Zoladex (Goserelin Acetate)



Goserelin Acetate

LHRH Analog

Action And Clinical Pharmacology: Goserelin is a synthetic decapeptide analog of gonadotropin releasing hormone (GnRH or LHRH). When given acutely, goserelin releases luteinizing hormone (LH) from the pituitary gland. However, following chronic administration, goserelin is a potent inhibitor of gonadotropin production resulting in gonadal and consequently, accessory sex organ regression. This effect is the basis for the inhibition of growth of chemically-induced rat mammary tumors and transplantable rat prostate and pituitary tumors.

In animals and man, following an initial stimulation of pituitary LH secretion and a transient elevation in serum testosterone in males and serum estradiol in females, chronic administration results in inhibition of gonadotropin secretion. Approximately 21 days after the initiation of therapy, a sustained suppression of pituitary LH results in the reduction of serum testosterone levels to a range normally seen in surgically castrated men, and of serum estradiol to levels comparable with those observed in postmenopausal women. This suppression of testosterone and estradiol is then maintained as long as therapy is continued. When used in women this suppression of serum estradiol will induce amenorrhea in the majority of patients after the first 4 weeks of treatment especially if started during the menstrual phase of the cycle. During early treatment with goserelin some women may experience vaginal bleeding of variable duration and intensity. Such bleeding may represent estrogen withdrawal bleeding and is expected to stop spontaneously.

Zoladex is a depot formulation of goserelin acetate dispersed in a cylindrical rod of biodegradable and biocompatible D-L Lactide-glycolide copolymer.

The bioavailability of goserelin from Zoladex depot is almost complete. When injected s.c., goserelin is released continuously over at least 28 days. Administration of a depot every 4 weeks ensures that effective concentrations are maintained with no accumulation. Goserelin is poorly protein bound and has a serum elimination half-life of about 4.2 hours in male subjects and 2.3 hours in female subjects with normal renal function. Although the half-life is increased in patients with impaired renal function, this has minimal effects, and hence, no change from a monthly dosing schedule is necessary. There is no significant change in the clearance of goserelin in patients with hepatic impairment with normal renal function.

Indications And Clinical Uses: For a number of hormone-dependent conditions as shown below under the headings Prostate Cancer, Breast Cancer and Benign Conditions.

Prostate Cancer: For the palliative treatment of patients with hormone-dependent advanced carcinoma of the prostate (Stage D2).

Breast Cancer: For the palliative treatment of advanced breast cancer in pre- and perimenopausal women whose tumor contains estrogen and/or progesterone receptors.

Benign Conditions: For the hormonal management of endometriosis, including pain relief and reduction of endometriotic lesions. Experience with Zoladex for the management of endometriosis has been limited to women 18 years of age and older, treated for 6 months.

For use as an endometrial thinning agent prior to endometrial ablation.

Contra-Indications: In patients with hypersensitivity to the drug or any of its components.

Goserelin should not be administered to females having undiagnosed abnormal vaginal bleeding.

Pregnancy: Goserelin should not be used during pregnancy. As with other LHRH agonists it is not known whether goserelin causes fetal abnormalities in humans. Women of childbearing potential should be carefully examined before treatment to exclude pregnancy. Nonhormonal methods of contraception should be employed during therapy (see Precautions).

Lactation: The use of goserelin during breast-feeding is not recommended.

Manufacturers’ Warnings In Clinical States: General: Initially, goserelin transiently increases serum testosterone in males and serum estradiol in females and other gonadal hormones. Although not necessarily related, isolated cases of short-term worsening of signs and symptoms have been reported during the first 4 weeks of therapy.

Worsening of the clinical condition may occasionally require discontinuation of therapy and/or surgical intervention.

Patients with Vertebral Metastases: During the first month of therapy with goserelin, patients with vertebral metastases who are thought to be at particular risk of spinal cord compression should be closely monitored (see Precautions).

Males: Patients with Genitourinary Tract Symptoms: During the first month of therapy with goserelin, patients at risk of developing ureteric obstruction should be closely monitored (see Precautions).

Induced Hypogonadism: Suppression of pituitary gonadotropins and gonadal hormone production will occur with continued administration of goserelin. These changes have been observed to reverse on discontinuation of therapy. However, whether the clinical symptoms of induced hypogonadism will reverse in all patients has not yet been established.

Precautions: Transient exacerbation of signs and symptoms: Worsening of bone pain and other signs and symptoms have been reported infrequently in males and to a lesser extent in females during the first month of therapy with goserelin (see Warnings). It is unclear whether there is any relationship between these clinical events and the initial rise in serum testosterone or estradiol levels observed during the first few days following administration of the first depot injection.

In those who reported an increase in bone pain, the pain ranged in intensity from mild to severe and required either symptomatic management, including non-narcotic analgesics or in some severe cases, narcotic analgesics.

Ureteric obstruction may develop in male patients with a history of obstructive uropathy. If spinal cord compression or renal impairment due to ureteric obstruction are present, or develop, specific standard treatment of these complications should be instituted.

Monitoring of Patients: During therapy with goserelin, patients should be routinely monitored by physical examinations and appropriate laboratory tests. In prostate cancer patients tumor markers such as prostatic acid phosphatase (PAP), prostatic specific antigen (PSA) or acid phosphatase could be monitored. Additionally, if deemed appropriate by the physician, serum testosterone or serum estradiol may be monitored; however, this is not routinely required.

In prostate cancer patients an assessment of bone lesions may require the use of bone scans. Prostatic lesions may be monitored by ultrasonography and/or CT scan in addition to digital rectal examination. The status of obstructive uropathy in males may be assessed and/or diagnosed using i.v. pyelography, ultrasonography or CT scan.

Changes in Bone Density: Since bone loss can be anticipated as part of natural menopause, it may also be expected to occur during a medically induced hypoestrogenic state caused by goserelin.

In patients receiving goserelin for the treatment of endometriosis, the addition of hormone replacement therapy (a daily estrogenic agent and a progestogenic agent) has been shown to reduce bone mineral density loss and vasomotor symptoms.

In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, presumed or strong family history of osteoporosis or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, goserelin may pose an additional risk. In these patients the risks and benefits must be weighed carefully before therapy with goserelin is instituted.

Use of goserelin for longer than the recommended 6 months or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss.

The use of LHRH agonists in men may cause a loss of bone mineral density.

Laboratory Tests: Although serum testosterone or serum estradiol may be elevated during the first few days after administration of the first depot, they return to normal within 1 week, and are suppressed by the end of 3 weeks. They remain suppressed throughout therapy with goserelin.

Prostate cancer tumor markers (PSA and PAP), are not routinely monitored in the first few days of therapy; however, if the cancer is responsive to goserelin therapy, then these levels, if elevated prior to the commencement of treatment, are usually reduced by the end of the first month.

Renal function tests, BUN and creatinine may rarely be elevated during the first few days of therapy in prostate cancer patients before returning to normal.

Diagnostic Interference: Administration of goserelin in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored approximately 8 weeks after the last dose of goserelin. Diagnostic tests of pituitary-gonadal function conducted during the treatment and within 8 weeks after discontinuation of goserelin therapy may therefore be misleading.

Allergic Reactions: Antibody formation has not been observed during administration of goserelin. Local reactions, such as mild bruising have been related to the trauma of the injection itself and not to the copolymer material of the depot or to the prolonged presence of goserelin at the site of depot injection.

Dependence Liability: There have been no reports of drug dependence following the use of goserelin.

Children: The safety and effectiveness of goserelin in children has not been established.

Pregnancy: Safe use of the drug in pregnancy has not been established, therefore a nonhormonal method of contraception should be used during treatment. Patients should be advised that if they miss or postpone a dose of goserelin, ovulation may occur with the potential for conception. If a patient becomes pregnant during treatment, she should discontinue treatment and consult her physician.

Fertility: Nearly 500 patients with endometriosis who have been treated with goserelin for 6 months were followed up for a further 1 year to assess fertility. Of these, 100 (20%) became pregnant.

One hundred and seventy seven of these patients had previously been considered infertile and of these 53 (30%) conceived. There is no evidence that pregnancy rates are enhanced or adversely affected by the use of goserelin in the post-treatment period.

There is no evidence to suggest that there is any problem associated with conception after the use of goserelin for 6 months.

Menses usually resumed within 8 weeks following completion of therapy. Rarely, some women may enter menopause during treatment with LHRH analogues and do not resume menses on cessation of therapy.

Duration of Endometriosis Treatment: The safety of treatment, as well as retreatment, beyond 6 months with goserelin has not been established.

Endometrial Thinning: The use of goserelin may cause an increase in cervical resistance. Therefore, care should be taken when dilating the cervix.

Adverse Reactions: The adverse effects seen with goserelin are due primarily to its pharmacologic action of sex hormone suppression.

Changes in blood pressure, manifest as hypotension or hypertension, have been occasionally observed in patients administered goserelin. The changes are usually transient, resolving either during continued therapy or after cessation of therapy with goserelin. Such changes have rarely required medical intervention including withdrawal of goserelin treatment.

Rare incidences of hypersensitivity reactions, which may include some manifestations of anaphylaxis, have been reported.

Prostate Cancer Patients: Five hundred and eighteen (518) prostate patients who had not been previously treated and who entered into 14 open multicentre studies were monitored for adverse reactions to goserelin. The mean duration of treatment in these patients was 23 weeks.

The following reports from these clinical trials are considered to be possibly related to treatment with goserelin: hot flushes (51%), decreased libido (53%), decreased erections (57%), breast tenderness (3%), gynecomastia (2%), local intolerance at injection site (pain, erythema) (4%), and skin rash including erythema and urticaria (1.9%).

Also in these clinical studies, an initial rise in mean serum testosterone levels occurred during the first few days of treatment with goserelin. In a few instances, patients experienced a worsening of signs and symptoms, during the first month after initiation of therapy (see Warnings and Precautions). For these patients, this was usually an increase in bone pain (4.2%), however, isolated cases of ureteric obstruction (1.1%) and/or spinal cord compression (1.2%) have also been reported during the initial 4 weeks of goserelin therapy. The relationship of these observations to goserelin is unknown.

The potential for exacerbation of signs and symptoms during the first few weeks of treatment is a concern particularly in male patients with impending neurologic compromise and in patients with severe obstructive uropathy (see Warnings).

When 942 male patients treated with goserelin are considered, the adverse reactions listed below were reported to occur in less than 1% of patients with the exception of bone pain (2.9%), increased alkaline phosphatase (2.4%) and nausea/vomiting (1.4%).

Possible adverse reactions reported in the 942 male patients were as follows:

Cardiovascular: thrombophlebitis, pulmonary embolism, edema, tachycardia, atrial fibrillation, angina pectoris, congestive cardiac failure, hypertension, myocardial infarction, deep vein thrombosis, palpitations, cerebrovascular accident, central retinal vein thrombosis.

Dermatologic: pruritus, skin rashes including erythema, eczema and urticaria, worsening of ecchymoses and hair growth.

Gastrointestinal: dry mouth/thirst, polydipsia, nausea, vomiting, hematemesis, diarrhea, pain in abdomen, constipation, anorexia, flatulence, intolerance to alcohol, gingival atrophy.

Hematologic/Lymphatic: neutropenia, neutrophilia, lymphocytopenia, lymphocytosis, lowered protein/albumin and palpable lymph nodes.

Musculoskeletal: bone pain, signs and symptoms of spinal cord compression, (e.g., paresthesia, paraparesis, paraplegia), muscular fatigue, myopathy, pain (other than bone), hyperesthesia, arthritis, suprapubic pain, polyarthralgia and neurological troubles with lower limbs.

CNS: vertigo, headaches, blackouts, flashes of light, decreased/blurred vision, glaucoma, drowsiness, lassitude, lethargy, malaise, disorientation, mental confusion, sensitivity to noise, taste disturbance.

Urogenital: renal impairment, renal tract obstruction, urinary retention, chronic renal failure, hydronephrosis, nocturia, testicular atrophy.

Laboratory Tests: elevation of liver function test parameters, (e.g., gamma GT, alanine aminotransferase, aspartate aminotransferase, and bilirubin), raised alkaline phosphatase, serum calcium and hyperkalemia.

Miscellaneous: fever, sore throat, influenza, herpes zoster, gangrene, decreased appetite.

Breast Cancer Patients: The adverse event profile for women with advanced breast cancer treated with goserelin is consistent with the profile described for women treated with goserelin for endometriosis. In a controlled clinical trial (SWOG-8692) comparing goserelin with oophorectomy in premenopausal and perimenopausal women with advanced breast cancer, the following events were reported at a frequency of 5% or greater in either treatment group regardless of causality.

In the Phase II clinical trial program in 333 pre- and perimenopausal women with advanced breast cancer, hot flashes and decreased libido were assessed by specific patient inquiry. Hot flashes occurred in 75.9% of the 203 women in whom they were not present at baseline and decreased libido occurred in 47.7% of the 194 women with libido present at baseline. These events reflect the pharmacological actions of goserelin.

Injection site reactions were reported in less than 1% of patients.

Benign Conditions: In controlled clinical trials, comparing goserelin every 28 days with danazol daily for the treatment of endometriosis, Table II lists events elicited by direct questioning reported at a frequency of 5% or more.

From the endometriosis trials and other supporting safety studies, other adverse reactions, not listed in Table II, elicited at a frequency of 1% or more are shown below. The relationship of these possible adverse reactions to therapy with goserelin is unknown.

Whole Body: allergic reaction, chest pain, fever, malaise.

Cardiovascular: hemorrhage, hypertension, migraine, palpitations, tachycardia.

Digestive: anorexia, constipation, diarrhea, dry mouth, dyspepsia, flatulence.

Hemic and Lympatic: ecchymosis.

Metabolic and Nutritional: edema.

Musculoskeletal: arthralgia, joint disorder.

Nervous: anxiety, paresthesia, somnolence, thinking abnormal.

Respiratory: bronchitis, cough increased, epistaxis, pharyngitis, rhinitis, sinusitis.

Skin: alopecia, dry skin, rash, pruritus, skin discoloration.

Special Senses: amblyopia, dry eyes.

Urogenital: dysmenorrhea, urinary frequency, urinary tract infection, vaginal hemorrhage.

Changes in Bone Mineral Density: After 6 months of goserelin treatment, 97 female patients treated with goserelin showed an average 4.6% decrease of vertebral trabecular bone mineral density (BMD) as compared to pretreatment values. BMD was measured by dual-photon absorptiometry or dual energy x-ray absorptiometry. Forty-four of these patients were assessed for BMD loss 6 months after the completion (post-therapy) of the 6 month therapy period. Data from these patients showed an average 2.6% BMD loss compared to pretreatment values. Nine of the 97 patients were assessed for BMD at 12 months post-therapy. Data from these patients showed an average decrease of 2.5% in BMD compared to pretreatment values. These data suggest a possibility of partial reversibility.

Changes in Laboratory Values: Plasma enzymes: elevation of liver enzymes (AST, ALT) have been reported in less than 1% of all female patients. There was no other evidence of abnormal liver function. Causality between these changes and goserelin have not been established.

Lipids: In a controlled trial, goserelin therapy resulted in a minor, but statistically significant effect on serum lipids. In patients treated for endometriosis at 6 months following initiation of therapy, goserelin treatment resulted in mean increases in LDL cholesterol of 0.55 mmol/L and HDL cholesterol of 0.07 mmol/L. Triglycerides increased by 0.09 mmol/L as well as total cholesterol by 0.65 mmol/L. At the end of 6 months of treatment, HDL cholesterol fractions (HDL2 and HDL3) were increased by 0.05 mmol/L and 0.02 mmol/L, respectively.

In the pivotal trials for endometrial thinning (n=258), the adverse reaction profile for goserelin was similar to that seen in the endometriosis trials, however the frequency was generally lower.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The pharmacologic properties of goserelin and its mode of delivery make accidental or intentional overdosage unlikely. There is no experience of overdosage from the clinical trials, but animal studies indicate that no increased pharmacologic effect would occur in man with higher doses or more frequent administration than those recommended. S.C. doses of the drug as high as 1 mg/kg/day in rats and dogs produced no nonendocrine related sequelae; this dose is approximately 400 times that proposed for human use. If overdosage occurs, this should be managed symptomatically.

Dosage And Administration: Administer s.c. every 28 days into the anterior abdominal wall following the procedure recommended on the package leaflet (see Instructions for Use).

Although, isolated cases of vaginal spotting or bleeding during treatment have been reported, this is not associated with lack of pharmacodynamic effect in most instances. The majority of patients become amenorrheic within 8 weeks of starting treatment. In the small number of women who experience continued menstrual bleeding, estradiol blood levels should be measured. If menstrual bleeding persists and estradiol measurements correspond to postmenopausal values, appropriate diagnostic measures should be undertaken to rule out an intrauterine pathology.

In clinical studies, subjects with impaired renal function (creatinine clearance 70 mL/min). This increase of approximately 8 hours in serum half-life is insufficient to warrant extending the 28-day dosing interval of the 3.6 mg depot, but will lead to modestly higher serum concentrations of the drug in such patients. No dose adjustment, therefore, is necessary for patients with renal failure.

Hepatic impairment does not compromise the clearance of goserelin, therefore, a dosage adjustment is not needed for patients with hepatic impairment.

Endometrial Thinning: For use as an endometrial thinning agent prior to endometrial ablation, goserelin should be administered as 2 depots, 4 weeks apart, with surgery planned for between 0 and 2 weeks after the second depot injection.

Instructions for Use: Caution: Do not depress plunger until Step 5. Read all instructions before use. Refer to package leaflet for diagrams.

1. Swab abdominal injection site.

2. Open pouch at arrows and remove syringe. Do not remove red clip. Check that the depot is present in the window.

3. Remove red clip taking care not to accidentally express depot. Remove needle cover. Do not depress the plunger.

4. Correct grip: fingers around barrel. Insert needle into loosely gathered fold of skin.

5. Depress plunger fully to inject depot. Cover injection site with a sterile dressing.

6. Incorrect grip and angle of presentation for needle insertion.

Availability And Storage: Each sterile, ready-to-use syringe with 16 gauge needle contains: goserelin 3.6 mg (as goserelin acetate) and D-L Lactide-glycolide copolymer to total weight 18.0 mg (as a cylindrical, biodegradable, biocompatible rod). Sterile pouches of 1 syringe for single s.c. injection. Protect from light and moisture. Store in the intact package below 25°C.

ZOLADEX® Zeneca Goserelin Acetate LHRH Analog

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