Goserelin Acetate

Class: Antineoplastic Agents
VA Class: AN500
Chemical Name: 2-(Aminocarbonyl)hydrazide-6-[O-(1,1-dimethylethyl)-d-serine]-10-deglycinamide luteinizing hormone-releasing factor (pig)
Molecular Formula: C59H84N18O14
CAS Number: 65807-02-5
Brands: Zoladex

Introduction

Synthetic analog of gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone, gonadorelin); used as an antineoplastic agent and for its endocrine effects.1 2

Uses for Goserelin Acetate

Prostate Cancer

Palliative treatment of advanced prostate cancer.1 2 4 5 6 9 10 17 18 Considered one of several first-line options for hormonal therapy; other options include orchiectomy, estrogens, and antiandrogens.9

In clinical studies, goserelin (3.6 mg every 4 weeks) was as effective as orchiectomy.1 2 4 5 17 18 Clinical outcome in patients receiving goserelin 10.8 mg every 12 weeks expected to be similar to that of patients receiving goserelin 3.6 mg every 4 weeks.2 6

Slideshow: Flashback: FDA Drug Approvals 2013

Also used as an adjunct to radiation therapy in patients with stage III[C]) prostate cancer.8 10

Treatment of locally confined stage T2b-T4 (B2-C) prostate cancer in conjunction with flutamide and radiation therapy.1 2 20

Endometriosis

Palliative treatment of endometriosis.1 3 5 11 12 Experience with goserelin has been limited to women ≥18 years of age who received consecutive therapy (3.6 mg every 4 weeks) for 6 months.1

Breast Cancer

Palliative treatment of advanced breast cancer in premenopausal and perimenopausal women.1 5 13 15

Dysfunctional Uterine Bleeding

Used as an endometrial-thinning agent prior to endometrial ablation procedures for the treatment of dysfunctional uterine bleeding.1 3 16

Goserelin Acetate Dosage and Administration

Administration

Sub-Q

Administered as a biodegradable implant into the anterior abdominal wall below the navel line.1 2 3 4

Implants containing goserelin 3.6 mg are administered every 4 weeks.1 2 3 4

Implants containing goserelin 10.8 mg are administered every 12 weeks.2 6

Adherence to the recommended schedule recommended; a delay of a few days is permitted.1 2

The implant may be located by ultrasound in the event that it needs to be removed.1 2

Consult the manufacturer’s labeling for proper methods of administration and associated precautions.1 2

Dosage

Available as goserelin acetate; dosage expressed in terms of goserelin.1 2

Adults

Prostate Cancer
Advanced Prostate Cancer
Sub-Q

One implant containing 3.6 mg every 4 weeks or one implant containing 10.8 mg every 12 weeks.1 2 4 6 Intended for long-term administration 1 2 8 unless it is clinically inappropriate.1 2

Stage III[C]) prostate cancer (as an adjunct to radiation therapy): One implant containing 3.6 mg every 4 weeks; initiate therapy on the first day of radiation or during the last week of radiation.8 10

Stage B2-C Prostate Cancer
Sub-Q

One implant containing 3.6 mg every 4 weeks starting 8 weeks prior to radiation therapy and continuing for a total of 4 doses recommended by the manufacturer.1 2 7 Alternatively, one implant containing 3.6 mg implanted 8 weeks prior to radiation therapy and followed by one implant containing 10.8 mg on day 28 (4 weeks after initial 3.6-mg dose) recommended by the manufacturer.1 2

Endometriosis
Sub-Q

One implant containing 3.6 mg every 4 weeks for 6 consecutive months.1 3 11 12 Retreatment with additional courses currently not recommended; safety has only been established for a 6-month course of therapy; there are concerns about potential long-term effects on bone density.1 Assess bone density if retreatment for recurrence is considered.1 (See Musculoskeletal Effects under Cautions.)

Breast Cancer
Sub-Q

One implant containing 3.6 mg every 4 weeks.1 13 Consider dosage increase to 7.2 mg (3.6 mg implanted to 2 different sites) every 4 weeks in women whose serum estradiol concentrations are not reduced to postmenopausal levels after 8 weeks.1 13 Intended for long-term administration unless clinically inappropriate.1 2

Dysfunctional Uterine Bleeding
Sub-Q

One implant containing 3.6 mg 4 weeks before endometrial ablation.1 Alternatively, the initial 3.6-mg dose of goserelin can be followed by a second 3.6-mg dose 4 weeks after the first dose; surgery should be performed 2–4 weeks after the second dose.1

Prescribing Limits

Adults

Endometriosis
Sub-Q

Maximum 3.6 mg every 4 weeks for 6 consecutive months.1

Special Populations

Hepatic Impairment

Dosage adjustment not needed in patients with mild to moderate hepatic impairment.1 2 Not studied in patients with severe hepatic insufficiency.1 2

Renal Impairment

Dosage adjustment not needed.1 2 (See Special Populations under Pharmacokinetics.)

Geriatric Patients

Dosage adjustment not needed.1 2

Cautions for Goserelin Acetate

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

Interactions for Goserelin Acetate

No formal drug interaction studies to date.1 2

Goserelin Acetate Pharmacokinetics

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

Stability

Storage

Sub-Q

Implant

Room temperature (<25°C).1 2

Actions

  • 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

Advice to Patients

  • Risk of worsening manifestations of prostate or breast cancer during initial weeks of therapy.1 2

  • Risk of anaphylactoid and other sensitivity reactions.1 2

  • Risk of other adverse effects, including decreases in bone mineral density.1 2

  • Risk of diabetes or loss of glycemic control in patients with preexisting diabetes.1 2 23 Importance of undergoing recommended monitoring of blood glucose or HbA1c concentrations.1 2 23

  • Possibility of increased risk of MI, sudden cardiac death, and stroke in men receiving GnRH agonists for the treatment of prostate cancer.1 2 23 Importance of being monitored for manifestations of cardiovascular disease.1 2 23

  • Importance of promptly reporting sudden onset of headache, vomiting, or visual changes to clinician.1 2

  • Necessity of advising women to avoid pregnancy (using nonhormonal contraception) during therapy and for 12 weeks after administration of the last 3.6-mg dose of goserelin.1 If used during pregnancy, advise patient of potential fetal hazard.1

  • Necessity of advising women not to breast-feed.1

  • Importance of women informing their clinician if regular menstruation persists.1 Women also should be advised that breakthrough bleeding or ovulation (with potential for conception) may occur if one or more successive doses of the drug are missed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

  • Importance of informing patients of other important precautionary information.1 2 (See Cautions.)

Preparations

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

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

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 7, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. AstraZeneca. Zoladex, 3.6 mg (goserelin acetate implant) prescribing information. Wilmington, DE; 2010 Dec. Available at . Accessed 2011 May 26.

2. AstraZeneca. Zoladex, 3-month 10.8 mg (goserelin acetate implant) prescribing information. Wilmington, DE; 2010 Dec. Available at . Accessed 2011 May 26.

3. Perry CM, Brogden RN. Goserelin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in benign gynaecologic disorders. Drugs. 1996; 51:319-46. [PubMed 8808170]

4. Brogden RN, Faulds D. Goserelin: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in prostate cancer. Drugs Aging. 1995; 6:324-43. [PubMed 7613021]

5. Cockshott ID. Clinical pharmacokinetics of goserelin. Clin Pharmacokinet. 2000; 39:27-48. [PubMed 10926349]

6. Fernandez del Moral P, Dijkman GA, Debruyne FM et al. Three-month depot of goserelin acetate: clinical efficacy and endocrine profile: Dutch South East Cooperative Urological Group. Urology. 1996; 48:894-900. [PubMed 8973673]

7. Pilepich MV, Krall JM, al-Sarraf M et al. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic cancer: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology. 1995; 45:616-23. [PubMed 7716842]

8. Bolla M, Gonzalez D, Warde P et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997; 337:295-300. [IDIS 390252] [PubMed 9233866]

9. Prostate Cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2002 Jul.

10. Pilepich MV, Caplan R, Byhardt RW et al. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85-31. J Clin Oncol. 1997; 15:1013-21. [IDIS 328228] [PubMed 9060541]

11. Rock JA, Truglia JA, Caplan RJ et al. Zoladex (goserelin acetate implant) in the treatment of endometriosis: a randomized comparison with danazol. Obstet Gynecol. 1993; 82:198-205. [IDIS 318007] [PubMed 8336864]

12. Shaw RW. An open randomized comparative study of the effect of goserelin depot and danazol in the treatment of endometriosis. Fertil Steril. 1992; 58:265-72. [IDIS 300230] [PubMed 1386029]

13. Taylor CW, Green S, Dalton WS et al. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol. 1998; 16:994-9. [IDIS 402272] [PubMed 9508182]

14. Bajetta E, Zilembo N, Buzzoni R et al. Goserelin in premenopausal advanced breast cancer: clinical and endocrine evaluation of responsive patients. Oncology. 1994; 51:262-9. [PubMed 8196909]

15. Breast Cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2002 Jul.

16. Donnez J, Vilos G, Gannon MJ et al. Goserelin acetate (Zoladex) plus endometrial ablation for dysfunctional uterine bleeding: a large randomized, double-blind study. Fertil Steril. 1997; 68:29- 36. [IDIS 389652] [PubMed 9207580]

17. Cersosimo RJ, Carr D. Prostate cancer: current and evolving strategies. Am J Health-Syst Pharm. 1996; 53:381-96. [IDIS 360612] [PubMed 8673658]

18. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostatic cancer. Summary, Evidence Report/Technology Assessment (No. 4). Agency for Health Care Policy and Research, Rockville, MD. 1999 Jan.

19. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Medical management of endometriosis. Practice Bulletin No. 11. Washington, DC: American College of Obstetricians and Gynecologists; 1999 Dec.

20. Schering. Eulexin (flutamide) capsules prescribing information. Kenilworth, NJ; 1999 Sept.

21. AstraZeneca, Wilmington, DE: personal communication.

22. Food and Drug Administration. GnRH agonists: safety review of drug class used to treat prostate cancer (sold under the brand names Lupron, Zoladex, Trelstar, Viadur, Vantas, Eligard, Synarel, and generics). Rockville, MD; 2010 May 3. From FDA web site (http: / / www.fda.gov / Safety / MedWatch / SafetyInformation / SafetyAlertsforHumanMedicalProducts / ucm210576.htm).

23. Food and Drug Administration. GnRH agonists: label change--increased risk of diabetes and cardiovascular disease (update). Rockville, MD; 2010 Oct 20. From FDA web site (http: / / www.fda.gov / Safety / MedWatch / SafetyInformation / SafetyAlertsforHumanMedicalProducts / ucm230359.htm).

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