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) and Clinical 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 [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.
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.
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.
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) and Adverse Reactions (6.10)].
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 Adverse Reactions (6.10) and 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) and Adverse Reactions (6.10)].
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.
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:
| (n=231) flutamide + Zoladex + Radiation | (n = 235) Radiation Only | ||
|---|---|---|---|
| % All | % All | ||
Rectum/Large Bowel | 80 | 76 | |
Bladder | 58 | 60 | |
Skin | 37 | 37 |
| (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.
| Zoladex (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 | 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:
| 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.
| 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.
| 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 (17.1) and (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.
Post-Marketing
Hypersensitivity: Rarely, hypersensitivity reactions (including urticaria and anaphylaxis) have been reported in patients receiving Zoladex [see Contraindications (4.1) and Warnings and Precautions (5.6)].
Bone Mineral Density: There have been post-marketing reports of osteoporosis, decreased bone mineral density and bony fracture in men treated with Zoladex for prostate cancer [see Patient Counseling Information (17.1) and (17.2)].
Cardiovascular: Cases of serious venous and arterial thromboembolism have been reported in women receiving GnRH agonists, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack. 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: As with other GnRH agonists, there have been reports of ovarian cyst formation and, when Zoladex 3.6 mg is used in combination with gonadotropins, of ovarian hyperstimulation syndrome (OHSS).
Changes in Blood Pressure: Changes in blood pressure, manifest as hypotension or hypertension, have been occasionally observed in patients administered Zoladex. The changes are usually transient, resolving either during continued therapy or after cessation of therapy with Zoladex. Rarely, such changes have been sufficient to require medical intervention including withdrawal of treatment from Zoladex.
Pituitary Apoplexy and Tumors: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed. Most of the pituitary apoplexy cases occurred within 2 weeks of the first dose, and some occurred within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. Very rare cases of pituitary tumors have been reported.
Glucose Tolerance: Reduction in glucose tolerance, manifesting as diabetes or loss of glycemic control in those with pre-existing diabetes, has been reported during treatment with GnRH agonists, including Zoladex [see Warnings and Precautions (5.3) and Patient Counseling Information (17.1)].
Other Adverse Reactions: Psychotic disorders have also been reported.
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 est
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