Zoladex La 10.800 mg

Interactions with herbal products have not been established.

Interactions with particular foods have not been established.

There are no known drug-drug interactions requiring dose adjustment.

Interactions with laboratory tests have not been established.

No dosage adjustment is necessary in the elderly.

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.

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 a non-steroidal antiandrogen and radiotherapy for patients with Stage T2b-T4 prostatic carcinoma, treatment should be started 8 weeks prior to initiating radiotherapy and should continue until completion of the 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 until completion of the radiation therapy, can be administered.

Although, isolated cases of vaginal spotting or bleeding during treatment have been reported, this is not associated with lack of pharmacodynamic effect in most instances. The majority of patients become amenorrheic within 8 weeks of starting treatment. In the small number of women who experience continued menstrual bleeding, estradiol blood levels should be measured. If menstrual bleeding persists and estradiol measurements correspond to postmenopausal values, appropriate diagnostic measures should be undertaken to rule out an intrauterine pathology.

Caution: Do not depress plunger until Step 5. Read all instructions before use.

1. Put the patient in a comfortable position with the upper part of the body slightly raised. Swab abdominal injection site.

   
   

2. 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 depot is visible.

   
   

3. Grasp the 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 depot.

   
   

4. Holding the syringe around the protective sleeve, pinch the patient's skin and insert the needle at a slight angle (30 to 45 degrees) to the skin. With the opening of the needle facing up, insert needle into the subcutaneous tissue of the anterior abdominal wall below the navel line, until the protective sleeve touches the patient's skin.

   
   

   Do not penetrate into muscle or peritoneum.

   
   

5. Moving your hand back to the finger grip, depress the plunger fully, until you can depress no more, to discharge the ZOLADEX depot and to activate the protective sleeve. You may hear a “click” and will feel the protective sleeve automatically begin to slide to cover the needle. If the plunger is not depressed fully the protective sleeve will not activate.

   
   

6. Holding the syringe as shown, withdraw the needle and allow protective sleeve to continue to slide and cover needle. Dispose of the syringe in an approved sharps collector.

Hepatic impairment does not compromise the clearance of ZOLADEX LA, therefore a dosage adjustment is not needed for patients with hepatic impairment.

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.

The safety and effectiveness of ZOLADEX LA in children has not been established. (See Warnings and Precautions.)

In clinical studies, subjects with impaired renal function (creatinine clearance <20 mL/min), had a mean serum elimination half-life of 12.1 hours for ZOLADEX compared to 4.2 hours for male subjects with normal renal function (creatinine clearance >70 mL/min). When ZOLADEX LA is given, as recommended, this change will not lead to any accumulation hence, no change in dosing is necessary for patients with renal failure.

Anaemia occurred in 6% of patients, leukopenia 3%, and thrombocytopenia 1%.

Elevations of liver enzymes (AST, ALT) have been reported in less than 1% of all female patients. There was no other evidence of abnormal liver function. Causality between these changes and ZOLADEX LA have not been established.

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.

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, ZOLADEX treatment resulted in mean increases in LDL cholesterol of 0.55 mmol/L and HDL cholesterol of 0.07 mmol/L. Triglycerides increased by 0.09 mmol/L as well as total cholesterol by 0.65 mmol/L. At the end of 6 months of treatment, HDL cholesterol fractions (HDL2 and HDL3) were increased by 0.05 mmol/L and 0.02 mmol/L, respectively.

Hypertension in 1% of patients. Rarely thrombophlebitis, pulmonary embolism, and myocardial infarction.

As shown in Table 2, 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.

Gynecomastia in 9% of patients. Rarely breast tenderness sometimes accompanied by galactorrhoea.

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.

Clinically evident hepatitis and jaundice occurred in <1% of patients.

The adverse effects seen with ZOLADEX LA (goserelin acetate) are due primarily to its pharmacological action of sex hormone suppression and may give rise to certain expected effects that vary by sex.

Adverse events that have been observed at an equal frequency in both males and females follow. Very common adverse events (≥10%) consist of: change in libido, hot flushes, and sweating. Common adverse reactions (≥1% to <10%) are: paraesthesia, fluctuations in blood pressure, rash and bone mineral density loss. Hypersensitivity reactions were reported uncommonly (≥0.1% to <1). Anaphylaxis has been reported rarely (≥0.01% to <0.1). Cases of pituitary tumour and psychotic disorders have also been occasionally reported during post-marketed use. As with other agents in this class, cases of pituitary apoplexy have occasionally been reported following initial administration of ZOLADEX during post-marketed use.

Changes in blood pressure, manifest as hypotension or hypertension, are commonly observed in patients administered ZOLADEX LA. The changes are usually transient, resolving either during continued therapy or after cessation of therapy with ZOLADEX LA. Such changes have rarely required medical intervention including withdrawal of ZOLADEX LA treatment.

In males, a decrease in potency was reported very commonly (≥10%). Commonly reported adverse reactions (≥1% to <10%) consist of: spinal cord compression, bone pain, breast swelling and injection site reactions. Uncommon adverse reactions (≥0.1% to <1) are: arthralgia, ureteric obstruction and breast tenderness.

In females, very common adverse reactions (≥10%) consist of: vaginal dryness, change in breast size and injection site reactions. Common adverse reactions (≥1% to <10%) are: mood changes including depression, headache, arthralgia and increased signs and symptoms of breast cancer. Rare (≥0.01% to <0.1) cases of ovarian cyst have been reported. Degeneration of fibroids occurs at an unknown frequency.

Following the administration of ZOLADEX LA, skin rashes have been reported as generally mild, often regressing without discontinuation of therapy.

Initially, prostate cancer patients may experience a temporary increase in bone pain, which can be managed symptomatically.

The use of LHRH agonists may cause a reduction in bone mineral density (see Warnings and Precautions).

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.

Irritation at the injection site and rash occurred in 3% of patients. Photosensitivity reactions have been reported in five patients.

Pharmacological effects of ZOLADEX LA 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.

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).

The safety and effectiveness of ZOLADEX LA in children has not been established.

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.

The use of LHRH agonists may cause a reduction in bone mineral density. In men and women, 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.

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 with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, presumed or strong 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. In women being treated for endometriosis, the use of ZOLADEX for longer than the recommended six months or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss.

Worsening of bone pain and other signs and symptoms have been reported infrequently in males and to a lesser extent in females during the first month of therapy with ZOLADEX LA. 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 or estradiol levels observed during the first few days following administration of the first depot injection.

In those who reported an increase in bone pain, the pain ranged in intensity from mild to severe and required either symptomatic management, including non-narcotic analgesics or in some severe cases, narcotic analgesics.

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.

During therapy with ZOLADEX LA, patients should be routinely monitored by physical examinations and appropriate laboratory tests. In prostate cancer patients tumour 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.

Impaired glucose tolerance has been observed in males using LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes mellitus. Consideration should therefore be given to monitoring blood glucose.

There is no evidence that ZOLADEX LA results in impairment of ability to drive or operate machinery.

During the first month of therapy with ZOLADEX LA, patients at risk of developing ureteric obstruction should be closely monitored.

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.

The safety and effectiveness of ZOLADEX LA in children has not been established.

ZOLADEX LA should not be used in pregnancy as there is a theoretical risk of abortion or fetal 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.

Impaired glucose tolerance has been observed in males using LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes mellitus. Consideration should therefore be given to monitoring blood glucose.

The labelling reflects the safety and effectiveness of ZOLADEX LA in the population over 65 years of age.

Although serum testosterone or serum estradiol may be elevated during the first few days after administration of the first depot, they return to normal within one week, and are suppressed by the end of three weeks. They remain suppressed throughout therapy with ZOLADEX LA.

Prostate cancer tumour markers (PSA and PAP), are not routinely monitored in the first few days of therapy; however, if the cancer is responsive to ZOLADEX LA 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.

There have been no reports of drug dependence following the use of ZOLADEX LA.

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.

Initially, ZOLADEX LA (goserelin acetate) transiently increases serum testosterone in males and serum estradiol concentrations in females. 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.

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).

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.

Suppression of serum estradiol will induce amenorrhea in the majority of patients after the first four weeks of treatment especially if started during the menstrual phase of the cycle. During early treatment with ZOLADEX LA some women may experience vaginal bleeding of variable duration and intensity. Such bleeding may represent estrogen withdrawal bleeding and is expected to stop spontaneously. Amenorrhea is expected to be maintained until 12 weeks after the last dose of ZOLADEX LA. Rarely, some women may enter the natural menopause during treatment with LHRH analogues and do not resume menses on cessation of therapy.

Time to return of menses after cessation of therapy with ZOLADEX LA may be prolonged in some patients.

A non-hormonal method of contraception should be used during treatment. Patients should be advised that if they miss or postpone a dose of ZOLADEX LA, ovulation may occur with the potential for conception. If a patient becomes pregnant during treatment, she should discontinue treatment and consult her physician.

The safety of treatment, as well as re-treatment, beyond 6 months with ZOLADEX LA has not been established.

The use of ZOLADEX LA may cause an increase in cervical resistance and care should be taken when dilating the cervix.

The use of ZOLADEX LA during breast feeding is not recommended.

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.

There is no significant change in pharmacokinetics in patients with hepatic failure. Hepatic impairment does not compromise the clearance of ZOLADEX LA, therefore a dosage adjustment is not needed for patients with hepatic impairment (see Dosage and Administration).

No dosage adjustment is necessary in the elderly (see Dosage and Administration).

Administration of ZOLADEX LA, in accordance with the dosage recommendations, ensures that exposure to goserelin is maintained with no clinically significant accumulation.

ZOLADEX LA is poorly protein bound and has a serum elimination half-life of about 4.2 hours in male subjects and 2.3 hours in female subjects with normal renal function. Although the half-life is increased in patients with impaired renal function absolute clearance is still relatively rapid. The existence of a non-renal, presumably hepatic, clearance and the absence of an increased incidence of possible adverse reactions in such patients implies that no adjustment in the proposed dosage regimen is necessary in patients with renal impairment. 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.

ZOLADEX LA (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, and of serum estradiol to levels comparable with those observed in post-menopausal women. This suppression of testosterone and estradiol is then maintained on repeat administration of ZOLADEX LA as long as therapy is continued.

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 LA some women may experience vaginal bleeding of variable duration and intensity. Such bleeding may represents estrogen withdrawal bleeding and is expected to stop spontaneously. Amenorrhea is expected to be maintained until 12 weeks after the last dose of ZOLADEX LA.

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 copolymer.

Administration of ZOLADEX LA, in accordance with the dosage recommendations, ensures that exposure to goserelin is maintained with no clinically significant accumulation.

ZOLADEX LA is poorly protein bound and has a serum elimination half-life of about 4.2 hours in male subjects and 2.3 hours in female subjects with normal renal function. Although the half-life is increased in patients with impaired renal function, this has minimal effects, and since, for the compound given, as recommended, in a 10.8 mg depot formulation, this change will not lead to any accumulation, 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 Pharmacokinetics).

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 (see Dosage and Administration).

Daily doses of goserelin acetate of 25 to 500 μg 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 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 amenorrhoea in the majority of patients.

The safety and effectiveness of ZOLADEX LA in children has not been established (see Warnings and Precautions).

The use of ZOLADEX LA during breast feeding is not recommended.

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 Warnings and Precautions).