Zoladex LA (Goserelin Acetate)

ZOLADEX® LA

Zeneca

Goserelin Acetate

Luteinizing Hormone-Releasing Hormone Analog (LHRH Analog)

Action And Clinical Pharmacology: Goserelin is a synthetic decapeptide analog of gonadotropin releasing hormone (GnRH or LHRH). When given acutely, goserelin stimulates the release of pituitary 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, 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 in serum testosterone levels to a range normally seen in surgically castrated men. This suppression of testosterone is then maintained on repeat administration of goserelin.

Zoladex LA is a depot formulation of goserelin acetate dispersed in a cylindrical rod of biodegradable and biocompatible blend of high and low molecular weight range D-L Lactide-glycolide copolymers.

Administration of Zoladex LA every 12 weeks ensures that exposure to goserelin is maintained with no clinically significant accumulation. Goserelin is poorly protein bound and has a serum elimination half-life of 2 to 4 hours in subjects with normal renal function. The half-life is increased in patients with impaired renal function. For the compound given in a 10.8 mg depot formulation every 12 weeks this change will not lead to any accumulation. Hence, no change in dosing is necessary in these patients. There is no significant change in the clearance of goserelin in patients with hepatic impairment with normal renal function.

Indications And Clinical Uses: For the palliative treatment of patients with hormone-dependent advanced carcinoma of the prostate (Stage D2).

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

Manufacturers’ Warnings In Clinical States: General: Initially, goserelin transiently increases serum testosterone in males. 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.

Zoladex LA is not indicated for use in females, since there is insufficient evidence of reliable suppression of serum estradiol. For female patients requiring treatment with goserelin, refer to the prescribing information for Zoladex (3.6 mg depot).

Goserelin is not indicated for use in children, as safety and efficacy have not been established in this group of patients.

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

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 during the first month of therapy with goserelin (see Warnings). Initially, goserelin like other LHRH agonists transiently increases serum testosterone concentrations. In men by around 21 days after the first depot injection, testosterone concentrations have typically fallen to within the castrate range and remain suppressed with treatment every 12 weeks. It is unclear whether there is any relationship between these clinical events and the initial rise in serum testosterone observed during the first few days following administration of the first depot injection.

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 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.

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, blood urea nitrogen and creatinine may rarely be elevated during the first few days of therapy in prostate cancer patients before returning to normal.

Changes in Bone Density: Some bone loss can be anticipated as part of the natural aging process. It may also be expected to occur during medically induced hypoandrogenic state caused by long-term goserelin treatment.

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

Diagnostic Interference: Administration of goserelin results in suppression of pituitary-gonadal system. Diagnostic tests of pituitary-gonadal function conducted during and subsequent to the treatment period 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: Goserelin is not indicated for use in children (see Warnings).

Pregnancy and Fertility: Zoladex LA is not indicated for use in females (see Warnings).

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

Pharmacological effects include hot flushes and a decrease in potency, seldom requiring withdrawal of therapy. Breast swelling and tenderness have been noted infrequently. Initially, prostate cancer patients may experience a temporary increase in bone pain, which can be managed symptomatically. Isolated cases of spinal cord compression have been recorded.

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.

Although not reported by patients in the clinical trial program of Zoladex LA, following the administration of Zoladex (3.6 mg depot), arthralgia, skin rashes which are generally mild and often regress without discontinuation of therapy, and isolated cases of ureteric obstruction have been recorded.

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

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).

Two controlled clinical trials were conducted with 157 patients, comparing treatment with goserelin 10.8 mg versus goserelin 3.6 mg depots. During the comparative phase, patients were randomized to receive either a single 10.8 mg depot or 3 consecutive 3.6 mg depots (1 every 4 weeks) over this initial 12 week period. The only adverse event reported in greater than 5% of these patients during this phase was hot flushes, with the goserelin 10.8 mg group having an incidence of 47% and the goserelin 3.6 mg group having 48%.

From weeks 12 to 48 all patients were treated with 1 Zoladex LA depot every 12 weeks. During this noncomparative phase, the following adverse events were reported in greater than 5% of patients; hot flushes [vasodilation] (63.7%), general pain (14%), gynecomastia (8.3%), pelvic pain (5.7%), bone pain (5.7%) and asthenia (5.1%).

The following adverse events reported in greater than 1%, but less than 5% of 157 patients treated with Zoladex LA depot every 12 weeks are shown in Table I. Some of these would be expected in a proportion of the elderly population.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no human experience of overdosage. Animal tests suggest that no effect other than the intended therapeutic effects on sex hormone concentrations and on the reproductive tract will be evident with higher doses of goserelin. If overdosage occurs, this should be managed symptomatically.

Dosage And Administration: Adult Males (including the elderly): 1 depot containing goserelin acetate equivalent to 10.8 mg goserelin, should be injected s.c. into the anterior abdominal wall every 12 weeks following the procedure recommended on the instruction card (see Instructions for Use on card attached to sterile pouch). While the 12-week schedule should be adhered to, a delay of a few days is permissible (see Pharmacology).

In patients with impaired renal function, the serum half-life is increased (serum half-life is 2 to 4 hours in patients with normal renal function). When goserelin is given every 12 weeks, this change will not lead to any accumulation hence, no change in dosing is necessary.

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

Zoladex LA is not indicated for use in females, since there is insufficient evidence of reliable suppression of serum estradiol. For female patients requiring treatment with goserelin, refer to the prescribing information for Zoladex (3.6 mg depot) (see Warnings).

Goserelin is not indicated for use in children (see Warnings).

Instructions for Use (see package insert for illustrations): Caution: Do not depress plunger until Step 5. Read all instructions before use. 1. Swab abdominal injection site. 2. Open pouch at arrows and remove syringe. Do not remove blue clip. Check the depot is present in the window. 3. Remove blue 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 depot contains: goserelin acetate equivalent to goserelin 10.8 mg. The depot is supplied as a cylindrical rod of biodegradable and biocompatible D-L Lactide-glycolide copolymers and is presented in a sterile ready-to-use syringe with a 14 gauge needle for a single s.c. injection. The entire syringe is packaged in a sterile pouch. Instructions for administration, once every 12 weeks, are attached. Protect from light and moisture. Store in the intact package between 2 and 25°C.

ZOLADEX® LA Zeneca Goserelin Acetate Luteinizing Hormone-Releasing Hormone Analog (LHRH Analog)

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