Zoladex

Zoladex is a prescription hormonal implant medication used:

• with flutamide to treat locally confined prostate cancer
• to treat advanced prostate cancer
• to manage endometriosis
• as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding
• to treat advanced breast cancer

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

No formal drug interactions have been performed by the manufacturer. However, you should tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Not all drug interactions are known or reported and new drug interactions are continually being reported.

Contraindications

• Known hypersensitivity to goserelin or any ingredient in the formulation, other GnRH agonists, or GnRH.1 2

• Known or suspected pregnancy unless being used for palliative treatment of advanced breast cancer.1

• Abnormal vaginal bleeding of unknown etiology.1

• The implant containing 10.8 mg of goserelin should not be used in women; insufficient data available to determine whether this preparation is associated with reliable suppression of serum estradiol.2

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Expected hormonal changes increase the risk for pregnancy loss and fetal harm when administered to a pregnant woman; increased risk of pregnancy loss demonstrated in animals.1 2

Women of childbearing potential should avoid pregnancy and use an effective nonhormonal method of contraception during therapy and for 12 weeks following the last dose of goserelin.1 21 Continuous use of goserelin usually inhibits ovulation and stops menstruation; however, prevention of pregnancy is not ensured.1

Exclude pregnancy before initiating therapy in women with benign gynecologic conditions.1 If a patient with endometriosis or undergoing endometrial thinning becomes pregnant during therapy, discontinue the drug and advise patient about potential fetal hazard.1 2

If used during pregnancy in women with advanced breast cancer, apprise of potential fetal hazard.1

Initial Worsening of Hormone-dependent Disease

Possible worsening of signs and/or symptoms of prostate or breast cancer (e.g., increased bone pain) and/or development of new manifestations due to transient increases in serum testosterone (in men) or estrogen (in women) concentrations during the initial weeks of therapy.1 2 Concomitant therapy with an antiandrogen (e.g., bicalutamide, flutamide, nilutamide) 1 week before and during the first few weeks of goserelin therapy may minimize disease flare in men with prostate cancer.4 9

Spinal cord compression and/or ureteral obstruction reported in men with prostate cancer.1 2 If spinal cord compression or renal impairment secondary to ureteral obstruction develops, institute standard treatment of these complications; consider immediate orchiectomy in extreme cases.1 2

Caution in patients at particular risk of developing spinal cord compression or ureteral obstruction; observe closely during the first month of therapy.1 2 4 Treat spinal cord compression or ureteral obstruction before initiating goserelin.1 2 4

Hyperglycemia

Possible hyperglycemia and increased risk of diabetes in patients receiving GnRH agonists for treatment of prostate cancer.1 2 23 Studies evaluating risk of diabetes in women and children receiving GnRH agonists not performed to date.22

Evaluate patients for risk factors for diabetes and carefully weigh benefits and risks of GnRH agonist therapy before selecting treatment for prostate cancer.23

Periodically monitor blood glucose and/or HbA1c in patients receiving GnRH agonists for treatment of prostate cancer.1 2 23 Manage hyperglycemia or diabetes according to current standards of care.1 2

Cardiovascular Effects

Possible increased risk of cardiovascular disease (e.g., MI, sudden cardiac death, stroke) in patients receiving GnRH agonists for treatment of prostate cancer.1 2 23 Studies evaluating risk of cardiovascular disease in women and children receiving GnRH agonists not performed to date.22

Evaluate patients for cardiovascular risk factors and carefully weigh benefits and risks of GnRH agonist therapy before selecting treatment for prostate cancer.1 2 23

Periodically monitor patients receiving GnRH agonists for manifestations of cardiovascular disease; manage cardiovascular disease according to current standards of care.1 2 23

Cases of serious venous and arterial thromboembolism (e.g., DVT, PE, MI, TIA, stroke) reported in women receiving GnRH agonists.1

Possible transient changes in BP (hypotension or hypertension).1

Possible increased total cholesterol, LDL cholesterol, and triglycerides and decreased HDL cholesterol.1

Hypercalcemia

Hypercalcemia reported in patients with prostate or breast cancer with bone metastases.1 2 Initiate appropriate treatment if hypercalcemia develops.1

Sensitivity Reactions

Hypersensitivity Reactions

Antibody formation, acute anaphylactic reactions, and urticaria reported with GnRH agonists, including goserelin.1 2

Major Toxicities

Pituitary Apoplexy

Pituitary apoplexy, a clinical syndrome resulting from infarction of the pituitary gland, reported rarely.1 2 Most cases occur within 2 weeks of the first dose, sometimes within the first hour.1 2 If manifestations occur (e.g., sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, sometimes cardiovascular collapse), immediate medical attention required.1 2 In most cases, pituitary adenoma diagnosed.1 2

General Precautions

Women Undergoing Endometrial Ablation

Possible increase in cervical resistance.1 Perform cervical dilation carefully following use of goserelin as an endometrial thinning agent.1

Patient Monitoring

Determine serum testosterone concentrations periodically in patients with prostate cancer in whom the anticipated clinical or biochemical response to goserelin has not been achieved.2

Reduction in serum prostate specific antigen (PSA) concentrations may provide information about duration of progression-free status in men with prostate cancer.9 However, decreases in PSA concentrations may occur independent of tumor response; clinicians cannot rely solely on PSA concentrations to monitor a patient’s response.9

Musculoskeletal Effects

Decreases in bone mineral density (BMD), osteoporosis, and bone fracture reported in men; decreases in BMD reported in women.1 2 Currently available data suggest that recovery of bone loss occurs following cessation of therapy most women.1

For management of endometriosis in women, concurrent use of hormone replacement therapy or bisphosphonates (e.g., alendronate) may minimize bone mineral loss associated with GnRH agonist therapy without compromising efficacy.1 19

For treatment of prostate cancer in men, concurrent use of bisphosphonates may minimize bone mineral loss associated with GnRH agonist therapy.1 2

Risk of BMD loss may be increased in patients with a history of prior therapy that resulted in BMD loss and/or patients with risk factors for decreased BMD (e.g., chronic alcohol abuse, tobacco abuse, family history of osteoporosis, chronic use of anticonvulsants or corticosteroids).1

Specific Populations

Pregnancy

Category D (advanced breast cancer); category X (endometriosis, endometrial-thinning agent)1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1 2

Pediatric Use

Safety and efficacy not established.1 2

Geriatric Use

Clinical studies for use in prostate cancer have been conducted principally in patients ≥65 years of age.1 2 4 5 6 7 8 21 Clinical studies in women >65 years of age not performed to date.1

Renal Impairment

Incidence of adverse effects not increased in patients with renal impairment receiving goserelin 10.8 mg.2

Common Adverse Effects

Men: Hot flushes (flashes), sexual dysfunction, decreased erections, lower urinary tract symptoms, pain (worsened in the first month).1 2 4 17

Women: Hot flushes (flashes), vaginitis, headache, emotional lability, decreased/increased libido, sweating, depression, acne, breast atrophy, breast enlargement.1 3

No formal drug interaction studies to date.1 2

Absorption

Bioavailability

Well absorbed following sub-Q administration.1 2

3.6 mg: Peak plasma concentrations achieved within 12–15 days in men and 8–22 days in women.1 2

10.8 mg: Peak plasma concentrations achieved within 24 hours in men.1 2

Duration

3.6 mg: 4 weeks.1 2 5

10.8 mg: 12 weeks.1 2 5

Special Populations

Long-term administration of goserelin 10.8 mg in patients with renal impairment not associated with accumulation of goserelin.2

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1 Crosses the placenta in rats and rabbits.1

Plasma Protein Binding

27.3%.1 2

Elimination

Metabolism

Undergoes hydrolysis of the C-terminal amino acids.1 2

Elimination Route

Eliminated predominately in urine (90%) as metabolites and unchanged drug (20%).1 2

Half-life

Men: 4.2 hours.1 2

Special Populations

Men with Clcr <20 mL/minute: Half-life of 12.1 hours reported.1 2

Similar total body clearance and elimination half-life in normal subjects and patients with moderate hepatic impairment.2 Pharmacokinetic data in patients with severe hepatic insufficiency not available.2

• A synthetic decapeptide analog of GnRH; structurally related to leuprolide, nafarelin, and triptorelin.1 2 3 4 5 8

• A potent inhibitor of gonadotropin secretion when given continuously.1 2 3 4 5

• Initially, circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol surge transiently.1 2 3 4 5 Following chronic and continuous administration (generally, 2–4 weeks after initiation of therapy), produces a sustained decrease in LH and FSH secretion and a marked reduction of testicular and ovarian steroidogenesis.1 2 3 4 5

• Reductions in serum testosterone concentrations in males receiving goserelin are comparable to those achieved after surgical castration (i.e., <50 ng/dL).1 2 4 5 6 17 Consequently, physiologic functions and tissues dependent on testosterone for maintenance become quiescent.1 2 4

• In most premenopausal women, serum estradiol concentrations are reduced to levels comparable to those observed after menopause within 3 weeks of initiating therapy.1 3 5 Consequently, physiologic functions and tissues dependent on gonadal steroids (estrogen) for maintenance become quiescent.1 3

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Goserelin Acetate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Implants	3.6 mg (of goserelin)	Zoladex (available as prefilled disposable syringe)	AstraZeneca
		10.8 mg (of goserelin)	Zoladex (available as prefilled disposable syringe)	AstraZeneca

Zoladex, at a dose of 3.6 mg, should be administered subcutaneously every 28 days into the anterior abdominal wall below the navel line using an aseptic technique under the supervision of a physician [see Dosage and Administration (2.7)].

While a delay of a few days is permissible, every effort should be made to adhere to the 28-day schedule.

Stage B2-C Prostatic Carcinoma

When Zoladex is given in combination with radiotherapy and flutamide for patients with Stage T2b-T4 (Stage B2-C) prostatic carcinoma, treatment should be started 8 weeks prior to initiating radiotherapy and should continue during radiation therapy. A treatment regimen using a Zoladex 3.6 mg depot 8 weeks before radiotherapy, followed in 28 days by the Zoladex 10.8 mg depot, can be administered. Alternatively, four injections of 3.6 mg depot can be administered at 28-day intervals, two depots preceding and two during radiotherapy.

Prostatic Carcinoma

For the management of advanced prostate cancer, Zoladex is intended for long-term administration unless clinically inappropriate.

Endometriosis

For the management of endometriosis, the recommended duration of administration is 6 months.

Currently, there are no clinical data on the effect of treatment of benign gynecological conditions with Zoladex for periods in excess of 6 months.

Retreatment cannot be recommended for the management of endometriosis since safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with Zoladex is contemplated, consideration should be given to monitoring bone mineral density. 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 without compromising the efficacy of Zoladex in relieving the symptoms of endometriosis. The addition of Hormone Replacement Therapy may also reduce the occurrence of vasomotor symptoms and vaginal dryness associated with hypoestrogenism. The optimal drugs, dose and duration of treatment has not been established.

Endometrial Thinning

For use as an endometrial-thinning agent prior to endometrial ablation, the dosing recommendation is one or two depots (with each depot given four weeks apart). When one depot is administered, surgery should be performed at four weeks. When two depots are administered, surgery should be performed within two to four weeks following administration of the second depot.

Breast Cancer

For the management of advanced breast cancer, Zoladex is intended for long-term administration unless clinically inappropriate.

Renal or Hepatic Impairment

No dosage adjustment is necessary for patients with renal or hepatic impairment.

Administration Technique

The proper method of administration of Zoladex is described in the instructions that follow.

1. Put the patient in a comfortable position with the upper part of the body slightly raised. Prepare an area of the anterior abdominal wall below the navel line with an alcohol swab.   NOTE: Caution should be taken while injecting Zoladex into the anterior abdominal wall due to the proximity of underlying inferior epigastric artery and its branches. 2. Examine the foil pouch and syringe for damage. Remove the syringe from the opened foil pouch and hold the syringe at a slight angle to the light. Check that at least part of the Zoladex implant is visible.
3. Grasp the red plastic safety tab and pull away from the syringe, and discard. Remove needle cover. Unlike liquid injections, there is no need to remove air bubbles as attempts to do so may displace the Zoladex implant.
4. Holding the syringe around the protective sleeve, using an aseptic technique, pinch the skin of the patient’s anterior abdominal wall below the navel line. With the bevel of the needle facing up, insert the needle at a 30 to 45 degree angle to the skin in one continuous deliberate motion until the protective sleeve touches the patient’s skin.   NOTE: The Zoladex syringe cannot be used for aspiration. If the hypodermic needle penetrates a large vessel, blood will be seen instantly in the syringe chamber. If a vessel is penetrated, withdraw the needle and inject with a new syringe elsewhere. Monitor patients for signs or symptoms of abdominal hemorrhage. Use extra care when administering Zoladex to patients with a low BMI and/or to patients receiving full dose anticoagulation [see Warnings and Precautions (5.9)]. 5. Do not penetrate into muscle or peritoneum.
6. To administer the Zoladex implant and to activate the protective sleeve, grasp the barrel at the finger grip and depress the plunger until you cannot depress it any further. If the plunger is not depressed fully, the protective sleeve will NOT activate. When the protective sleeve ‘clicks’, the protective sleeve will automatically begin to slide to cover the needle.   NOTE: The needle does not retract. 7. Withdraw the needle and allow protective sleeve to slide and cover needle. Dispose of the syringe in an approved sharps collector.

NOTE: In the unlikely event of the need to surgically remove Zoladex, it may be localized by ultrasound.

Stage B2-C Prostatic Carcinoma

The effects of hormonal treatment combined with radiation were studied in 466 patients (231 Zoladex + flutamide + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), with or without pelvic node involvement.

In this multicentered, controlled trial, administration of Zoladex (3.6 mg depot) and flutamide capsules (250 mg t.i.d.) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs 33% at 4 years, P<0.001). The combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs 36% at 4 years, P =0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs 2.6 years, P<0.001). Inclusion of normal PSA level as a criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs 1.5 years, P<0.001).

Prostatic Carcinoma

In controlled studies of patients with advanced prostatic cancer comparing Zoladex to orchiectomy, the long-term endocrine responses and objective responses were similar between the two treatment arms. Additionally, duration of survival was similar between the two treatment arms in a comparative trial.

Endometriosis

In controlled clinical studies using the 3.6 mg formulation every 28 days for 6 months, Zoladex was shown to be as effective as danazol therapy in relieving clinical symptoms (dysmenorrhea, dyspareunia and pelvic pain) and signs (pelvic tenderness, pelvic induration) of endometriosis and decreasing the size of endometrial lesions as determined by laparoscopy. In one study comparing Zoladex with danazol (800 mg/day), 63% of Zoladex-treated patients and 42% of danazol-treated patients had a greater than or equal to 50% reduction in the extent of endometrial lesions. In the second study comparing Zoladex with danazol (600 mg/day), 62% of Zoladex-treated and 51% of danazol-treated patients had a greater than or equal to 50% reduction in the extent of endometrial lesions. The clinical significance of a decrease in endometriotic lesions is not known at this time; and in addition, laparoscopic staging of endometriosis does not necessarily correlate with severity of symptoms.

In these two studies, Zoladex led to amenorrhea in 92% and 80%, respectively, of all treated women within 8 weeks after initial administration. Menses usually resumed within 8 weeks following completion of therapy.

Within 4 weeks following initial administration, clinical symptoms were significantly reduced, and at the end of treatment were, on average, reduced by approximately 84%.

During the first two months of Zoladex use, some women experience vaginal bleeding of variable duration and intensity. In all likelihood, this bleeding represents estrogen withdrawal bleeding, and is expected to stop spontaneously.

There is insufficient evidence to determine whether pregnancy rates are enhanced or adversely affected by the use of Zoladex.

Endometrial Thinning

Two trials were conducted with Zoladex prior to endometrial ablation for dysfunctional uterine bleeding.

Trial 0022, was a double-blind, prospective, randomized, parallel-group multicenter trial conducted in 358 premenopausal women with dysfunctional uterine bleeding. Eligible patients were randomized to receive either two depots of Zoladex 3.6 mg (n=180) or two placebo injections (n=178) administered four weeks apart. One hundred seventy five patients in each group underwent endometrial ablation using either diathermy loop alone or in combination with rollerball approximately 2 weeks after the second injection. Endometrial thickness was assessed immediately before surgery using a transvaginal ultrasonic probe. The incidence of amenorrhea was compared between the Zoladex and placebo groups at 24 weeks after endometrial ablation.

The median endometrial thickness before surgery was significantly less in the Zoladex treatment group (1.50 mm) compared to the placebo group (3.55 mm). Six months after surgery, 40% of patients (70/175) treated with Zoladex in Trial 0022 reported amenorrhea as compared with 26% who had received placebo injections (44/171), a difference that was statistically significant.

Trial 0003, was a single center, open-label, randomized trial in premenopausal women with dysfunctional uterine bleeding. The trial allowed for a comparison of 1 depot of Zoladex and 2 depots of Zoladex administered 4 weeks apart with ablation using Nd: YAG laser occurring 4 weeks after Zoladex administration. Forty patients were randomized into each of the Zoladex treatment groups.

The median endometrial thickness before surgery was significantly less in the group treated with two depots (0.5 mm) compared to the group treated with one depot (1 mm). No difference in the incidence of amenorrhea was found at 24 weeks (24% in both groups). Of the 74 patients that completed the trial, 53% reported hypomenorrhea and 20% reported normal menses six months after surgery.

Breast Cancer

The Southwest Oncology Group conducted a prospective, randomized clinical trial (SWOG-8692 [INT-0075]) in premenopausal women with advanced estrogen receptor positive or progesterone receptor positive breast cancer which compared Zoladex with oophorectomy. On the basis of interim data from 124 women, the best objective response (CR+PR) for the Zoladex group is 22% versus 12% for the oophorectomy group. The median time to treatment failure is 6.7 months for patients treated with Zoladex and 5.5 months for patients treated with oophorectomy. The median survival time for the Zoladex arm is 33.2 months and for the oophorectomy arm is 33.6 months.

Subjective responses based on measures of pain control and performance status were observed with both treatments; 48% of the women in the Zoladex treatment group and 50% in the oophorectomy group had subjective responses. In the clinical trial (SWOG-8692 [INT–0075]), the mean post treatment estradiol level was reported as 17.8 pg/mL. (The mean estradiol level in post-menopausal women as reported in the literature is 13 pg/mL.) During the conduct of the clinical trial, women whose estradiol levels were not reduced to the postmenopausal range, received two Zoladex depots, thus, increasing the dose of Zoladex from 3.6 mg to 7.2 mg.

Findings were similar in uncontrolled clinical trials involving patients with hormone receptor positive and negative breast cancer. Premenopausal women with estrogen receptor (ER) status of positive, negative, or unknown participated in the uncontrolled (Phase II and Trial 2302) clinical trials. Objective tumor responses were seen regardless of ER status, as shown in the following table.

Table 8 OBJECTIVE RESPONSE BY ER STATUS

	CR + PR/Total No. (%)
ER Status	Phase II (N=228)	Trial 2302 (N=159)
Positive	43/119 (36)	31/86 (36)
Negative	6/33 (18)	3/26 (10)
Unknown	20/76 (26)	18/44 (41)

NDC 0310-0950-36

Zoladex® 3.6 mg

GOSERELIN ACETATE IMPLANT

Equivalent to 3.6 mg goserelin

One Single-Use Syringe

For Subcutaneous Injection

Zoladex  goserelin acetate implant

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0310-0950 Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength GOSERELIN ACETATE (GOSERELIN) GOSERELIN 3.6 mg

Inactive Ingredients Ingredient Name Strength LACTIC ACID, DL-   GLYCOLIC ACID

Packaging # Item Code Package Description 1 NDC:0310-0950-36 1 POUCH in 1 CARTON 1 1 SYRINGE in 1 POUCH 1 1 IMPLANT in 1 SYRINGE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA019726 05/05/2003

Labeler - AstraZeneca Pharmaceuticals LP (054743190)

Registrant - AstraZeneca PLC (230790719)

Revised: 02/2016   AstraZeneca Pharmaceuticals LP