Zoladex (goserelin acetate) Implant: Side Effects & Warnings

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)

Table 2 : ADVERSE EVENTS DURING LATE RADIATION PHASE
(after 90 days of radiation therapy)

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

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

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

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

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.

• 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.