Zoladex implant

Call your doctor for instructions if you miss an appointment for your goserelin implant injection.

Since the goserelin implant contains a specific amount of the medication, you are not likely to receive an overdose.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• painful or difficult urination;

• pain, bruising, swelling, redness, oozing, or bleeding where the implant was injected;

• high blood sugar--increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, weight loss;

• high calcium levels--nausea, vomiting, constipation, increased thirst or urination, muscle pain or weakness, bone pain, confusion, and feeling tired or restless;

• heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;

• nerve problems--back pain, muscle weakness, problems with balance or coordination, severe numbness or tingling in your legs or feet, loss of bladder or bowel control; or

• signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance.

Common side effects may include:

• hot flashes, sweating;

• mood changes, increased or decreased interest in sex;

• changes in sexual function, fewer erections than normal;

• headache;

• swelling in your hands or feet;

• vaginal dryness, itching, or discharge;

• changes in breast size; or

• acne, mild skin rash or itching.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

The pharmacologic properties of ZOLADEX and its mode of administration make accidental or intentional overdosage unlikely. There is no experience of overdosage from clinical trials. Animal studies indicate that no increased pharmacologic effect occurred at higher doses or more frequent administration. Subcutaneous doses of the drug as high as 1 mg/kg/day in rats and dogs did not produce any nonendocrine related sequelae; this dose is up to 250 times the estimated human daily dose based on the body surface area. If overdosage occurs, it should be managed symptomatically.

Mechanism of Action

ZOLADEX is a synthetic decapeptide analogue of GnRH. ZOLADEX acts as an inhibitor of pituitary gonadotropin secretion when administered in the biodegradable formulation.

In animal and in vitro studies, administration of goserelin resulted in the regression or inhibition of growth of the hormonally sensitive dimethylbenzanthracene (DMBA)-induced rat mammary tumor and Dunning R3327 prostate tumor.

Pharmacodynamics

Following initial administration, ZOLADEX causes an initial increase in serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels with subsequent increases in serum levels of testosterone. Chronic administration of ZOLADEX leads to sustained suppression of pituitary gonadotropins, and serum levels of testosterone consequently fall into the range normally seen in surgically castrated men approximately 21 days after initiation of therapy. This leads to accessory sex organ regression.

In clinical trials using ZOLADEX 3.6 mg with follow-up of more than 2 years, suppression of serum testosterone to castrate levels has been maintained for the duration of therapy.

Pharmacokinetics

Absorption

The pharmacokinetics of ZOLADEX have been determined in healthy male volunteers and patients. In healthy males, radiolabeled goserelin was administered as a single 250 mcg (aqueous solution) dose by the subcutaneous route. The absorption of radiolabeled drug was rapid, and the peak blood radioactivity levels occurred between 0.5 and 1.0 hour after dosing.

The overall pharmacokinetic profile of goserelin following administration of a ZOLADEX 10.8 mg depot to patients with prostate cancer was determined. The initial release of goserelin from the depot was relatively rapid resulting in a peak concentration at 2 hours after dosing. From Day 4 until the end of the 12-week dosing interval, the sustained release of goserelin from the depot produced reasonably stable systemic exposure. Mean (Standard Deviation) pharmacokinetic data are presented in Table 4. There is no clinically significant accumulation of goserelin following administration of four depots administered at 12-week intervals.

SD = standard deviation

Serum goserelin concentrations in prostate cancer patients administered three 3.6 mg depots followed by one 10.8 mg depot are displayed in Figure 1. The profiles for both formulations are primarily dependent upon the rate of drug release from the depots. For the 3.6 mg depot, mean concentrations gradually rise to reach a peak of about 3 ng/mL at around 15 days after administration and then decline to approximately 0.5 ng/mL by the end of the treatment period. For the 10.8 mg depot, mean concentrations increase to reach a peak of about 8 ng/mL within the first 24 hours and then decline rapidly up to Day 4. Thereafter, mean concentrations remain relatively stable in the range of about 0.3 to 1 ng/mL up to the end of the treatment period.

Administration of four ZOLADEX 10.8 mg depots to patients with prostate cancer resulted in testosterone levels that were suppressed to and maintained within the range normally observed in surgically castrated men (0 – 1.73 nmol/L or 0-50 ng/dL), over the dosing interval in approximately 91% (145/160) of patients studied. In 6 of 15 patients that escaped from castrate range, serum testosterone levels were maintained below 2.0 nmol/L (58 ng/dL) and in only one of the 15 patients did the depot completely fail to maintain serum testosterone levels to within the castrate range over a 336-day period (4 depot injections). In the 8 additional patients, a transient escape was followed 14 days later by a level within the castrate range.

Distribution

The apparent volume of distribution determined after subcutaneous administration of 250 mcg aqueous solution of goserelin was 44.1 ± 13.6 liters for healthy males. The plasma protein binding of goserelin was found to be 27%.

Metabolism

Metabolism of goserelin, by hydrolysis of the C-terminal amino acids, is the major clearance mechanism. The major circulating component in serum appeared to be 1–7 fragment, and the major component present in urine of one healthy male volunteer was 5-10 fragment. The metabolism of goserelin in humans yields a similar but narrow profile of metabolites to that found in other species. All metabolites found in humans have also been found in toxicology species.

Excretion

Clearance of goserelin following subcutaneous administration of a radiolabeled solution of goserelin was very rapid and occurred via a combination of hepatic and urinary excretion. More than 90% of a subcutaneous radiolabeled solution formulation dose of goserelin was excreted in urine. Approximately 20% of the dose recovered in urine was accounted for by unchanged goserelin.

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 two controlled clinical trials, 160 patients with advanced prostate cancer were randomized to receive either one 3.6 mg Zoladex Implant every four weeks or a single 10.8 mg Zoladex Implant every 12 weeks. Mean serum testosterone suppression was similar between the two arms. PSA falls at three months were 94% in patients who received the 10.8 mg implant and 92.5% in patients that received three 3.6 mg implants.

Periodic monitoring of serum testosterone levels should be considered if the anticipated clinical or biochemical response to treatment has not been achieved. A clinical outcome similar to that produced with the use of the 3.6 mg implant administered every 28 days is predicted with ZOLADEX 10.8 mg implant administered every 12 weeks (84 days). Total testosterone was measured by the DPC Coat-A-Count radioimmunoassay method which, as defined by the manufacturers, is highly specific and accurate. Acceptable variability of approximately 20% at low testosterone levels has been demonstrated in the clinical studies performed with the ZOLADEX 10.8 mg depot.

Zoladex implant is inserted through a needle into the skin of your upper stomach, once every 28 days. You will receive the implant in a clinic or doctor's office.

Your dosing schedule may be different if you are also receiving chemotherapy. Follow your doctor's instructions. It is very important to receive your Zoladex injections on time each month.

You are not likely to be able to feel the implant through your skin, and it should not cause pain or discomfort. The implant will dissolve in your body over time.

While your hormone levels are adjusting, you may notice new or worsening symptoms of your condition during the first few weeks of treatment. Tell your doctor if your symptoms do not improve after several weeks.

If you are a premenopausal woman, you should stop having menstrual periods while the Zoladex implant is in place. Call your doctor if you still have regular periods. Missing a dose can cause breakthrough bleeding. After you stop using Zoladex, you should begin having regular periods within 12 weeks.

Your blood sugar may need to be checked while using Zoladex, even if you are not diabetic. You may need other blood tests at your doctor's office.

Zoladex can cause you to have unusual results with certain medical tests. Tell any doctor who treats you that you are using Zoladex.

Applies to goserelin: subcutaneous implant

Along with its needed effects, goserelin (the active ingredient contained in Zoladex) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking goserelin:

• Fast or irregular heartbeat

• Bone, muscle, or joint pain
• changes in skin color of the face
• fainting
• fast or irregular breathing
• numbness or tingling of the hands or feet
• puffiness or swelling of the eyelids or around the eyes
• skin rash, hives, or itching
• sudden, severe decrease in blood pressure and collapse
• tightness in the chest
• troubled breathing

• Anxiety
• deepening of voice
• increased hair growth
• mental depression
• mood changes

• Pain in the chest
• pain in the groin or legs (especially in the calves of the legs)

Some side effects of goserelin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Sudden sweating and feelings of warmth (also called hot flashes)

• Blurred vision
• burning, itching, redness, or swelling at the place of injection
• decreased interest in sexual intercourse
• dizziness
• headache
• nausea or vomiting
• swelling and increased tenderness of the breasts
• swelling of the feet or lower legs
• trouble sleeping
• weight gain

• Light, irregular vaginal bleeding
• stopping of menstrual periods

• Burning, dryness, or itching of the vagina
• pelvic pain

• Bone pain
• constipation
• decreased size of the testicles
• inability to have or keep an erection

Applies to goserelin: subcutaneous implant

General

In general, hot flashes (in males (M) 54% to 80% and in females (F) 70% to 96%) have been the most frequently reported side effect. Headache (F 59% to 75% and M 14%), tumor flare (F 23%), flu syndrome, malaise, fatigue and lethargy (all F 5%) have been reported. Pain (F 17% and M 8% to 14%) has been reported including; breast pain (F 7%), abdominal pain (F 7%), back pain (F 7%) and pelvic bone pain (M 6%).[Ref]

Some clinicians have used the addition of the oral progestational agent megestrol acetate to reduce the hot flashes. A dose of megestrol acetate 20 mg two times a day may be appropriate. Tumor flare may also occur in males if antiandrogens are not administered.[Ref]

Genitourinary

Genitourinary side effects in female patients have included vaginitis (75%), libido decrease (61%) or increase (12%), vaginal dryness (58%), breast atrophy (33%) or enlargement (18%), pelvic symptoms (18%) and dyspareunia (14%). In male patients, sexual dysfunction (21%), decreased erections (18%), lower urinary tract symptoms (13%) and gynecomastia (8%) have been reported. Renal insufficiency, urinary obstruction, urinary tract infection, bladder neoplasm, hematuria, impotence, urinary frequency, urinary incontinence, urinary tract disorder and impaired urination have also been reported to occur in 1% to 5% of patients. Breast tenderness, breast pain, ovarian cyst formation, and ovarian hyperstimulation syndrome, and prolonged hypogonadism have also been reported.[Ref]

During the first two months of therapy, some women have reported vaginal bleeding. This bleeding may have been due to estrogen withdrawal.[Ref]

Psychiatric

Psychiatric side effects including emotional lability (F 47% to 60%) and depression (F 40% to 54%) have been reported. Anxiety and abnormal thinking have also been reported.

Postmarketing psychiatric side effects including psychotic disorders and mood swings have been reported.[Ref]

Dermatologic

Dermatologic side effects including sweating (F 45% to 77% and M 6% to 10%), acne (F 42%), seborrhea (F 26%), hirsutism (F 7%), rash (M 6% to 14%), hair disorders (F 4%) and pruritus (F 2%) have been reported. Alopecia, dry skin, skin discoloration and herpes simplex have also been reported.

Postmarketing dermatologic side effects including acne have been reported.[Ref]

Cardiovascular

Cardiovascular side effects including edema (F 21% and M 7% to 26%), chest pain (M 13%) and congestive heart failure (M 5%) have been reported. Cerebrovascular accident, arrhythmia, hypertension, myocardial infarction, peripheral vascular disorder, angina pectoris, cerebral ischemia, heart failure, pulmonary embolus and varicose veins have been reported to occur in 1% to 5% of patients. Hemorrhage, migraine, palpitations and tachycardia have also been reported. Myocardial infarction, sudden cardiac death, and stroke have been reported in patients treated with GnRH agonists.[Ref]

Nervous system

Nervous system side effects including lethargy (M 8% to 26%), dizziness (F 6% and M 1% to 18%), paresthesia (M 12%), asthenia (F 11%), insomnia (F 5% to 11% and M 12%) and nervousness (F 3%) have been reported. Anxiety and urinary retention have been reported to occur in 1% to 5% of patients. Somnolence has also been reported. As a result of increased prostate tumor growth caused by initial testosterone level elevation, a case of spinal cord compression resulting in paraplegia has been reported.

Postmarketing nervous system side effects including convulsions have been reported.[Ref]

Gastrointestinal

Gastrointestinal side effects including constipation (M 12%), nausea (F 8% to 11% and M 5%), anorexia (M 5%), vomiting (F 4%) and increased appetite (2%) have been reported. Diarrhea and hematemesis have been reported to occur in 1% to 5% of patients. Ulcer, dyspepsia, dry mouth and flatulence have also been reported.[Ref]

Respiratory

Respiratory side effects including pharyngitis (F 5%) and voice alterations (F 3%) have been reported.[Ref]

Hypersensitivity

Hypersensitivity reactions, both at the injection site (F 6%) and to the whole body have been reported.[Ref]

Musculoskeletal

Musculoskeletal side effects including an average 4.3% decrease in vertebral trabecular bone mineral density (BMD) after six months of therapy (n=109 F patients), when compared to their pretreatment values. Myalgia (F 3%), leg cramps (F 3%) and hypertonia (F 1%) have been reported. Arthralgia and joint disorders have also been reported.[Ref]

Data suggest the decrease in BMD is partially reversible upon discontinuation of therapy.[Ref]

Metabolic

Metabolic side effects including gout, hyperglycemia, weight increase, and diabetes mellitus have been reported to occur in 1% to 5% of patients.[Ref]

Hematologic

Hematologic side effects including ecchymosis and sepsis have been reported to occur in 1% to 5% of patients.[Ref]

Ocular

Ocular side effects including amblyopia and dry eyes have been reported.[Ref]

Endocrine

Endocrine side effects including very rare cases of pituitary apoplexy have been reported. Reduction in glucose tolerance, manifesting as diabetes or loss of glycemic control in those with preexisting diabetes, has also been reported during treatment with GnRH agonists, including goserelin (the active ingredient contained in Zoladex) [Ref]

Pituitary apoplexy is a clinical syndrome secondary to infarction of the pituitary gland. In a majority of the cases of pituitary apoplexy, a pituitary adenoma was diagnosed. Most of the pituitary apoplexy cases occurred within two weeks of the first dose, and some occurred within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.[Ref]

Oncologic

Oncologic side effects including very rare cases of pituitary tumors have been reported.[Ref]

Some side effects of Zoladex may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.