Indications and
Usage for Zoladex
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 [see Dosage and Administration (2.1)and Clinical Studies (14.1)].
Prostatic
Carcinoma
Zoladex is
indicated in the palliative treatment of advanced carcinoma of the
prostate [see Dosage and Administration (2.2) and Clinical Studies (14.2)].
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 [see Dosage and Administration (2.3) andClinical Studies (14.3)].
Endometrial
Thinning
Zoladex is
indicated for use as an endometrial-thinning agent prior to endometrial
ablation for dysfunctional uterine bleeding [see Dosage and Administration (2.4) and Clinical Studies (14.4)].
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 [seeDosage 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.
Zoladex 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 [see Dosage and Administration (2.7)].
While a delay of
a few days is permissible, every effort should be made to adhere to the 28-day
schedule.
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.
Prostatic
Carcinoma
For the
management of advanced prostate cancer, Zoladex is intended for long-term
administration unless clinically inappropriate.
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.
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.
Breast Cancer
For the
management of advanced breast cancer, Zoladex is intended for long-term
administration unless clinically inappropriate.
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.
1.
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.
NOTE: Caution
should be taken while injecting Zoladex into the anterior abdominal wall due to
the proximity of underlying inferior epigastric artery and its branches.
2.
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.
3.
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.
4.
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. Monitor patients for signs or
symptoms of abdominal hemorrhage. Use extra care when administering Zoladex to
patients with a low BMI and/or to patients receiving full dose anticoagulation
[see Warnings and Precautions (5.9)].
5.
Do not penetrate
into muscle or peritoneum.
6.
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.
7.
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.
Dosage Forms and Strengths
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).
Contraindications
Hypersensitivity
Anaphylactic
reactions to Zoladex have been reported in the medical literature. Zoladex is
contraindicated in those patients who have a known hypersensitivity to GnRH,
GnRH agonist analogues or any of the components in Zoladex [see Warnings and Precautions (5.6)].
Pregnancy
Zoladex is
contraindicated during pregnancy unless Zoladex is being used for palliative
treatment of advanced breast cancer. Zoladex 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
treatment [see Use in Specific Populations (8.1)].
Warnings and Precautions
Women of Childbearing Potential and Pregnancy
Before starting
treatment with Zoladex, pregnancy must be excluded for women using Zoladex 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 therapy and for 12 weeks following discontinuation of therapy. When
used every 28 days, Zoladex 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 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 [see Use in Specific Populations (8.1)].
Tumor Flare Phenomenon
Initially,
Zoladex, 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 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.
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 (HbA1c) periodically in patients
receiving a GnRH agonist and manage with current practice for treatment of
hyperglycemia or diabetes [see Patient Counseling Information (17.1)].
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 [see Patient Counseling Information (17.1)].
Hypercalcemia
As with other
GnRH 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.
Hypersensitivity
Hypersensitivity,
antibody formation and acute anaphylactic reactions have been reported with
GnRH agonist analogues [see Contraindications (4.1)].
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.
Cervical Resistance
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.
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.
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. Extra care should be taken when administering Zoladex to
patients with a low BMI and/or to patients receiving full dose
anticoagulation [seeDosage and Administration (2.7)andPatient
Counseling Information (17.1 and 17.2)].
Adverse Reactions
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 listed below:
Table 1 ADVERSE EVENTS DURING ACUTE RADIATION THERAPY
(within first 90 days of radiation therapy)
|
|
|
(n=231) flutamide + Zoladex + Radiation
|
(n=235) Radiation Only
|
|
|
% All
|
%All
|
|
Rectum/Large Bowel
|
80
|
76
|
|
Bladder
|
58
|
60
|
|
Skin
|
37
|
37
|
Table 2 ADVERSE EVENTS DURING LATE RADIATION PHASE
(after 90 days of radiation therapy)
|
|
|
(n=231) flutamide + Zoladex + 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%).
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.
Tumor Flare Phenomenon: Initially, Zoladex, 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 and orchiectomy. The relationship
of these events to therapy is uncertain [see Warnings and Precautions (5.2)].
In the
controlled clinical trials of Zoladex versus orchiectomy, the following events
were reported as adverse reactions in greater than 5% of the patients.
Table 3 TREATMENT RECEIVED
|
|
|
Zoladex
(n=242)
|
ORCHIECTOMY
(n=254)
|
|
ADVERSE EVENT
|
%
|
%
|
|
*
Complications
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%).
|
|
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
|
18*
|
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.
Females
As would be
expected with a drug that results in hypoestrogenism, the most frequently
reported adverse reactions were those related to this effect.
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:
Table 4 TREATMENT RECEIVED
|
|
|
Zoladex
(n=411)
|
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.
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.
Table 5 ADVERSE EVENTS REPORTED AT A FREQUENCY OF 5%
OR GREATER IN Zoladex AND PLACEBO TREATMENT GROUPS OF TRIAL 0022
|
|
|
Zoladex
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
|
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.
Table 6 TREATMENT RECEIVED
|
|
|
Zoladex
(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.
Injection site
reactions were reported in less than 1% of patients.
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 [see Patient Counseling Information (17.2)].
Changes in Laboratory Values During Treatment
Plasma Enzymes: Elevation of liver enzymes (AST,
ALT) have been reported in female patients exposed to Zoladex (representing
less than 1% of all patients).
Lipids: In a controlled trial, Zoladex 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 increased total cholesterol and LDL
cholesterol during 6 months of treatment. However, Zoladex 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.
Postmarketing Experience
The following
adverse reactions have been identified during post-approval use of Zoladex. 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 [see Patient
Counseling Information (17.1) and (17.2)].
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.
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.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D in patients with advanced breast
cancer.
Pregnancy Category X in patients with endometriosis and
endometrial thinning.
Zoladex is
contraindicated during pregnancy unless Zoladex is being used for palliative
treatment of advanced breast cancer. There are no adequate and well-controlled
studies in pregnant women using Zoladex. Based on mechanism of action in humans
and findings of increased pregnancy loss in animal studies, Zoladex 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 treatment.
Zoladex 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).
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, a
decision should be made to either discontinue nursing or discontinue the drug,
taking into account the importance of the drug to the mother.
Pediatric Use
Safety and
effectiveness in pediatric patients have not been established.
Geriatric Use
There is no need
for any dosage adjustment when administering Zoladex to male geriatric
patients. Zoladex has not been studied in women over 65 years.
Renal Insufficiency
In clinical
trials with the solution formulation of goserelin, male patients with impaired
renal function (creatinine clearance < 20 mL/min) 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.
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.
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 up to 250 times the estimated
human daily dose based on the body surface area. If overdosage occurs, it
should be managed symptomatically.
Zoladex Description
Zoladex®
(goserelin acetate implant) is a GnRH agonist. Goserelin acetate 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].
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.
Zoladex - Clinical Pharmacology
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 vitrostudies, 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 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 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 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 after administration of 3.6 mg
depot for 2 months in males and females are presented in the following table.
Table 7 PHARMACOKINETIC PARAMETER ESTIMATES
|
|
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 every 28 days resulted in testosterone levels that
were suppressed to and maintained in the range normally seen in surgically
castrated men.
When Zoladex 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.
Nonclinical Toxicology
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.
Clinical Studies
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 controlled
studies of patients with advanced prostatic cancer comparing Zoladex 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.
Endometriosis
In controlled
clinical studies using the 3.6 mg formulation every 28 days for 6 months,
Zoladex was shown to be as effective as danazol therapy in relieving clinical
symptoms (dysmenorrhea, dyspareunia and pelvic pain) and signs (pelvic
tenderness, pelvic induration) of endometriosis and decreasing the size of
endometrial lesions as determined by laparoscopy. In one study comparing
Zoladex 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 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 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 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.
Endometrial Thinning
Two trials were
conducted with Zoladex 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 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 and placebo groups at
24 weeks after endometrial ablation.
The median
endometrial thickness before surgery was significantly less in the Zoladex
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 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 and 2 depots of Zoladex administered 4 weeks apart with ablation
using Nd: YAG laser occurring 4 weeks after Zoladex administration. Forty
patients were randomized into each of the Zoladex 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.
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 with
oophorectomy. On the basis of interim data from 124 women, the best objective
response (CR+PR) for the Zoladex group is 22% versus 12% for the oophorectomy
group. The median time to treatment failure is 6.7 months for patients treated
with Zoladex and 5.5 months for patients treated with oophorectomy. The median
survival time for the Zoladex 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 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 depots, thus, increasing the dose of Zoladex 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.
Table 8 OBJECTIVE RESPONSE BY ER STATUS
|
|
|
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)
|
How Supplied/Storage and Handling
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]).
Patient Counseling Information
Males
The use of
Zoladex 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 therapy [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].
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. Therefore, consideration should be given to monitoring blood
glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients
receiving Zoladex [see Warnings and Precautions (5.3)].
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. 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)].
Females
1.
Menstruation
should stop with effective doses of Zoladex. The patient should notify her
physician if regular menstruation persists. Patients missing one or more
successive doses of Zoladex may experience breakthrough menstrual
bleeding [see Warnings and Precautions (5.1)].
2.
Zoladex should
not be used in a pregnant or breastfeeding woman except for the palliative
treatment of advanced breast cancer. Zoladex may harm the fetus and increase
the risk for pregnancy loss [see Contraindications (4.2), Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
3.
A woman should
not begin Zoladex treatment if she has undiagnosed abnormal vaginal bleeding,
or is allergic to any of the components of Zoladex [see Clinical Studies (14.3)].
4.
Premenopausal
women using Zoladex must use nonhormonal contraception during treatment and for
12 weeks after treatment ends [see Warnings and Precautions (5.1)].
5.
If a patient
becomes pregnant while using Zoladex for endometriosis or endometrial thinning,
Zoladex treatment should be discontinued. The patient should be advised of the
possible risks to the pregnancy and fetus, including an increased risk of
pregnancy loss [see Contraindications (4.2)and Use in Specific Populations (8.1)].
6.
Those adverse
events occurring most frequently in clinical studies with Zoladex are
associated with hypoestrogenism; of these, the most frequently reported are hot
flashes (flushes), headaches, vaginal dryness, emotional lability, change in
libido, depression, sweating and change in breast size. Clinical studies in
endometriosis 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 [see Dosage and Administration (2.3) and
Adverse Reactions (6.5) and (6.7)].
7.
The use of GnRH
agonists in women may cause a reduction in bone mineral density. In women,
current available data suggest that recovery of bone loss occurs on cessation
of therapy in the majority of patients.
In patients with a history of prior treatment that may have resulted in bone
mineral density loss and/or in patients with major risk factors for decreased
bone mineral density such as chronic alcohol abuse and/or tobacco abuse,
significant family history of osteoporosis, or chronic use of drugs that can
reduce bone density such as anticonvulsants or corticosteroids, Zoladex therapy
may pose an additional risk. In these patients the risks and benefits must be
weighed carefully before therapy with Zoladex is instituted [seeAdverse
Reactions (6.8) and (6.10)].
8.
Currently, there
are no clinical data on the effects of retreatment or treatment of benign
gynecological conditions with Zoladex for periods in excess of 6 months [seeDosage and
Administration (2.3)].
9.
As with other
hormonal interventions that disrupt the pituitary-gonadal axis, some patients
may have delayed return to menses. The rare patient, however, may experience
persistent amenorrhea [see Drug Interactions (7.1) and
Clinical Studies (14.3) and (14.4)].
10.
Injection site
injury has been reported following injection of Zoladex. 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 [seeWarnings and Precautions (5.9)].
|
Zoladex goserelin
acetate implant
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0310-0950
|
|
Route of Administration
|
SUBCUTANEOUS
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
GOSERELIN ACETATE (GOSERELIN)
|
GOSERELIN
|
3.6 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
LACTIC ACID, DL-
|
|
|
GLYCOLIC ACID
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0310-0950-36
|
1 POUCH in 1 CARTON
|
|
|
1
|
|
1 SYRINGE in 1 POUCH
|
|
|
1
|
|
1 IMPLANT in 1 SYRINGE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA019726
|
05/05/2003
|
|
|
|
Labeler - AstraZeneca Pharmaceuticals LP (054743190)
|
|
|
Registrant - AstraZeneca PLC (230790719)
|
Revised: 02/2016
AstraZeneca Pharmaceuticals LP
