Zoladex (goserelin acetate) Implant: Side Effects & Warnings


Generic drug: goserelin acetate

Brand name: Zoladex

What is Zoladex (goserelin acetate), and how does it work?

Zoladex (goserelin acetate) implant is a GnRH agonist used to treat a variety of conditions, including advanced breast cancer, prostate cancer, endometriosis, and endometrial thinning. 

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.

Prostatic Carcinoma

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

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.

Endometrial Thinning

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

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.

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

What are the side effects of Zoladex?

Stage B2-C Prostatic Carcinoma

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

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.

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

ADVERSE EVENT
Zoladex
(n=242) %
ORCHIECTOMY
(n=254) %

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*

* 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%).

The following additional adverse reactions were reported
in greater than 1% but less than 5% of the patients treated with Zoladex:

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

ADVERSE EVENT
Zoladex
(n=411) %
DANAZOL
(n=207) %

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:

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

ADVERSE EVENT
Zoladex 3.6 mg
(n=180) %
Placebo
(n=177) %

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

ADVERSE EVENT
Zoladex
(n=57) % of Pts.
OOPHORECTOMY
(n=55) % 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.
  • Sixtysix of
    these patients were assessed for BMD loss 6 months after the completion
    (posttherapy) of the 6- month therapy period.
  • Data from these patients showed
    an average 2.4% BMD loss compared to pretreatment values.
  • Twenty-eight of the
    109 patients were assessed for BMD at 12 months posttherapy. Data from these patients
    showed an average decrease of 2.5% in BMD compared to pretreatment values. These
    data suggest a possibility of partial reversibility.
  • Clinical studies suggest
    the addition of Hormone Replacement Therapy (estrogens and/or progestins) to
    Zoladex is effective in reducing the bone mineral loss which occurs with
    Zoladex alone without compromising the efficacy of Zoladex in relieving the
    symptoms of endometriosis. The optimal drugs, dose and duration of treatment
    has not been established.

Changes In Laboratory Values During Treatment

  • 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 HDL2) 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.

What is the dosage for Zoladex?

  • Zoladex, at a dose of 3.6 mg, should be administered
    subcutaneously every 28 days into the
    anterior abdominal wall below the navel
    line using an
    aseptic
    technique under the supervision of a physician.
  • While a delay of a few days is permissible, every effort
    should be made to adhere to the 28-day schedule.

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.

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What drugs interact with Zoladex?

  • 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.

Is Zoladex safe to use while pregnant or breastfeeding?

  • 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.
  • It is not known if goserelin is excreted in human milk. 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.

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