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Zoladex Depot

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Zoladex Depot uses


1 INDICATIONS AND USAGE

Zoladex Depot is a Gonadotropin Releasing Hormone agonist indicated for:

1.1 Stage B2-C Prostatic Carcinoma

Zoladex Depot 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 Depot and flutamide should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy [see Dosage and Administration (2.1) and Clinical Studies (14.1)].

1.2 Prostatic Carcinoma

Zoladex Depot is indicated in the palliative treatment of advanced carcinoma of the prostate .

1.3 Endometriosis

Zoladex Depot is indicated for the management of endometriosis, including pain relief and reduction of endometriotic lesions for the duration of therapy. Experience with Zoladex Depot for the management of endometriosis has been limited to women 18 years of age and older treated for 6 months [see Dosage and Administration (2.3) and Clinical Studies (14.3)].

1.4 Endometrial Thinning

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

1.5 Advanced Breast Cancer

Zoladex Depot 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 Depot therapy is likely to be beneficial [see Dosage and Administration (2.6), Clinical Pharmacology (12.1), and Clinical Studies (14.5)].

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

2 DOSAGE AND ADMINISTRATION

Zoladex Depot, 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.

2.1 Stage B2-C Prostatic Carcinoma

When Zoladex Depot 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 Depot 3.6 mg depot 8 weeks before radiotherapy, followed in 28 days by the Zoladex Depot 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.

2.2 Prostatic Carcinoma

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

2.3 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 Depot 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 Depot is contemplated, consideration should be given to monitoring bone mineral density. Clinical studies suggest the addition of Hormone Replacement Therapy to Zoladex Depot is effective in reducing the bone mineral loss which occurs with Zoladex Depot alone without compromising the efficacy of Zoladex Depot 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.

2.4 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.

2.5 Breast Cancer

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

2.6 Renal or Hepatic Impairment

No dosage adjustment is necessary for patients with renal or hepatic impairment.

2.7 Administration Technique

The proper method of administration of Zoladex Depot is described in the instructions that follow.

3 DOSAGE FORMS AND STRENGTHS

Zoladex Depot is supplied as a sterile and totally biodegradable D,L-lactic and glycolic acids copolymer (13.3-14.3 mg/dose) impregnated with Zoladex Depot 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).

Implant 3.6 mg (3)

4 CONTRAINDICATIONS

4.1 Hypersensitivity

Anaphylactic reactions to Zoladex Depot have been reported in the medical literature. Zoladex Depot is contraindicated in those patients who have a known hypersensitivity to GnRH, GnRH agonist analogues or any of the components in Zoladex Depot .

4.2 Pregnancy

Zoladex Depot is contraindicated during pregnancy unless Zoladex Depot is being used for palliative treatment of advanced breast cancer. Zoladex Depot can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. There is an increased risk for pregnancy loss due to expected hormone changes that occur with Zoladex Depot treatment .

5 WARNINGS AND PRECAUTIONS

5.1 Women of Childbearing Potential and Pregnancy

Before starting treatment with Zoladex Depot, pregnancy must be excluded for women using Zoladex Depot for benign gynecological conditions. Women of childbearing potential should be advised to avoid becoming pregnant.

Effective nonhormonal contraception must be used by all premenopausal women during Zoladex Depot therapy and for 12 weeks following discontinuation of therapy. When used every 28 days, Zoladex Depot usually inhibits ovulation and stops menstruation; however, pregnancy prevention is not ensured. Effects on reproductive function are expected to occur with chronic administration as a result of the anti-gonadotrophic properties of the drug.

Based on mechanism of action in humans and findings of increased pregnancy loss in animal studies, Zoladex Depot can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy for the palliative treatment of breast cancer, then the patient should be apprised of the potential hazard to the fetus .

5.2 Tumor Flare Phenomenon

Initially, Zoladex Depot, like other GnRH 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 Depot treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically.

As with other GnRH 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 secondary to ureteral obstruction develops, standard treatment of these complications should be instituted. For extreme cases in prostate cancer patients, an immediate orchiectomy should be considered.

5.3 Hyperglycemia and Diabetes

Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes .

5.4 Cardiovascular Diseases

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice .

5.5 Hypercalcemia

As with other GnRH agonists or hormonal therapies, hypercalcemia has been reported in some prostate and breast cancer patients with bone metastases after starting treatment with Zoladex Depot. If hypercalcemia does occur, appropriate treatment measures should be initiated.

5.6 Hypersensitivity

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

Of 115 women worldwide treated with Zoladex Depot and tested for development of binding to goserelin following treatment with Zoladex Depot, 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.

5.7 Cervical Resistance

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

5.8 Effect on QT/QTc Interval

Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.

5.9 Injection Site Injury

Injection site injury and vascular injury including pain, hematoma, hemorrhage and hemorrhagic shock, requiring blood transfusions and surgical intervention, have been reported with Zoladex Depot. Extra care should be taken when administering Zoladex Depot to patients with a low BMI and/or to patients receiving full dose anticoagulation [see Dosage and Administration (2.7) and Patient Counseling Information (17.1 and 17.2)].

6 ADVERSE REACTIONS

The most common, clinically significant adverse reactions occurring in >10% of men: hot flashes, sexual dysfunction, decreased erections and lower urinary tract symptoms

The adverse event profile was similar for women treated for breast cancer, dysfunctional uterine bleeding or endometriosis and included (>20%): hot flushes, headache, sweating, acne, emotional lability, depression, decreased libido, vaginitis, breast atrophy, seborrhea, and peripheral edema (6)

Tumor flare can occur on the initiation of Zoladex Depot for both men and women being treated for cancer (6)

To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Stage B2-C Prostatic Carcinoma

Treatment with Zoladex Depot 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 Depot + flutamide + radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below:


(n=231) flutamide + Zoladex Depot + Radiation

(n=235) Radiation Only

% All

%All

Rectum/Large Bowel

80

76

Bladder

58

60

Skin

37

37

(n=231) flutamide + Zoladex Depot + Radiation

(n=235) 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%).

6.2 Prostatic Carcinoma

Zoladex Depot 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 Depot treatment. As seen with other hormonal therapies, the most commonly observed adverse events during Zoladex Depot therapy were due to the expected physiological effects from decreased testosterone levels. These included hot flashes, sexual dysfunction and decreased erections.

Tumor Flare Phenomenon: Initially, Zoladex Depot, like other GnRH agonists, causes transient increases in serum levels of testosterone. A small percentage of patients experienced a temporary worsening of signs and symptoms, 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 Depot and orchiectomy. The relationship of these events to therapy is uncertain .

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

Zoladex Depot

(n=242)

ORCHIECTOMY

(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 Depot 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 Depot: 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.

6.3 Females

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

6.4 Endometriosis

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

Zoladex Depot

DANAZOL

(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 listed 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.

6.5 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 Depot group than in the placebo group.

Zoladex Depot

3.6 mg

(n=180)

Placebo

(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

6.6 Breast Cancer

The adverse event profile for women with advanced breast cancer treated with Zoladex Depot is consistent with the profile described above for women treated with Zoladex Depot for endometriosis. In a controlled clinical trial comparing Zoladex Depot 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.

Zoladex Depot

(n=57)

OOPHORECTOMY

(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 Depot.

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

6.7 Hormone Replacement Therapy

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

6.8 Changes in Bone Mineral Density

After 6 months of Zoladex Depot treatment, 109 female patients treated with Zoladex Depot showed an average 4.3% decrease of vertebral trabecular bone mineral density 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 Depot is effective in reducing the bone mineral loss which occurs with Zoladex Depot alone without compromising the efficacy of Zoladex Depot in relieving the symptoms of endometriosis. The optimal drugs, dose and duration of treatment has not been established .

6.9 Changes in Laboratory Values During Treatment

Plasma Enzymes: Elevation of liver enzymes (AST, ALT) have been reported in female patients exposed to Zoladex Depot (representing less than 1% of all patients).

Lipids: In a controlled trial, Zoladex Depot therapy resulted in a minor, but statistically significant effect on serum lipids. In patients treated for endometriosis at 6 months following initiation of therapy, danazol treatment resulted in a mean increase in LDL cholesterol of 33.3 mg/dL and a decrease in HDL cholesterol of 21.3 mg/dL compared to increases of 21.3 and 2.7 mg/dL in LDL cholesterol and HDL cholesterol, respectively, for ZOLADEX-treated patients. Triglycerides increased by 8.0 mg/dL in ZOLADEX-treated patients compared to a decrease of 8.9 mg/dL in danazol-treated patients.

In patients treated for endometriosis, Zoladex Depot increased total cholesterol and LDL cholesterol during 6 months of treatment. However, Zoladex Depot therapy resulted in HDL cholesterol levels which were significantly higher relative to danazol therapy. At the end of 6 months of treatment, HDL cholesterol fractions (HDL2 and HDL3) were decreased by 13.5 and 7.7 mg/dL, respectively, for danazol-treated patients compared to treatment increases of 1.9 and 0.8 mg/dL, respectively, for ZOLADEX-treated patients.

6.10 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Zoladex Depot. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Bone Mineral Density: Osteoporosis, decreased bone mineral density and bone fracture in men .

Cardiovascular: Deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack have been observed in women treated with GnRH agonists. Although a temporal relationship was reported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH analogs and these events.

Ovarian Cyst: Ovarian cyst formation and, in combination with gonadotropins, ovarian hyperstimulation syndrome (OHSS).

Changes in Blood Pressure: Hypotension and hypertension have been reported. These changes are usually transient, resolving either during continued therapy or after cessation of therapy.

Pituitary Apoplexy and Tumors: Pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) and pituitary adenoma have been 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. Pituitary tumors have been reported.

Acne: Usually within one month of starting treatment.

Other Adverse Reactions: Psychotic disorders, convulsions and mood swings.

7 DRUG INTERACTIONS

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

7.1 Drug/Laboratory Test Interactions

Administration of Zoladex Depot 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D in patients with advanced breast cancer.

Pregnancy Category X in patients with endometriosis and endometrial thinning.

Zoladex Depot is contraindicated during pregnancy unless Zoladex Depot is being used for palliative treatment of advanced breast cancer. There are no adequate and well-controlled studies in pregnant women using Zoladex Depot. Based on mechanism of action in humans and findings of increased pregnancy loss in animal studies, Zoladex Depot can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. There is an increased risk for pregnancy loss due to expected hormone changes that occur with Zoladex Depot treatment.

Zoladex Depot crosses the placenta in rats and rabbits following subcutaneous administration. Administration of goserelin to pregnant rats and rabbits during organogenesis resulted in increased preimplantation loss and increased resorptions. When pregnant rats received goserelin throughout gestation and lactation, there was a dose-related increase in umbilical hernia in offspring. In additional reproduction studies in rats, goserelin decreased fetus and pup survival. Human dose/exposure multiples could not be calculated from available animal data.

Actual animal doses: rat (≥ 2 mcg/kg/day for pregnancy loss; > 10 mcg/kg/day for umbilical hernia in offspring); rabbits (> 20 mcg/kg/day).

8.3 Nursing Mothers

It is not known if goserelin is excreted in human milk. Goserelin is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Zoladex Depot, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

There is no need for any dosage adjustment when administering Zoladex Depot to male geriatric patients. Zoladex Depot has not been studied in women over 65 years.

8.6 Renal Insufficiency

In clinical trials with the solution formulation of goserelin, male patients with impaired renal function had a total body clearance and serum elimination half-life of 31.5 mL/min and 12.1 hours, respectively, compared to 133 mL/min and 4.2 hours for subjects with normal renal function (creatinine clearance > 70 mL/min). In females, the effects of reduced goserelin clearance due to impaired renal function on drug efficacy and toxicity are unknown. Pharmacokinetic studies in patients with renal impairment do not indicate a need for dose adjustment with the use of the depot formulation.

8.7 Hepatic Insufficiency

The total body clearances and serum elimination half-lives were similar between normal subjects and patients with moderate hepatic impairment (alanine transaminase < 3xULN and asparate aminotransferase < 3xULN) when treated with a 250 mcg subcutaneous formulation of goserelin. This pharmacokinetic study indicates that no dose adjustment is needed in patients with moderately impaired liver function. There is no pharmacokinetic data with goserelin in patients with severe hepatic insufficiency.

10 OVERDOSAGE

The pharmacologic properties of Zoladex Depot 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.

11 DESCRIPTION

ZOLADEX® (goserelin acetate implant) is a GnRH agonist. Zoladex Depot is chemically described as an acetate salt of [D-Ser(But)6,Azgly10]. 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].

Zoladex Depot 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. Zoladex Depot is practically insoluble in acetone, chloroform and ether.

Zoladex Depot is supplied as a sterile, biodegradable product containing Zoladex Depot equivalent to 3.6 mg of goserelin. Zoladex Depot is designed for subcutaneous injection with continuous release over a 28-day period. Zoladex Depot 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Zoladex Depot is a synthetic decapeptide analogue of GnRH. Zoladex Depot 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 -induced rat mammary tumor and Dunning R3327 prostate tumor.

12.2 Pharmacodynamics

Following initial administration in males, Zoladex Depot 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 Depot 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 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 Depot 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 Depot. In 5% or less of women treated with Zoladex Depot, 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 Depot. Estradiol, LH and FSH levels return to pretreatment values within 12 weeks following the last implant administration in all but rare cases.

12.3 Pharmacokinetics

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

Absorption

The absorption of radiolabeled drug was rapid, and the peak blood radioactivity levels occurred between 0.5 and 1.0 hour after dosing. The mean (± standard deviation) pharmacokinetic parameter estimates of Zoladex Depot after administration of 3.6 mg depot for 2 months in males and females are presented in the following table.

Parameter

(units)

Males

n=7

Females

n=9


Peak Plasma Concentration (ng/mL)

2.84 ± 1.81

1.46 ± 0.82

Time to Peak Concentration (days)

12-15

8-22

Area Under the Curve (0-28 days) (ng.d/mL)

27.8 ± 15.3

18.5 ± 10.3

Systemic Clearance (mL/min)

110.5 ± 47.5

163.9 ± 71.0

Goserelin is released from the depot at a much slower rate initially for the first 8 days, and then there is more rapid and continuous release for the remainder of the 28-day dosing period. Despite the change in the releasing rate of goserelin, administration of Zoladex Depot every 28 days resulted in testosterone levels that were suppressed to and maintained in the range normally seen in surgically castrated men.

When Zoladex Depot 3.6 mg depot was used for treating male and female patients with normal renal and hepatic function, there was no significant evidence of drug accumulation. However, in clinical trials the minimum serum levels of a few patients were increased. These levels can be attributed to interpatient variation.

Distribution

The apparent volumes of distribution determined after subcutaneous administration of 250 mcg aqueous solution of goserelin were 44.1 and 20.3 liters for males and females, respectively. The plasma protein binding of goserelin obtained from one sample was found to be 27.3%.

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 presented 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 the solution formulation of goserelin is very rapid and occurs via a combination of hepatic metabolism and urinary excretion. More than 90% of a subcutaneous radiolabeled solution formulation dose of goserelin is excreted in urine. Approximately 20% of the dose in urine is accounted for by unchanged goserelin. The total body clearance of goserelin (administered subcutaneously as a 3.6 mg depot) was significantly (p<0.05) greater (163.9 versus 110.5 L/min) in females compared to males.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Subcutaneous implantation of goserelin in male and female rats once every 4 weeks for 1 year and recovery for 23 weeks at doses of about 80 and 150 mcg/kg (males) and 50 and 100 mcg/kg (females) daily resulted in an increased incidence of pituitary adenomas. An increased incidence of pituitary adenomas was also observed following subcutaneous implant of goserelin 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 goserelin every 3 weeks for 2 years delivered to mice at doses of up to 2400 mcg/kg/day resulted in an increased incidence of histiocytic sarcoma of the vertebral column and femur. Human dose/exposure multiples could not be calculated from available animal data.

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 mcg/kg/day, 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 mcg/kg/day, 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 mcg/kg/day goserelin when drug treatment was stopped after continuous administration for 1 year. Human dose/exposure multiples could not be calculated from available animal data.

14 CLINICAL STUDIES

14.1 Stage B2-C Prostatic Carcinoma

The effects of hormonal treatment combined with radiation were studied in 466 patients 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 Depot (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).

14.2 Prostatic Carcinoma

In controlled studies of patients with advanced prostatic cancer comparing Zoladex Depot to orchiectomy, the long-term endocrine responses and objective responses were similar between the two treatment arms. Additionally, duration of survival was similar between the two treatment arms in a comparative trial.

14.3 Endometriosis

In controlled clinical studies using the 3.6 mg formulation every 28 days for 6 months, Zoladex Depot was shown to be as effective as danazol therapy in relieving clinical symptoms and signs (pelvic tenderness, pelvic induration) of endometriosis and decreasing the size of endometrial lesions as determined by laparoscopy. In one study comparing Zoladex Depot with danazol (800 mg/day), 63% of ZOLADEX-treated patients and 42% of danazol-treated patients had a greater than or equal to 50% reduction in the extent of endometrial lesions. In the second study comparing Zoladex Depot with danazol (600 mg/day), 62% of ZOLADEX-treated and 51% of danazol-treated patients had a greater than or equal to 50% reduction in the extent of endometrial lesions. The clinical significance of a decrease in endometriotic lesions is not known at this time; and in addition, laparoscopic staging of endometriosis does not necessarily correlate with severity of symptoms.

In these two studies, Zoladex Depot led to amenorrhea in 92% and 80%, respectively, of all treated women within 8 weeks after initial administration. Menses usually resumed within 8 weeks following completion of therapy.

Within 4 weeks following initial administration, clinical symptoms were significantly reduced, and at the end of treatment were, on average, reduced by approximately 84%.

During the first two months of Zoladex Depot use, some women experience vaginal bleeding of variable duration and intensity. In all likelihood, this bleeding represents estrogen withdrawal bleeding, and is expected to stop spontaneously.

There is insufficient evidence to determine whether pregnancy rates are enhanced or adversely affected by the use of Zoladex Depot.

14.4 Endometrial Thinning

Two trials were conducted with Zoladex Depot prior to endometrial ablation for dysfunctional uterine bleeding.

Trial 0022, was a double-blind, prospective, randomized, parallel-group multicenter trial conducted in 358 premenopausal women with dysfunctional uterine bleeding. Eligible patients were randomized to receive either two depots of Zoladex Depot 3.6 mg (n=180) or two placebo injections (n=178) administered four weeks apart. One hundred seventy five patients in each group underwent endometrial ablation using either diathermy loop alone or in combination with rollerball approximately 2 weeks after the second injection. Endometrial thickness was assessed immediately before surgery using a transvaginal ultrasonic probe. The incidence of amenorrhea was compared between the Zoladex Depot and placebo groups at 24 weeks after endometrial ablation.

The median endometrial thickness before surgery was significantly less in the Zoladex Depot treatment group (1.50 mm) compared to the placebo group (3.55 mm). Six months after surgery, 40% of patients (70/175) treated with Zoladex Depot in Trial 0022 reported amenorrhea as compared with 26% who had received placebo injections (44/171), a difference that was statistically significant.

Trial 0003, was a single center, open-label, randomized trial in premenopausal women with dysfunctional uterine bleeding. The trial allowed for a comparison of 1 depot of Zoladex Depot and 2 depots of Zoladex Depot administered 4 weeks apart with ablation using Nd: YAG laser occurring 4 weeks after Zoladex Depot administration. Forty patients were randomized into each of the Zoladex Depot treatment groups.

The median endometrial thickness before surgery was significantly less in the group treated with two depots (0.5 mm) compared to the group treated with one depot (1 mm). No difference in the incidence of amenorrhea was found at 24 weeks (24% in both groups). Of the 74 patients that completed the trial, 53% reported hypomenorrhea and 20% reported normal menses six months after surgery.

14.5 Breast Cancer

The Southwest Oncology Group conducted a prospective, randomized clinical trial (SWOG-8692 [INT-0075]) in premenopausal women with advanced estrogen receptor positive or progesterone receptor positive breast cancer which compared Zoladex Depot with oophorectomy. On the basis of interim data from 124 women, the best objective response (CR+PR) for the Zoladex Depot group is 22% versus 12% for the oophorectomy group. The median time to treatment failure is 6.7 months for patients treated with Zoladex Depot and 5.5 months for patients treated with oophorectomy. The median survival time for the Zoladex Depot arm is 33.2 months and for the oophorectomy arm is 33.6 months.

Subjective responses based on measures of pain control and performance status were observed with both treatments; 48% of the women in the Zoladex Depot treatment group and 50% in the oophorectomy group had subjective responses. In the clinical trial (SWOG-8692 [INT–0075]), the mean post treatment estradiol level was reported as 17.8 pg/mL. (The mean estradiol level in post-menopausal women as reported in the literature is 13 pg/mL.) During the conduct of the clinical trial, women whose estradiol levels were not reduced to the postmenopausal range, received two Zoladex Depot depots, thus, increasing the dose of Zoladex Depot from 3.6 mg to 7.2 mg.

Findings were similar in uncontrolled clinical trials involving patients with hormone receptor positive and negative breast cancer. Premenopausal women with estrogen receptor (ER) status of positive, negative, or unknown participated in the uncontrolled (Phase II and Trial 2302) clinical trials. Objective tumor responses were seen regardless of ER status, as shown in the following table.

CR + PR/Total No.

(%)

ER Status Phase II

(N=228)

Trial 2302

(N=159)


Positive

43/119

(36)

31/86

(36)

Negative

6/33

(18)

3/26

(10)

Unknown

20/76

(26)

18/44

(41)

16 HOW SUPPLIED/STORAGE AND HANDLING

Zoladex Depot is supplied as a sterile and totally biodegradable D,L-lactic and glycolic acids copolymer (13.3-14.3 mg/dose) impregnated with Zoladex Depot 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]).

17 PATIENT COUNSELING INFORMATION

17.1 Males

The use of Zoladex Depot in patients at particular risk of developing ureteral obstruction or spinal cord compression should be considered carefully and the patients monitored closely during the first month of therapy. Patients with ureteral obstruction or spinal cord compression should have appropriate treatment prior to initiation of Zoladex Depot therapy .

The use of GnRH agonists may cause a reduction in bone mineral density. In men, data suggest the use of a bisphosphonate in combination with a GnRH agonist may reduce bone mineral loss [see Adverse Reactions (6.8) and (6.10) ].

Patients should be informed that diabetes or loss of glycemic control in patients with pre-existing diabetes has been reported during treatment with GnRH agonists, including Zoladex Depot. Therefore, consideration should be given to monitoring blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving Zoladex Depot .

A small increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice [see Warnings and Precautions (5.4) ].

Injection site injury has been reported following injection of Zoladex Depot. Inform patients to contact their doctor immediately if they experience any of the following symptoms: abdominal pain, abdominal distension, dyspnea, dizziness, hypotension and/or any altered levels of consciousness [see Warnings and Precautions (5.9) ].

17.2 Females


Zoladex Depot is a trademark of the AstraZeneca group of companies.

©AstraZeneca 2014

Distributed by:

AstraZeneca Pharmaceuticals LP

Wilmington, DE 19850

Rev. 02/2016

NDC 0310-0950-36

Zoladex® 3.6 mg

Zoladex Depot IMPLANT

Equivalent to 3.6 mg goserelin

One Single-Use Syringe

For Subcutaneous Injection

serializtion 3.6

Zoladex Depot pharmaceutical active ingredients containing related brand and generic drugs:


Zoladex Depot available forms, composition, doses:


Zoladex Depot destination | category:


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References

  1. Dailymed."ZOLADEX (GOSERELIN ACETATE) IMPLANT [ASTRAZENECA PHARMACEUTICALS LP]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."GOSERELIN ACETATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "goserelin". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Zoladex Depot?

Depending on the reaction of the Zoladex Depot after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Zoladex Depot not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Zoladex Depot addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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