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ZOLADEX®
(goserelin acetate implant)
3.6 MG

Equivalent to 3.6 mg goserelin

DESCRIPTION

ZOLADEX® (goserelin acetate implant), contains a potent synthetic decapeptide analogue of luteinizing hormone-releasing hormone (LHRH), also known as a gonadotropin releasing hormone (GnRH) agonist analogue. Goserelin acetate is chemically described as an acetate salt of [D-Ser(But)6,Azgly10]LHRH. Its chemical structure is pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C59H84N18O14•(C2H4O2)x where x = 1 to 2.4].

Goserelin acetate is an off-white powder with a molecular weight of 1269 Daltons (free base). It is freely soluble in glacial acetic acid. It is soluble in water, 0.1M hydrochloric acid, 0.1M sodium hydroxide, dimethylformamide and dimethyl sulfoxide. Goserelin acetate is practically insoluble in acetone, chloroform and ether.

ZOLADEX is supplied as a sterile, biodegradable product containing goserelin acetate equivalent to 3.6 mg of goserelin. ZOLADEX is designed for subcutaneous injection with continuous release over a 28-day period. Goserelin acetate is dispersed in a matrix of D,L-lactic and glycolic acids copolymer (13.3-14.3 mg/dose) containing less than 2.5% acetic acid and up to 12% goserelin-related substances and presented as a sterile, white to cream colored 1-mm diameter cylinder, preloaded in a special single use syringe with a 16-gauge x 36 +/- 0.5 mm siliconized needle with protective needle sleeve (SafeSystem™ Syringe) in a sealed, light and moisture proof, aluminum foil laminate pouch containing a desiccant capsule. Studies of the D,L-lactic and glycolic acids copolymer have indicated that it is completely biodegradable and has no demonstrable antigenic potential.

CLINICAL PHARMACOLOGY

Mechanism of Action

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

Following initial administration in males, 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 2-4 weeks after initiation of therapy. This leads to accessory sex organ regression. 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. In clinical trials with follow-up of more than 2 years, suppression of serum testosterone to castrate levels has been maintained for the duration of therapy.

In females, a similar down-regulation of the pituitary gland by chronic exposure to ZOLADEX leads to suppression of gonadotropin secretion, a decrease in serum estradiol to levels consistent with the postmenopausal state, and would be expected to lead to a reduction of ovarian size and function, reduction in the size of the uterus and mammary gland, as well as a regression of sex hormone-responsive tumors, if present. Serum estradiol is suppressed to levels similar to those observed in postmenopausal women within 3 weeks following initial administration; however, after suppression was attained, isolated elevations of estradiol were seen in 10% of the patients enrolled in clinical trials. Serum LH and FSH are suppressed to follicular phase levels within four weeks after initial administration of drug and are usually maintained at that range with continued use of ZOLADEX. In 5% or less of women treated with ZOLADEX, FSH and LH levels may not be suppressed to follicular phase levels on day 28 post treatment with use of a single 3.6 mg depot injection. In certain individuals, suppression of any of these hormones to such levels may not be achieved with ZOLADEX. Estradiol, LH and FSH levels return to pretreatment values within 12 weeks following the last implant administration in all but rare cases.

Pharmacokinetics

The pharmacokinetics of ZOLADEX have been determined in both male and female healthy volunteers and patients. In these studies, ZOLADEX was administered as a single 250 µg (aqueous solution) dose and as a single or multiple 3.6 mg depot dose by subcutaneous route.

Special Populations:

Clinical Studies

INDICATIONS AND USAGE

Prostatic Carcinoma:

ZOLADEX is indicated in the palliative treatment of advanced carcinoma of the prostate.

Stage B2-C Prostatic Carcinoma:

ZOLADEX is indicated for use in combination with flutamide for the management of locally confined Stage T2b-T4 (Stage B2-C) carcinoma of the prostate. Treatment with ZOLADEX and flutamide should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.

Endometriosis:

ZOLADEX is indicated for the management of endometriosis, including pain relief and reduction of endometriotic lesions for the duration of therapy. Experience with ZOLADEX for the management of endometriosis has been limited to women 18 years of age and older treated for 6 months.

Advanced Breast Cancer:

ZOLADEX is indicated for use in the palliative treatment of advanced breast cancer in pre- and perimenopausal women.

The estrogen and progesterone receptor values may help to predict whether ZOLADEX therapy is likely to be beneficial. (See CLINICAL PHARMACOLOGY.)

Endometrial Thinning:

ZOLADEX is indicated for use as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding.

The automatic safety feature of the syringe aids in the prevention of needlestick injury.

CONTRAINDICATIONS

A report of an anaphylactic reaction to synthetic GnRH (Factrel) has been reported in the medical literature. ZOLADEX is contraindicated in those patients who have a known hypersensitivity to LHRH, LHRH agonist analogues or any of the components in ZOLADEX.

ZOLADEX is contraindicated in women being treated for endometriosis or endometrial thinning who are or may become pregnant while receiving the drug. ZOLADEX can cause fetal harm when administered to a pregnant woman. Effects on reproductive function, as a result of antigonadotrophic properties of the drug, are expected to occur on chronic administration.

Effective nonhormonal contraception must be used by all premenopausal women during ZOLADEX therapy and for 12 weeks following discontinuation of therapy. There are no adequate and well-controlled studies in pregnant women using ZOLADEX. If this drug is used during pregnancy, or the patient being treated for endometriosis or endometrial thinning becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant.

For a description of findings in animal reproductive toxicity studies, see WARNINGS.

ZOLADEX is contraindicated in women who are breast feeding (see Nursing Mothers section).

WARNINGS

Before starting treatment with ZOLADEX, pregnancy must be excluded. Safe use of ZOLADEX in pregnancy has not been established. ZOLADEX can cause fetal harm when administered to a pregnant woman. ZOLADEX has been found to cross the placenta following subcutaneous administration of 50 and 1000 μg/kg in rats and rabbits, respectively. Studies in both rats and rabbits at doses equal to or greater than 2 and 20 mg/kg/day, respectively (about 1/10 and 2 times the daily maximum recommended human dose, respectively, on a μg/m2 basis), administered during the period of organogenesis, have confirmed that ZOLADEX will increase pregnancy loss, and is embryotoxic/fetotoxic (characterized by increased preimplantation loss, increased resorption and an increase in umbilical hernia in rats at a dose of ≥ 10 μg/kg/day [about 1/2 the recommended human dose on a mg/m2 basis]); effects were dose-related. In additional reproduction studies in rats, ZOLADEX was found to decrease fetus and pup survival.

There are no adequate and well-controlled studies in pregnant women using ZOLADEX. Women of childbearing potential should be advised to avoid becoming pregnant.

When used every 28 days, ZOLADEX usually inhibits ovulation and stops menstruation. Contraception is not ensured, however, by taking ZOLADEX. During treatment, pregnancy must be avoided by the use of nonhormonal methods of contraception. If ZOLADEX is used during pregnancy (in a patient with advanced breast cancer) or the patient becomes pregnant while receiving this drug, the patient must be apprised of the potential risk for loss of the pregnancy due to possible hormonal imbalance as a result of the expected pharmacologic action of ZOLADEX treatment.

Following the last ZOLADEX injection, nonhormonal methods of contraception must be continued until the return of menses or for at least 12 weeks. (See CONTRAINDICATIONS.)

Prostate and Breast Cancer:

Initially, ZOLADEX, like other LHRH agonists, causes transient increases in serum levels of testosterone in men with prostate cancer, and estrogen in women with breast cancer. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate or breast cancer, may occasionally develop during the first few weeks of ZOLADEX treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other LHRH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed in patients with prostate cancer. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted. For extreme cases in prostate cancer patients, an immediate orchiectomy should be considered.

As with other LHRH agonists or hormonal therapies (antiestrogens, estrogens, etc.), hypercalcemia has been reported in some prostate and breast cancer patients with bone metastases after starting treatment with ZOLADEX. If hypercalcemia does occur, appropriate treatment measures should be initiated.

PRECAUTIONS

General:

Hypersensitivity, antibody formation and acute anaphylactic reactions have been reported with LHRH agonist analogues.

Of 115 women worldwide treated with ZOLADEX and tested for development of binding to goserelin following treatment with ZOLADEX, one patient showed low-titer binding to goserelin. On further testing of this patient's plasma obtained following treatment, her goserelin binding component was found not to be precipitated with rabbit antihuman immunoglobulin polyvalent sera. These findings suggest the possibility of antibody formation.

The pharmacologic action of ZOLADEX on the uterus and cervix may cause an increase in cervical resistance. Therefore, care should be taken when dilating the cervix for endometrial ablation.

Information for Patients:

Drug Interactions:

No formal drug-drug interaction studies have been performed. No confirmed interactions have been reported between ZOLADEX and other drugs.

Drug/Laboratory Test Interactions:

Administration of ZOLADEX in therapeutic doses results in suppression of the pituitary-gonadal system. Because of this suppression, diagnostic tests of pituitary-gonadotropic and gonadal functions conducted during treatment and until the resumption of menses may show results which are misleading. Normal function is usually restored within 12 weeks after treatment is discontinued.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Subcutaneous implant of ZOLADEX in male and female rats once every 4 weeks for 1 year and recovery for 23 weeks at doses of about 80 and 150 μg/kg (males) and 50 and 100 μg/kg (females) daily (about 3 to 9 times the recommended human dose on a mg/m2 basis) resulted in an increased incidence of pituitary adenomas. An increased incidence of pituitary adenomas was also observed following subcutaneous implant of ZOLADEX in rats at similar dose levels for a period of 72 weeks in males and 101 weeks in females. The relevance of the rat pituitary adenomas to humans has not been established. Subcutaneous implants of ZOLADEX every 3 weeks for 2 years delivered to mice at doses of up to 2400 μg/kg/day (about 70 times the recommended human dose on a mg/m2 basis) resulted in an increased incidence of histiocytic sarcoma of the vertebral column and femur.

Mutagenicity tests using bacterial and mammalian systems for point mutations and cytogenetic effects have provided no evidence for mutagenic potential.

Administration of goserelin led to changes that were consistent with gonadal suppression in both male and female rats as a result of its endocrine action. In male rats administered 500-1000 μg/kg/day (about 30-60 times the recommended human dose on a mg/m2 basis), a decrease in weight and atrophic histological changes were observed in the testes, epididymis, seminal vesicle and prostate gland with complete suppression of spermatogenesis. In female rats administered 50-1000 μg/kg/day (about 3-60 times the recommended daily human dose on a mg/m2 basis), suppression of ovarian function led to decreased size and weight of ovaries and secondary sex organs; follicular development was arrested at the antral stage and the corpora lutea were reduced in size and number. Except for the testes, almost complete histologic reversal of these effects in males and females was observed several weeks after dosing was stopped; however, fertility and general reproductive performance were reduced in those that became pregnant after goserelin was discontinued. Fertile matings occurred within 2 weeks after cessation of dosing, even though total recovery of reproductive function may not have occurred before mating took place; and, the ovulation rate, the corresponding implantation rate, and number of live fetuses were reduced.

Based on histological examination, drug effects on reproductive organs were reversible in male and female dogs administered 107-214 μg/kg/day ZOLADEX (about 20-40 times the recommended daily human dose on a mg/m2 basis) when drug treatment was stopped after continuous administration for 1 year.

Pregnancy:

Nursing Mothers:

ZOLADEX has been shown to be excreted in the milk of lactating rats. It is not known if this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from ZOLADEX in nursing infants, mothers should discontinue nursing prior to taking the drug.

Pediatric Use:

The safety and efficacy of ZOLADEX in pediatric patients have not been established.

ADVERSE REACTIONS

General:

Rarely, hypersensitivity reactions (including urticaria and anaphylaxis) have been reported in patients receiving ZOLADEX.

Changes in blood pressure, manifest as hypotension or hypertension, have been occasionally observed in patients administered ZOLADEX. The changes are usually transient, resolving either during continued therapy or after cessation of therapy with ZOLADEX. Rarely, such changes have been sufficient to require medical intervention including withdrawal of treatment from ZOLADEX.

Males - Prostatic Carcinoma:

ZOLADEX has been found to be generally well tolerated in clinical trials. Adverse reactions reported in these trials were rarely severe enough to result in the patients' withdrawal from ZOLADEX treatment. As seen with other hormonal therapies, the most commonly observed adverse events during ZOLADEX therapy were due to the expected physiological effects from decreased testosterone levels. These included hot flashes, sexual dysfunction and decreased erections.

Initially, ZOLADEX, like other LHRH agonists, causes transient increases in serum levels of testosterone. A small percentage of patients experienced a temporary worsening of signs and symptoms (see WARNINGS section), usually manifested by an increase in cancer-related pain which was managed symptomatically. Isolated cases of exacerbation of disease symptoms, either ureteral obstruction or spinal cord compression, occurred at similar rates in controlled clinical trials with both ZOLADEX and orchiectomy. The relationship of these events to therapy is uncertain.

There have been post-marketing reports of osteoporosis, decreased bone mineral density and bony fracture in men treated with ZOLADEX for prostate cancer.

In the controlled clinical trials of ZOLADEX versus orchiectomy, the following events were reported as adverse reactions in greater than 5% of the patients.

TREATMENT RECEIVED

ZOLADEX

ORCHIECTOMY

(n=242)

(n=254)

ADVERSE EVENT

%

%

Hot Flashes

62

53

Sexual Dysfunction

21

15

Decreased Erections

18

16

Lower Urinary Tract Symptoms

13

8

Lethargy

8

4

Pain (worsened in the first 30 days)

8

3

Edema

7

8

Upper Respiratory Infection

7

2

Rash

6

1

Sweating

6

4

Anorexia

5

2

Chronic Obstructive Pulmonary Disease

5

3

Congestive Heart Failure

5

1

Dizziness

5

4

Insomnia

5

1

Nausea

5

2

Complications of Surgery

0

18Complications related to surgery were reported in 18% of the orchiectomy patients, while only 3% of ZOLADEX patients reported adverse reactions at the injection site. The surgical complications included scrotal infection (5.9%), groin pain (4.7%), wound seepage (3.1%), scrotal hematoma (2.8%), incisional discomfort (1.6%) and skin necrosis (1.2%).

The following additional adverse reactions were reported in greater than 1% but less than 5% of the patients treated with ZOLADEX: CARDIOVASCULAR - arrhythmia, cerebrovascular accident, hypertension, myocardial infarction, peripheral vascular disorder, chest pain; CENTRAL NERVOUS SYSTEM - anxiety, depression, headache; GASTROINTESTINAL - constipation, diarrhea, ulcer, vomiting; HEMATOLOGIC - anemia; METABOLIC/NUTRITIONAL - gout, hyperglycemia, weight increase; MISCELLANEOUS - chills, fever; UROGENITAL - renal insufficiency, urinary obstruction, urinary tract infection, breast swelling and tenderness.

Stage B2-C Prostatic Carcinoma:

Treatment with ZOLADEX and flutamide did not add substantially to the toxicity of radiation treatment alone. The following adverse experiences were reported during a multicenter clinical trial comparing ZOLADEX + flutamide + radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are uled below:

ADVERSE EVENTS DURING ACUTE RADIATION THERAPY (within first 90 days of radition therapy)

(n=231)

(n = 235)

flutamide + ZOLADEX + Radiation

Radiation Only

% All

% All

Rectum/Large Bowel

80

76

Bladder

58

60

Skin

37

37

ADVERSE EVENTS DURING LATE RADIATION PHASE (after 90 days of radiation therapy)

(n=231)

(n = 235)

flutamide + ZOLADEX + Radiation

Radiation Only

% All

% All

Diarrhea

36

40

Cystitis

16

16

Rectal Bleeding

14

20

Proctitis

8

8

Hematuria

7

12

Additional adverse event data was collected for the combination therapy with radiation group over both the hormonal treatment and hormonal treatment plus radiation phases of the study. Adverse experiences occurring in more than 5% of patients in this group, over both parts of the study, were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%).

Females:

As would be expected with a drug that results in hypoestrogenism, the most frequently reported adverse reactions were those related to this effect.

As with other LHRH agonists, there have been reports of ovarian cyst formation and, when ZOLADEX 3.6 mg is used in combination with gonadotropins, of ovarian hyperstimulation syndrome (OHSS).

Endometriosis:

In controlled clinical trials comparing ZOLADEX every 28 days and danazol daily for the treatment of endometriosis, the following events were reported at a frequency of 5% or greater:

TREATMENT RECEIVED

ZOLADEX

DANAZOL

(n=411)

(n=207)

ADVERSE EVENT

%

%

Hot Flushes

96

67

Vaginitis

75

43

Headache

75

63

Emotional Lability

60

56

Libido Decreased

61

44

Sweating

45

30

Depression

54

48

Acne

42

55

Breast Atrophy

33

42

Seborrhea

26

52

Peripheral Edema

21

34

Breast Enlargement

18

15

Pelvic Symptoms

18

23

Pain

17

16

Dyspareunia

14

5

Libido Increased

12

19

Infection

13

11

Asthenia

11

13

Nausea

8

14

Hirsutism

7

15

Insomnia

11

4

Breast Pain

7

4

Abdominal Pain

7

7

Back Pain

7

13

Flu Syndrome

5

5

Dizziness

6

4

Application Site Reaction

6

-

Voice Alterations

3

8

Pharyngitis

5

2

Hair Disorders

4

11

Myalgia

3

11

Nervousness

3

5

Weight Gain

3

23

Leg Cramps

2

6

Increased Appetite

2

5

Pruritus

2

6

Hypertonia

1

10

The following adverse events not already uled above were reported at a frequency of 1% or greater, regardless of causality, in ZOLADEX-treated women from all clinical trials: WHOLE BODY - allergic reaction, chest pain, fever, malaise; CARDIOVASCULAR - hemorrhage, hypertension, migraine, palpitations, tachycardia; DIGESTIVE - anorexia, constipation, diarrhea, dry mouth, dyspepsia, flatulence; HEMATOLOGIC - ecchymosis; METABOLIC AND NUTRITIONAL - edema; MUSCULOSKELETAL - arthralgia, joint disorder; CNS - anxiety, paresthesia, somnolence, thinking abnormal; RESPIRATORY - bronchitis, cough increased, epistaxis, rhinitis, sinusitis; SKIN - alopecia, dry skin, rash, skin discoloration; SPECIAL SENSES - amblyopia, dry eyes; UROGENITAL - dysmenorrhea, urinary frequency, urinary tract infection, vaginal hemorrhage.

Hormone Replacement Therapy:

Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to ZOLADEX may decrease the occurrence of vasomotor symptoms and vaginal dryness associated with hypoestrogenism without compromising the efficacy of ZOLADEX in relieving pelvic symptoms. The optimal drugs, dose and duration of treatment has not been established.

Changes in Bone Mineral Density:

After 6 months of ZOLADEX treatment, 109 female patients treated with ZOLADEX showed an average 4.3% 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. Sixty-six of these patients were assessed for BMD loss 6 months after the completion (posttherapy) of the 6-month therapy period. Data from these patients showed an average 2.4% BMD loss compared to pretreatment values. Twenty-eight of the 109 patients were assessed for BMD at 12 months posttherapy. 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. 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 optimal drugs, dose and duration of treatment has not been established.

Changes in Laboratory Values During Treatment:

Breast Cancer:

The adverse event profile for women with advanced breast cancer treated with ZOLADEX is consistent with the profile described above for women treated with ZOLADEX for endometriosis. In a controlled clinical trial (SWOG-8692) comparing ZOLADEX 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.

TREATMENT RECEIVED

ZOLADEX

OOPHORECTOMY

(n=57)

(n=55)

ADVERSE EVENT

% of Pts.

% of Pts.

Hot Flashes

70

47

Tumor Flare

23

4

Nausea

11

7

Edema

5

0

Malaise/Fatigue/Lethargy

5

2

Vomiting

4

7

In the Phase II clinical trial program in 333 pre- and perimenopausal women with advanced breast cancer, hot flashes were reported in 75.9% of patients and decreased libido was noted in 47.7% of patients. These two adverse events reflect the pharmacological actions of ZOLADEX.

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

Endometrial Thinning:

The following adverse events were reported at a frequency of 5% or greater in premenopausal women presenting with dysfunctional uterine bleeding in Trial 0022 for endometrial thinning. These results indicate that headache, hot flushes and sweating were more common in the ZOLADEX group than in the placebo group.

ADVERSE EVENTS REPORTED AT A FREQUENCY OF 5% OR GREATER IN ZOLADEX AND PLACEBO TREATMENT GROUPS OF TRIAL 0022

ZOLADEX 3.6 mg

Placebo

(n=180)

(n=177)

ADVERSE EVENT

%

%

Whole Body

Headache

32

22

Abdominal Pain

11

10

Pelvic Pain

9

6

Back Pain

4

7

Cardiovascular

Vasodilatation

57

18

Migraine

7

4

Hypertension

6

2

Digestive

Nausea

5

6

Nervous

Nervousness

5

3

Depression

3

7

Respiratory

Pharyngitis

6

9

Sinusitis

3

6

Skin and appendages

Sweating

16

5

Urogenital

Dysmenorrhea

7

9

Uterine Hemorrhage

6

4

Vulvovaginitis

5

1

Menorrhagia

4

5

Vaginitis

1

6

Post-Marketing:

Pituitary Apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed. Most of the pituitary apoplexy cases occurred within 2 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.

OVERDOSAGE

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 greater than 400 times that proposed for human use. If overdosage occurs, it should be managed symptomatically.

DOSAGE AND ADMINISTRATION

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.

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

Prostate Cancer:

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

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.

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.

Breast Cancer:

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

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.

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.

  • 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.

  • 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.

  • 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.

  • 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.

  • Do not penetrate into muscle or peritoneum.

  • 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

  • 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.

HOW SUPPLIED

ZOLADEX is supplied as a sterile and totally biodegradable D,L-lactic and glycolic acids copolymer (13.3-14.3 mg/dose) impregnated with goserelin acetate equivalent to 3.6 mg of goserelin in a disposable syringe device fitted with a 16-gauge x 36 +/- 0.5 mm siliconized hypodermic needle with protective needle sleeve [SafeSystem™ Syringe] (NDC 0310-0950-36). The unit is sterile and comes in a sealed, light and moisture proof, aluminum foil laminate pouch containing a desiccant capsule. Store at room temperature (do not exceed 25°C [77°F]).

Manufactured for:

AstraZeneca Pharmaceuticals LP

Wilmington, DE 19850

by: AstraZeneca UK Limited

Macclesfield, England

Made in United Kingdom

Rev 10-05 SIC 30265–00

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