10.8 mg Goserelin/depot Luteinizing Hormone - Releasing Hormone Analog (LHRH Analog)
AstraZeneca Canada Inc. 1004 Middlegate Road
Mississauga, Ontario
Date of Preparation: February 2, 2000
1M4 Date of Revision:
Control Number: 115159
ZOLADEX(r) is a trade-mark of the AstraZeneca group of companies.
ZOLADEX(r) LA (Goserelin Acetate Depot) 10.8 mg Goserelin/depot
Luteinizing Hormone - Releasing Hormone Analog (LHRH Analog)
ZOLADEX (goserelin acetate) is a synthetic decapeptide analog of gonadotropin releasing hormone (GnRH or LHRH). When given acutely, goserelin acetate stimulates the release of pituitary luteinizing hormone (LH) from the pituitary gland. However, following chronic administration, goserelin acetate is a potent inhibitor of gonadotropin production resulting in gonadal and consequently, accessory sex organ regression. This effect is the basis for the inhibition of growth of chemically-induced rat mammary tumours and transplantable rat prostate and pituitary tumours. In animals and man, following an initial stimulation of pituitary LH secretion and a transient elevation in serum testosterone in males and serum estradiol in females, chronic administration results in inhibition of gonadotropin secretion. In men, approximately 21 days after the initiation of therapy, a sustained suppression of pituitary LH results in the reduction in serum testosterone levels to a range normally seen in surgically castrated men. This suppression of testosterone is then maintained on repeat administration of ZOLADEX LA. In women, serum estradiol concentrations are suppressed by around 4 weeks after the first depot injection and remain suppressed until the end of the treatment period. In patients with estradiol already suppressed by an LHRH analogue, suppression is maintained on the change of therapy to ZOLADEX LA. Suppression of estradiol is associated with a response in endometriosis and will result in amenorrhea in the majority of patients. During early treatment with ZOLADEX some women may experience vaginal bleeding of variable duration and intensity. Such bleeding probably represents estrogen withdrawal bleeding and is expected to stop spontaneously. ZOLADEX LA is a depot formulation of goserelin acetate dispersed in a cylindrical rod of biodegradable and biocompatible blend of high and low molecular weight range D-L Lactide- glycolide copolymers. Administration of ZOLADEX LA, in accordance with the dosage recommendations, ensures that exposure to goserelin is maintained with no clinically significant accumulation. ZOLADEX is poorly protein bound and has a serum elimination half-life of two to four hours in subjects with normal renal function. The half-life is increased in patients with impaired renal function. For the compound given, as recommended, in a 10.8 mg depot formulation this change will not lead to any accumulation. Hence, no change in dosing is necessary in these patients. There is no significant change in the clearance of ZOLADEX LA in patients with hepatic impairment with normal renal function (see PHARMACOLOGY/ ENDOCRINOLOGY).
Prostate Cancer
ZOLADEX LA (goserelin acetate) is indicated for the palliative treatment of patients with hormone-dependent advanced carcinoma of the prostate (Stage M1 according to the Tumour- Node-Metastasis [TNM] classification system or Stage D2 according to the American Urologic Association [AUA] classification). ZOLADEX LA is indicated for use in combination with a non-steroidal antiandrogen for the management of locally advanced, bulky Stage T2b, T2c, T3, and T4 carcinoma of the prostate. Treatment with ZOLADEX LA and a non-steroidal antiandrogen should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy. ZOLADEX LA as adjuvant hormone therapy to external beam irradiation for patients with locally advanced prostate cancer (Stage T3-T4).
Benign Conditions
ZOLADEX LA is indicated for the hormonal management of endometriosis, including pain relief and reduction of endometriotic lesions. Experience with ZOLADEX for the management of endometriosis has been limited to women 18 years of age and older, treated for 6 months.
ZOLADEX LA (goserelin acetate) is contraindicated in patients with hypersensitivity to the drug or any of its components. ZOLADEX LA should not be administered to females having undiagnosed abnormal vaginal bleeding.
Pregnancy
: ZOLADEX LA should not be used during pregnancy. As with other LHRH agonists it is not known whether ZOLADEX LA causes fetal abnormalities in humans. Women of child bearing potential should be carefully examined before treatment to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy (see PRECAUTIONS).
Lactation
: The use of ZOLADEX LA during breast feeding is not recommended.
ZOLADEX LA is not indicated for use in children, as safety and efficacy have not been established in this group of patients. In women, ZOLADEX LA is only indicated for use in endometriosis. For female patients requiring treatment with goserelin for other conditions, refer to the prescribing information for ZOLADEX (3.6 mg depot).
Initially, ZOLADEX LA (goserelin acetate) transiently increases serum testosterone in males and serum estradiol concentrations in women. Although not necessarily related, isolated cases of short-term worsening of signs and symptoms have been reported during the first four weeks of therapy. Worsening of the clinical condition may occasionally require discontinuation of therapy and/or surgical intervention.
Patients with vertebral metastases
During the first month of therapy with ZOLADEX LA, patients with vertebral metastases who are thought to be of particular risk of spinal cord compression should be closely monitored (see PRECAUTIONS).
Patients with genitourinary tract symptoms
During the first month of therapy with ZOLADEX LA, patients at risk of developing ureteric obstruction should be closely monitored (see PRECAUTIONS).
Induced hypogonadism
Suppression of pituitary gonadotropins and gonadal hormone production will occur with continued administration of ZOLADEX. These changes have been observed to reverse on discontinuation of therapy. However, whether the clinical symptoms of induced hypogonadism will reverse in all patients has not yet been established.
Worsening of bone pain and other signs and symptoms have been reported infrequently in males during the first month of therapy with ZOLADEX LA (goserelin acetate) (see WARNINGS). Initially, ZOLADEX LA like other LHRH agonists transiently increases serum testosterone concentrations. In men by around 21 days after the first depot injection, testosterone concentrations have typically fallen to within the castrate range and remain suppressed with treatment every 3 months. It is unclear whether there is any relationship between these clinical events and the initial rise in serum testosterone observed during the first few days following administration of the first depot injection. Ureteric obstruction may develop in male patients with a history of obstructive uropathy. If spinal cord compression or renal impairment due to ureteric obstruction are present, or develop, specific standard treatment of these complications should be instituted.
During therapy with ZOLADEX LA, patients should be routinely monitored by physical examinations and appropriate laboratory tests. In prostate cancer patients tumor markers such as prostatic acid phosphatase (PAP), prostatic specific antigen (PSA) or acid phosphatase could be monitored. Additionally, if deemed appropriate by the physician, serum testosterone may be monitored; however, this is not routinely required. In prostate cancer patients an assessment of bone lesions may require the use of bone scans. Prostatic lesions may be monitored by ultrasonography and/or CT scan in addition to digital rectal examination. The status of obstructive uropathy in males may be assessed and/or diagnosed using intravenous pyelography, ultrasonography or CT scan. Prostate cancer tumor markers (PSA and PAP), are not routinely monitored in the first few days of therapy; however, if the cancer is responsive to ZOLADEX therapy, then these levels, if elevated prior to the commencement of treatment, are usually reduced by the end of the first month. Renal function tests, blood urea nitrogen and creatinine may rarely be elevated during the first few days of therapy in prostate cancer patients before returning to normal.
In men, some bone loss can be anticipated as part of the natural aging process. It may also be expected to occur during medically induced hypo-androgenic state caused by long term ZOLADEX LA treatment. In women, the use of LHRH agonists may cause a reduction in bone mineral density. While specific data from the use of ZOLADEX LA are not currently available, data from studies of ZOLADEX suggest that some recovery of bone mineral may occur on cessation of therapy. In patients receiving ZOLADEX for the treatment of endometriosis, the addition of hormone replacement therapy (a daily estrogenic agent and a progestogenic agent) has been shown to reduce bone mineral loss and vasomotor symptoms. There is no experience of the use of hormone replacement therapy in women receiving ZOLADEX LA. In patients with significant risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, presumed or family history of osteoporosis or chronic use of drugs that can reduce bone mass such as corticosteroids or anticonvulsants, ZOLADEX LA may pose an additional risk. In these patients the risks and benefits must be weighed carefully before ZOLADEX LA therapy is initiated.
Administration of ZOLADEX LA results in suppression of pituitary-gonadal system. Diagnostic tests of pituitary-gonadal function conducted during and subsequent to the treatment period may therefore be misleading.
Antibody formation has not been observed during administration of ZOLADEX LA. Local reactions, such as mild bruising have been related to the trauma of the injection itself and not to the copolymer material of the depot or to the prolonged presence of ZOLADEX at the site of depot injection.
There have been no reports of drug dependence following the use of ZOLADEX LA.
ZOLADEX LA is not indicated for use in children (See WARNINGS).
ZOLADEX LA should not be used in pregnancy as there is a theoretical risk of abortion or foetal abnormality if LHRH agonists are used during pregnancy. Potentially fertile women should be examined carefully before treatment to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy until menses resume (see CONTRAINDICATIONS). Time to return of menses after cessation of therapy with ZOLADEX LA may be prolonged in some patients. Rarely, some women may enter menopause during treatment with LHRH analogues and do not resume menses on cessation of therapy. The use of ZOLADEX LA may cause an increase in cervical resistance and care should be taken when dilating the cervix.
The safety of treatment beyond 6 months with ZOLADEX LA has not been established.
There is no human experience of overdosage. Animal tests suggest that no effect other than the intended therapeutic effects on sex hormone concentrations and on the reproductive tract will be evident with higher doses of ZOLADEX. If overdosage occurs, this should be managed symptomatically.
The adverse effects seen with ZOLADEX LA (goserelin acetate) are due primarily to its pharmacological action of sex hormone suppression. 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. Such changes have rarely required medical intervention including withdrawal of ZOLADEX treatment. Following the administration of ZOLADEX, arthralgia, skin rashes which are generally mild and often regress without discontinuation of therapy, and isolated cases of ureteric obstruction have been recorded. Non-specific paraesthesias have been reported. As with other agents in this class, very rare cases of pituitary apoplexy have been reported following initial administration of ZOLADEX 3.6 mg. Rare incidences of hypersensitivity reactions, which may include some manifestations of anaphylaxis, have been reported.
Prostate Cancer Patients
Pharmacological effects include hot flushes, sweating and a decrease in potency, seldom requiring withdrawal of therapy. Breast swelling and tenderness have been noted infrequently. Initially, prostate cancer patients may experience a temporary increase in bone pain, which can be managed symptomatically. Isolated cases of spinal cord compression have been recorded. The use of LHRH agonists in men may cause a reduction in bone mineral density. The potential for exacerbation of signs and symptoms during the first few weeks of treatment is a concern particularly in male patients with impending neurologic compromise and in patients with severe obstructive uropathy (see WARNINGS). Following the administration of ZOLADEX 3.6 mg depot, isolated cases of ureteric obstruction have been recorded. Two controlled clinical trials were conducted with 157 patients, comparing treatment with ZOLADEX LA (10.8 mg) versus ZOLADEX 3.6 mg depots. During the comparative phase, patients were randomised to receive either a single 10.8 mg depot or three consecutive 3.6 mg depots (one every 4 weeks) over this initial 12 week period. The only adverse event reported in greater than 5% of these patients during this phase, was hot flushes, with the ZOLADEX LA (10.8 mg) group having an incidence of 47% and the ZOLADEX 3.6 mg group having 48%. From weeks 12-48 all patients were treated with one ZOLADEX LA depot every 12 weeks. During this noncomparative phase, the following adverse events, were reported in greater than 5% of patients; hot flushes [vasodilation] (63.7%), general pain (14%), gynaecomastia (8.3%), pelvic pain (5.7%), bone pain (5.7%) and asthenia (5.1%). The following adverse events reported in greater than 1%, but less than 5% of 157 patients treated with ZOLADEX LA depot every 12 weeks are tabulated below. Some of these would be expected in a proportion of the elderly population.
Adverse events in controlled studies with an incidence of >=1% but less than 5%
| Body system/adverse events | Weeks 0 to 12 | Week 12 onwards | ||
| ZOLADEX 10.8mg (N = 78) N (%) | ZOLADEX 10.8 mg (N = 157) * N (%) | |||
| Whole Body | ||||
| Abdominal pain | 0 | (0.0) | 2 | (1.3) |
| Aggravation reaction | 0 | (0.0) | 5 | (3.2) |
| Back pain | 0 | (0.0) | 2 | (1.3) |
| Flu syndrome | 1 | (1.3) | 0 | (0.0) |
| Headache | 0 | (0.0) | 3 | (1.9) |
| Infection | 0 | (0.0) | 2 | (1.3) |
| Sepsis | 0 | (0.0) | 4 | (2.5) |
| Cardiovascular | ||||
| Angina pectoris | 1 | (1.3) | 1 | (0.6) |
| Cerebral ischemia | 0 | (0.0) | 2 | (1.3) |
| Cerebrovascular accident | 0 | (0.0) | 2 | (1.3) |
| Heart failure | 0 | (0.0) | 3 | (1.9) |
| Pulmonary embolus | 0 | (0.0) | 2 | (1.3) |
| Varicose veins | 1 | (1.3) | 0 | (0.0) |
| Body system/adverse events | Weeks 0 to 12 | Week 12 onwards | ||
| ZOLADEX 10.8mg (N = 78) N (%) | ZOLADEX 10.8 mg (N = 157) * N (%) | |||
| Digestive | ||||
| Diarrhoea | 1 | (1.3) | 4 | (2.5) |
| Haematemesis | 1 | (1.3) | 0 | (0.0) |
| Endocrine System | ||||
| Diabetes mellitus | 0 | (0.0) | 2 | (1.3) |
| Hemic and Lymphatic | ||||
| Anaemia | 0 | (0.0) | 3 | (1.9) |
| Metabolic and Nutritional | ||||
| Peripheral oedema | 2 | (2.6) | 5 | (3.2) |
| Nervous System | ||||
| Dizziness | 0 | (0.0) | 5 | (3.2) |
| Paraesthesia | 2 | (2.6) | 2 | (1.3) |
| Urinary retention | 0 | (0.0) | 2 | (1.3) |
| Respiratory system | ||||
| Cough increased | 0 | (0.0) | 4 | (2.5) |
| Dyspnoea | 0 | (0.0) | 6 | (3.8) |
| Pneumonia | 0 | (0.0) | 2 | (1.3) |
| Skin Appendages | ||||
| Herpes simplex | 1 | (1.3) | 1 | (0.6) |
| Pruritus | 0 | (0.0) | 2 | (1.3) |
| Urogenital | ||||
| Bladder neoplasm | 1 | (1.3) | 1 | (0.6) |
| Breast pain | 2 | (2.6) | 7 | (4.5) |
| Haematuria | 1 | (1.3) | 3 | (1.9) |
| Impotence | 2 | (2.6) | 2 | (1.3) |
| Urinary frequency | 0 | (0.0) | 2 | (1.3) |
| Urinary incontinence | 0 | (0.0) | 2 | (1.3) |
| Urinary tract disorder | 1 | (1.3) | 5 | (3.2) |
| Body system/adverse events | Weeks 0 to 12 | Week 12 onwards | ||
| ZOLADEX 10.8mg (N = 78) N (%) | ZOLADEX 10.8 mg (N = 157) * N (%) | |||
| Urinary tract infection | 3 | (3.8) | 7 | (4.5) |
| Urination Impaired | 0 | (0.0) | 3 | (1.9) |
* Adverse events occurring in the comparative phase of these studies (Weeks 0 to 12) are presented separately to data from the non-comparative phase (Week 12 onwards), as the differences in the two periods of observation made a direct comparison inappropriate.
In a controlled clinical trial conducted with 58 patients, ZOLADEX LA 10.8 mg was administered every 13 weeks (3 months). Adverse events were consistent with the results of earlier trials. The following adverse events were reported in 10% or more patients; hot flushes [vasodilation] (67%), general pain (31%), pelvic pain (22%), back pain (16%), insomnia (16%), sweating (14%), hypertension (12%), constipation (12%), urinary frequency (12%), and nocturia (10%). The most frequently reported (greater than 5%) adverse experiences during treatment with a LHRH-agonist in combination with flutamide are listed in the table below. For comparison, adverse experiences seen with a LHRH-agonist and placebo are also listed in the following table.
| (n=294) Flutamide + LHRH-agonist % All | (n=285) Placebo + LHRH-agonist % All | |
| Hot Flushes | 61 | 57 |
| Loss of Libido | 36 | 31 |
| Impotence | 33 | 29 |
| Diarrhea | 12 | 4 |
| Nausea/Vomiting | 11 | 10 |
| Gynecomastia | 9 | 11 |
| Other | 7 | 9 |
| Other GI | 6 | 4 |
As shown in the table, for both treatment groups, the most frequently occurring adverse experiences (hot flushes, loss of libido, impotence) were those known to be associated with low serum androgen levels and known to occur with LHRH-agonists alone. The only notable difference between these treatment groups was the higher incidence of diarrhea in the flutamide+LHRH-agonist group (12%) as compared to the placebo+LHRH- agonist group (4%). The cases of diarrhea reported were severe in less than 1% of the patients. In addition, the following adverse reactions were reported during treatment with flutamide+LHRH-agonist. No causal relatedness of these reactions to drug treatment has been made, and some of the adverse experiences reported are those that commonly occur in elderly patients.
Cardiovascular System
: Hypertension in 1% of patients. Rarely thrombophlebitis, pulmonary embolism, and myocardial infarction.
Central Nervous System
: CNS (drowsiness/confusion/depression/anxiety/nervousness) reactions occurred in 1% of patients. Rarely insomnia, tiredness, headache, dizziness, weakness, malaise, blurred vision and decreased libido have been reported.
Endocrine System
: Gynecomastia in 9% of patients. Rarely breast tenderness sometimes accompanied by galactorrhoea.
Gastrointestinal System
: Nausea/vomiting occurred in 11%; diarrhea 12%, anorexia 4%, and other GI disorders occurred in 6% of patients. Increased appetite, indigestion and constipation have also been reported.
Hematopoietic System
: Anaemia occurred in 6% of patients, leukopenia 3%, and thrombocytopenia 1%.
Liver and Biliary System
: Clinically evident hepatitis and jaundice occurred in <1% of patients.
Skin
: Irritation at the injection site and rash occurred in 3% of patients. Photosensitivity reactions have been reported in five patients.
Other
: Pruritus, ecchymosis, herpes zoster, thirst, lymphedema, lupus-like syndrome, hematuria, reduced sperm counts have been reported rarely in long-term treatment. Edema occurred in 4% of patients; neuromuscular, genitourinary symptoms occurred in 2% of patients. Pulmonary symptoms occurred in <1% of patients.
Benign Conditions
Pharmacological effects of ZOLADEX treatment in women include hot flushes and sweating, and a change in libido, seldom requiring withdrawal from therapy. Headaches, mood changes including depression, vaginal dryness and change in breast size have been noted infrequently. In women with fibroids, degeneration of fibroids may occur. As with other LHRH agonists, there have been reports of ovarian cyst formation.
One depot of ZOLADEX LA containing goserelin acetate equivalent to 10.8 mg goserelin, should be injected subcutaneously into the anterior abdominal wall every 3 months (13 weeks) following the procedure recommended on the instruction card (see Instructions for Use on card attached to sterile pouch). While the 3-month (13 week) schedule should be adhered to, a delay of a few days is permissible (See PHARMACOLOGY). If in exceptional circumstances repeat dosing does not occur at 3 months, data indicate that castrate levels of testosterone are maintained for up to 16 weeks in the majority of patients. When ZOLADEX LA is given in combination with radiotherapy and a non-steroidal antiandrogen for patients with Stage T2b-T4 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 LA (10.8 mg) depot, can be administered.
One depot of ZOLADEX LA containing goserelin acetate equivalent to 10.8 mg goserelin, should be injected subcutaneously into the anterior abdominal wall every 12 weeks following the procedure recommended on the instruction card (see Instructions for Use on card attached to sterile pouch). While the 12-week schedule should be adhered to, a delay of a few days is permissible (See PHARMACOLOGY).
In patients with impaired renal function, the serum half life is increased (serum half-life is 2-4 hours in patients with normal renal function). When ZOLADEX LA is given, as recommended, this change will not lead to any accumulation hence, no change in dosing is necessary. Hepatic impairment does not compromise the clearance of ZOLADEX LA, therefore a dosage adjustment is not needed for patients with hepatic impairment. No dosage adjustment is necessary in the elderly. ZOLADEX LA is not indicated for use in children (See WARNINGS).
Caution: Do not depress plunger until Step 5. Read all instructions before use.
| Drug Substance | |
| Proper name | Goserelin acetate |
| Chemical Name | L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl- D-(O-tert-butyl)seryl- L-leucyl-L-arginyl-L-prolyl- azaglycine amide acetate |
| Abbreviated Chemical Name | L-Glp-L-His-L-Trp-L-Ser-L-Tyr-D-Ser(But)-L-Leu-L-Arg- L- Pro-AzGlyNH 2 acetate |
| Other Names | 6-D-(O-tert-butyl)serine-10-azaglycine amide-LH-RH, acetate salt |
| Structural Formula | |
| Molecular Formula | C 59 H 84 N 18 O 14 |
| Molecular Weight | 1269.44 |
| Description | Goserelin acetate is a white to off-white powder. It is freely soluble in glacial acetic acid, soluble in water, 0.1M hydrochloric acid, 0.1M sodium hydroxide, dimethylformamide and dimethylsulphoxide. It is practically insoluble in acetone, chloroform and diethyl ether. Measured pKa (base) is 6.2 (associated with the protonation of the histidine residue). pH of a 2% aqueous solution is approximately 6 (dependent on level of acetic acid present) |
| Oil/Water Coefficient of Partition: | Soluble in water, insoluble in n-octanol. |
Active Constituent: goserelin acetate equivalent to 10.8 mg goserelin per depot. Other Constituents: Lactide-glycolide copolymers to total weight 36.0 mg per depot.
Protect from light and moisture. Store in the intact package between 2degC and 25degC.
ZOLADEX LA (goserelin acetate) depot is supplied as a cylindrical rod of biodegradable and biocompatible D-L Lactide-glycolide copolymers. Each ZOLADEX LA depot contains goserelin acetate equivalent to 10.8 mg of goserelin. This depot is presented in a sterile ready- to-use syringe with a 14 gauge needle for a single subcutaneous injection. This single-dose syringe is assembled with a protective sleeve (SafeSystem(tm) ) in a sealed, sterile pouch that contains a desiccant. Instructions for administration are attached.
Keep medications out of the reach of children. Before receiving your injection tell your doctor if: you have ever had an allergic reaction to ZOLADEX or ZOLADEX LA you are pregnant, are trying to become pregnant or are breast feeding ZOLADEX LA (goserelin acetate) is a drug containing 10.8 mg of goserelin in a hard, cream- coloured, rod-shaped depot. Your doctor has prescribed ZOLADEX LA for you only and the information provided below is intended to assist you in the effective use of this treatment. This information is not intended to supersede the instructions given by your doctor, since each case is unique; therefore, follow his or her instructions carefully. If you experience any difficulties, contact your doctor or pharmacist. ZOLADEX LA treatment, given as recommended, results in suppression of your sex hormones (testosterone in men and estradiol in women). Any complaints you experience may be related to this hormone-suppressing action of ZOLADEX LA. These complaints may include hot flushes, swollen or tender breasts and reduction in sex drive. PLEASE READ THE SECTION WHICH APPLIES TO YOU, EITHER MALE OR FEMALE
As with all medicines, other undesirable events are sometimes experienced. With ZOLADEX LA these may include: Skin rashes and, rarely, allergic reactions Pains in your joints Hot flushes and sweating Tingling in fingers or toes Thinning of bones Changes in blood pressure When you first start receiving ZOLADEX LA you may feel some pain in your bones. If this happens tell your doctor and you may be given something for this. Very occasionally you may have trouble passing urine or experience lower back pain. If this happens, tell your doctor and you may be given something for this. If these continue to make you feel uncomfortable, consult your doctor. If you have a tumour in your pituitary gland, ZOLADEX LA may make the tumour bleed or collapse. This is very rare but may cause severe headaches, sickness, loss of eyesight and unconsciousness. Tell your doctor or pharmacist if you experience any of these problems. Occasionally, a local skin reaction may occur at the injection site such as itching, redness, burning and swelling. These reactions generally are mild and disappear after a few days. If they get worse or do not go away, tell your doctor. Contact your doctor immediately if you develop: severe increased pain, numbness or weakness of the limbs, or persistent difficulty in urinating. Do not be alarmed by this list of possible events. You may not have any of them. Tell your doctor or pharmacist if you think you have any of these or any other problems with your medicine.
Check with your doctor or pharmacist before taking any other drugs, including non- prescription drugs (for colds, nausea, etc. ).
If you go into hospital, let the medical staff know you are receiving ZOLADEX LA.
If you forget to have ZOLADEX LA administered on the specified day, once every 3 months, have it administered as soon as you can.
It is very important your doctor checks your progress at regular medical visits.
Don't stop your ZOLADEX LA treatment if you feel better, consult your doctor before you decide to change your treatment. If you need more information, ask your doctor.
As with all medicines, undesirable events are sometimes experienced. With ZOLADEX LA these may include: Headaches Mood changes including depression Vaginal dryness Occasionally some women enter the menopause early, so when ZOLADEX LA treatment is stopped menstruation will not start again Skin rashes and, rarely, allergic reactions Pains in your joints Formation of ovarian cysts, which may cause pain for some women Tingling in fingers or toes Changes in blood pressure Vaginal bleeding may occur Suppression of your sex hormones can also result in a small loss of mineral from bone, some of which may not be reversible. There are certain conditions that may increase the possibility of thinning of your bones when you take a drug such as ZOLADEX LA. They are: family history of severe osteoporosis (thinning of the bones with fractures); taking other medications that can cause thinning of the bones You should discuss the possibility of osteoporosis or thinning of the bones with your physician before starting ZOLADEX LA. You should be aware that repeat treatments are not recommended since they may put you at greater risk of bone thinning particularly if you have the above conditions. If you have a tumour in your pituitary gland, ZOLADEX LA may make the tumour bleed or collapse. This is very rare but may cause severe headaches, sickness, loss of eyesight and unconsciousness. Tell your doctor or pharmacist if you experience any of these problems. There are no clinical data on the effect of treating benign gynecological conditions with ZOLADEX or ZOLADEX LA for periods in excess of six months. Occasionally, a local skin reaction may occur at the injection site such as itching, redness, burning and swelling. These reactions generally are mild and disappear after a few days. If they get worse or do not go away, tell your doctor. For pre-menopausal women: menstruation stops with the 12 week depot of ZOLADEX LA. If regular menstruation persists, notify your doctor. At the beginning of treatment, if you have fibroids a slight increase in symptoms, such as pain, may occur. These effects are usually short-lived and discontinue on continuation of treatment. If symptoms persist or you are uncomfortable, contact your doctor. You should not use ZOLADEX LA if you have ever had an allergic reaction to ZOLADEX or ZOLADEX LA, if you are pregnant, breast feeding or have undiagnosed abnormal bleeding. Contraception is not ensured during treatment with ZOLADEX LA. Therefore, pregnancy must be avoided by the use of non-hormonal methods of contraception. Following the last ZOLADEX LA depot, non-hormonal contraception must be continued until the return of menses. Do not be alarmed by this list of possible events. You may not have any of them. Tell your doctor or pharmacist if you think you have any of these or any other problems with your medicine.
Check with your doctor or pharmacist before taking any other drugs, including non- prescription drugs (for colds, nausea, etc. ).
If you go into hospital, let the medical staff know you are receiving ZOLADEX LA.
If you forget to have ZOLADEX LA administered on the specified day, once every 12 weeks, have it administered as soon as you can.
It is very important your doctor checks your progress at regular medical visits.
Don't stop your ZOLADEX LA treatment if you feel better, consult your doctor before you decide to change your treatment. If you need more information, ask your doctor.
Keep your injection in its original pack between 2degC and 25degC. Do not break the seal. If your doctor decides to stop your treatment, dispose of your injection in an appropriate way. The injection should not be used after the expiry date on the pack. NOTE: This INFORMATION TO THE PATIENT leaflet provides you with the most current information at the time of printing. For the most current information, the Information to the Patient leaflet plus the full Product Monograph, prepared for health professionals can be found at: www.astrazeneca.ca under Patients with Prescriptions, or by contacting the sponsor, AstraZeneca Canada Inc. at: Customer Inquiries - 1 (800) 668-6000, Renseignements: - 1 (800) 461-3787. This leaflet was prepared by: AstraZeneca Canada Inc. Mississauga, Ontario L4Y 1M4 ZOLADEX(r) and the AstraZeneca logo are trade-marks of the AstraZeneca group of companies.
(c)
AstraZeneca 2000
Last revised:
Where applicable the following PHARMACOLOGY AND ENDOCRINOLOGY information has been supplemented with information generated to support use of the ZOLADEX 3.6 mg depot, which is relevant to ZOLADEX LA.
Animal studies were undertaken to determine the endocrine and antitumour effects of goserelin acetate in both an aqueous and depot formulation. A single subcutaneous injection of 500 ug goserelin acetate as an aqueous formulation suppressed estrus for only 3.4 +- 0.4 days in normally cycling rats. By comparison a single subcutaneous depot containing 500 ug goserelin acetate suppressed estrus for 33.2 +- 1.4 days. Single subcutaneous depots containing either 500 ug or 5 mg goserelin acetate decreased serum luteinizing hormone (LH) and testosterone and reduced testes, seminal vesicle and ventral prostate gland weights in rats for four weeks; there was no effect on the weight of the pituitary gland. Serum hormones and testes and accessory sex organ weights recovered between weeks 6 and 8 of the study. Dimethylbenzanthracene (DMBA)-induced rat mammary tumours were reduced in size in response to a single subcutaneous injection of a depot containing 300 ug goserelin acetate. Around seven weeks after administration of the drug, the tumours regrew but retained hormone-responsiveness and regressed again after either further treatment with a depot containing 300 ug goserelin acetate or surgical oophorectomy. Depot administration on three occasions at days 0, 28 and 56 caused a higher incidence of complete remission and a longer duration of effect. Both treatments markedly reduced the number of new tumours appearing during the study. When given 30 days after DMBA, a single subcutaneous depot containing 300 ug goserelin acetate with repeat doses at 28-day intervals on two occasions caused a delay in tumour appearance of approximately 100 days. When given at 28-day intervals until the animals died or were killed, single subcutaneous depot doses of 300 ug goserelin acetate caused a prolonged delay in mammary tumour appearance, and 12 out of 21 rats died or were killed without mammary tumours being detected.
Pharmacodynamics
Daily doses of goserelin acetate of 25 to 500 ug in the aqueous formulation induce pituitary desensitization to endogenous and exogenous LHRH and after 7 to 21 days depress serum LH and testosterone. These findings indicate the locus of effect of goserelin acetate in man is at the pituitary gland. Initially, ZOLADEX LA like other LHRH agonists transiently increases serum testosterone concentrations. In men by around 21 days after the first ZOLADEX LA depot injection, testosterone concentrations have typically fallen to within the castrate range and remain suppressed with treatment every 3 months. In clinical trials using ZOLADEX LA for 48 weeks, suppression of serum testosterone to castrate levels has been maintained for the duration of therapy. Data exists which indicates that in the majority of patients (over 90%), serum testosterone levels remain suppressed to within the castrate range for up to 13 weeks (3 months). In women, serum oestradiol concentrations are suppressed by around 4 weeks after the first depot injection and remain suppressed until the end of the treatment period. In patients with oestradiol already suppressed by an LHRH analogue, suppression is maintained on the change of therapy to ZOLADEX LA. Suppression of oestradiol is associated with a response in endometriosis and will result in amenorrhoea in the majority of patients.
Pharmacokinetics
Administration of ZOLADEX LA, in accordance with the dosage recommendations, ensures that exposure to goserelin is maintained with no clinically significant accumulation. ZOLADEX is poorly protein bound and has a serum elimination half-life of two to four hours in subjects with normal renal function. The half-life is increased in patients with impaired renal function. For the compound given, as recommended, in a 10.8 mg depot formulation this change will not lead to any accumulation. Hence, no change in dosing is necessary in these patients. There is no significant change in the clearance of ZOLADEX LA in patients with hepatic impairment with normal renal function. The ZOLADEX LA (10.8 mg) depot formulation of goserelin acetate releases drug continuously with peak serum concentrations occurring approximately two hours after administration.
Following long-term repeated dosing with ZOLADEX, an increased incidence of benign pituitary tumours has been observed in male rats. Whilst this finding is similar to that previously noted in this species following surgical castration, any relevance to humans has not been established. In mice, long-term repeated dosing with multiples of the human dose produced histological changes in some regions of the digestive system. This is manifested by pancreatic islet cell hyperplasia and a benign proliferative condition in the pyloric region of the stomach, also reported as a spontaneous lesion in this species. The clinical relevance of these findings is unknown.
Acute toxicity studies were conducted in rats and mice. All animals survived following single subcutaneous doses of 200 mg/kg in rats and 400 mg/kg in mice. The LD50 by the subcutaneous route is, therefore, in excess of these values. The only signs reported were in the rats and are those related to discomfort of dosing. By the intravenous route LD50 was established at approximately 30-40 mg/kg for rats and 56-59 mg/kg for mice.
Multiple dosing studies have been conducted in rats, dogs and monkeys. Six and 12 month studies were done in rats and dogs. In the six month studies the doses were administered either as daily injections (aqueous solution) or depot injections every 28 days. The doses used were up to 1000 ug/kg/day in rats and dogs by daily subcutaneous injections and, nominally, 150 ug/kg/day in rats and 200 ug/kg/day in dogs by depot injections every 28 days. In the 12 month studies, only the depot injections were used and these provided maximal nominal dose levels of around 130 ug/kg/day in rats and 200 ug/kg/day in dogs. In a monkey study 6 depot doses were administered, one every 28 days (providing approximately 400 ug/kg/day). At the end of this period a proportion of animals were necropsied and the remainder given a period of 6 months drug withdrawal to study reversibility. Findings in all animal species were those of chemical castration as evidenced by reduced testicular size, suppression of estrus and histologic evidence of gonad and secondary sex organ atrophy in both sexes. Pituitary gland microadenomas were observed only in rats; in 2 males in the depot group of the 6 month study and also in a larger proportion of dosed males in the 12 month study (see CARCINOGENICITY section for additional information).
Administration of ZOLADEX led to changes that were consistent with gonadal suppression in both male and female rats as a result of its endocrine action at 30-60 and 20-40 times the recommended human dose respectively. Except for the testes, almost complete histologic reversal of these effects in male and female rats was observed several weeks after dosing was stopped. Fertility and general reproductive performance was reduced in those that became pregnant after ZOLADEX was discontinued. Fertile matings occurred within two weeks after cessation of dosing, even though total recovery of reproductive function may not have occurred before mating took place. The ovulation rate, the corresponding implantation rate and number of live fetuses were reduced. In male and female dogs, the suppression of fertility was fully reversible when drug treatment was stopped after continuous administration for 1 year at 100 times the recommended monthly dose. Studies in both rats and rabbits (up to 25 and 500 times the monthly dose respectively) confirm that ZOLADEX will increase pregnancy loss in a dose-related manner. In both rats and rabbits, there was no evidence that ZOLADEX possessed the potential to cause teratogenicity.
Compared to the control group animals an increased incidence of benign pituitary gland adenomas was found in male rats following long-term dosing in the carcinogenicity study where doses approximating to 60 and 120 ug/kg/day were administered every 28 days by depot injections. The chemical castration effect is responsible for the production of pituitary gland adenomas which appears to be a species-specific response. This response is similar to that seen in surgically castrated rats. There were no pituitary gland adenomas observed in the mouse where large doses of the compound were administered (depot doses approximating to 1200 and 2400 ug/kg/day for 2 years). At the end of two years dosing in the mouse, findings of hyperplasia of the pancreatic islet cells and adenomatous polyps in pyloric stomach were reported but there was no evidence of carcinogenicity. Extensive experience in human subjects with LHRH analogs, including goserelin acetate does not provide any evidence for a drug-related complication in the pituitary gland, stomach or pancreas. The findings discussed here are, therefore, unlikely to be relevant to the intended use in humans.
The mutagenic potential of the compound has been investigated in seven systems, five of them eukaryotic including two in vivo mammalian cell tests. Tests for point mutation were done using the Salmonella typhimurium and Escherichia coli bacterial systems and Saccharomyces cerevisiae strain D7 yeast. Concentrations used were up to the limit of solubility (2000 ug/mL culture; 5000 ug/plate). Clastogenic action on chromosomes was investigated in vivo using the mouse micronucleus test (2.5 mg and 5.0 mg/kg) and Chinese hamster bone marrow cytogenetics (15 mg/kg). For completion, two other in vitro mammalian cell culture tests (Chinese hamster ovary cells and human lymphocytes) were also done. In none of these investigations was there any evidence of genotoxic potential.
Dermal tolerance was studied by direct application of a solution of goserelin acetate to the abraded and nonabraded skin of the rabbit. This produced no evidence of irritancy at a concentration of 10 mg/mL. A positive reference substance gave the appropriate response, thereby confirming the validity of the test system. Ocular tolerance was established by instillation of 0.1 mL of a 10 mg/mL solution to the eyes of rabbits. Contact sensitization was investigated in the guinea pig using a modified Magnusson and Kligman procedure. No sensitizing potential was detected, and the positive reference material gave the appropriate response.
Endometriosis References
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