserelin treatment, almost complete histological reversal of these effects was noted in both sexes several weeks later; however, fertility and overall reproductive performance were diminished in those that became pregnant post-treatment. Fertile matings were observed within two weeks after discontinuation of dosing, although total recovery of reproductive function may not have been achieved prior to mating. This was reflected in a reduced ovulation rate, implantation rate, and number of live fetuses.

In terms of carcinogenicity, 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 increase in pituitary adenomas was noted following subcutaneous implantation of goserelin in rats at comparable dose levels over a duration of 72 weeks in males and 101 weeks in females. The relevance of these findings to human health remains unestablished. Additionally, subcutaneous implants of goserelin administered every three weeks for two 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.

Mutagenicity assessments conducted using bacterial and mammalian systems for point mutations and cytogenetic effects have not indicated any mutagenic potential. Furthermore, based on histological evaluations, the effects of goserelin on reproductive organs were found to be reversible in male and female dogs administered doses of 107-214 mcg/kg/day after one year of continuous treatment. Human dose/exposure multiples could not be determined from the available animal data.

Postmarketing Experience

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported during treatment with ZOLADEX.

Additionally, cases of diabetes or loss of glycemic control in patients with pre-existing diabetes have been documented in individuals receiving GnRH agonists, including ZOLADEX.

There is a reported small increased risk of developing myocardial infarction, sudden cardiac death, and stroke associated with the use of GnRH agonists in men.

Injection site injury has also been noted following the administration of ZOLADEX.

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). Healthcare providers should advise patients to 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.

It is important to discuss the potential impact of ZOLADEX on blood glucose levels, particularly in patients with pre-existing diabetes. Patients should be made aware that diabetes or loss of glycemic control has been reported during treatment with GnRH agonists, including ZOLADEX. Therefore, healthcare providers should consider periodic monitoring of blood glucose and/or glycosylated hemoglobin (HbA1c) in these patients.

Additionally, patients should be informed of a small increased risk of developing myocardial infarction, sudden cardiac death, and stroke associated with the use of GnRH agonists in men. Healthcare providers should monitor patients for symptoms and signs suggestive of cardiovascular disease and manage them according to current clinical practice guidelines.

Injection site injuries have also been reported following the administration of ZOLADEX. Patients should be instructed to contact their healthcare provider immediately if they experience any concerning symptoms, including abdominal pain, abdominal distension, dyspnea, dizziness, hypotension, or any altered levels of consciousness.

Storage and Handling

The product is supplied in a sealed, light- and moisture-proof aluminum foil laminate pouch, which includes a desiccant capsule to maintain product integrity. It is essential to store the product at room temperature, ensuring that the temperature does not exceed 25°C (77°F) to preserve its efficacy and safety. Proper handling and storage conditions are crucial to maintaining the quality 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)