Zoladex 3.6 mg Implant

Goserelin acetate equivalent to 3.6 mg goserelin.

For a full list of excipients, see section 6.1.

Implant.

White to cream-coloured, cylindrical implant in a pre-filled syringe.

(i) Prostate cancer: Zoladex 3.6 mg is indicated in the management of prostate cancer suitable for hormonal manipulation.

(ii) Breast cancer: Zoladex 3.6 mg is indicated in the management of breast cancer in pre and perimenopausal women suitable for hormonal manipulation.

(iii) Endometriosis: In the management of endometriosis, Zoladex 3.6 mg alleviates symptoms, including pain, and reduces the size and number of endometrial lesions.

(iv) Uterine fibroids: In the management of fibroids, Zoladex 3.6 mg shrinks the lesions, improves the patient's haematological status and reduces symptoms, including pain. It is used as an adjunct to surgery to facilitate the operative technique and reduce operative blood loss.

(v) Endometrial thinning: Use as an endometrial thinning agent prior to endometrial ablation. As a prethinning agent Zoladex 3.6 mg should be administered as two depots, four weeks apart, with surgery planned for between zero and two weeks after the second depot injection.

(vi) Assisted reproduction: Pituitary downregulation in preparation for superovulation.

For correct administration of Zoladex, see instructions on the pouch/carton.

Known severe hypersensitivity to the active substance or to any of the excipients of this product.

Pregnancy and lactation (see section 4.6).

Zoladex 3.6 mg is not indicated for use in children, as safety and efficacy have not been established in this patient group.

Males

The use of Zoladex 3.6 mg in men at particular risk of developing ureteric obstruction or spinal cord compression should be considered carefully and the patients monitored closely during the first month of therapy. Consideration should be given to the initial use of an anti-androgen (e.g. cyproterone acetate 300 mg daily for 3 days before and 3 weeks after commencement of Zoladex) at the start of LHRH analogue therapy, since this has been reported to prevent the possible sequelae of the initial rise in serum testosterone. 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 use of LHRH agonists may cause reduction in bone mineral density. In men, preliminary data suggest that the use of a bisphosphonate in combination with an LHRH agonist may reduce bone mineral loss. Particular caution is necessary in patients with additional risk factors for osteoporosis (e.g. chronic alcohol abusers, smokers, long-term therapy with anticonvulsants or corticosteroids, family history of osteoporosis).

Mood changes, including depression have been reported. Patients with known depression and patients with hypertension should be monitored carefully.

Reduction in glucose tolerance has been observed in men receiving LHRH agonists. This may manifest as diabetes or loss of glycaemic control in patients with pre-existing diabetes mellitus. Thus, monitoring of blood glucose levels should be considered.

Females

Breast cancer indication

Reduced bone mineral density:

The use of LHRH agonists may cause reduction in bone mineral density. Following two years treatment for early breast cancer, the average loss of bone mineral density was 6.2% and 11.5% at the femoral neck and lumbar spine respectively. This loss has been shown to be partially reversible at the one year off treatment follow-up with recovery to 3.4% and 6.4% relative to baseline at the femoral neck and lumbar spine respectively, although this recovery is based on very limited data. In the majority of women, currently available data suggest that recovery of bone loss occurs after cessation of therapy.

Preliminary data suggest that the use of Zoladex in combination with tamoxifen in patients with breast cancer may reduce bone mineral loss.

Benign indications

Loss of bone mineral density:

The use of LHRH agonists is likely to cause reduction in bone mineral density averaging 1% per month during a six month treatment period. Every 10% reduction in bone mineral density is linked with about a two to three times increased fracture risk. In the majority of women, currently available data suggest that recovery of bone loss occurs after cessation of therapy.

In patients receiving Zoladex for the treatment of endometriosis, the addition of hormone replacement therapy has been shown to reduce bone mineral density loss and vasomotor symptoms.

No specific data is available for patients with established osteoporosis or with risk factors for osteoporosis (e.g. chronic alcohol abusers, smokers, long-term therapy with drugs that reduce bone mineral density, e.g. anticonvulsants or corticosteroids, family history of osteoporosis, malnutrition, e.g. anorexia nervosa). Since reduction in bone mineral density is likely to be more detrimental in these patients, treatment with Zoladex should be considered on an individual basis and only be initiated if the benefits of treatment outweigh the risks following a very careful appraisal. Consideration should be given to additional measures in order to counteract loss of bone mineral density.

Withdrawal bleeding

During early treatment with Zoladex some women may experience vaginal bleeding of variable duration and intensity. If vaginal bleeding occurs it is usually in the first month after starting treatment. Such bleeding probably represents oestrogen withdrawal bleeding and is expected to stop spontaneously. If bleeding continues, the reason should be investigated.

There are no clinical data on the effects of treating benign gynaecological conditions with Zoladex 3.6 mg for periods in excess of six months.

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

Zoladex 3.6 mg should only be administered as part of a regimen for assisted reproduction under the supervision of a specialist experienced in the area.

As with other LHRH agonists, there have been reports of ovarian hyperstimulation syndrome (OHSS) associated with the use of Zoladex 3.6 mg, in combination with gonadotrophin. The stimulation cycle should be monitored carefully to identify patients at risk of developing OHSS. If OHSS risk is present, human chorionic gonadotrophin (hCG) should be withheld, if possible.

It is recommended that Zoladex 3.6 mg is used with caution in fertilisation treatment of patients with polycystic ovarian syndrome as follicle recruitment may be increased.

Fertile women should use non-hormonal contraceptive methods during treatment with Zoladex and until reset of menstruation following discontinuation of treatment with Zoladex.

Patients with known depression and patients with hypertension should be monitored carefully.

Treatment with Zoladex may lead to positive reactions in anti-doping tests.

Not known.

Pregnancy: Zoladex should not be used during pregnancy since concurrent use of LHRH agonists is associated with a theoretical risk of abortion or foetal abnormality. Prior to treatment, potentially fertile women should be examined carefully to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy until menses resume (see also warning concerning the time to return of menses in section 4.4).

Pregnancy should be excluded before Zoladex 3.6 mg is used for fertilisation treatment. When Zoladex is used in this setting, there is no clinical evidence to suggest a causal connection between Zoladex and any subsequent abnormalities of oocyte development or pregnancy or outcome.

Lactation: The use of Zoladex during breast-feeding is not recommended.

There is no evidence that Zoladex 3.6 mg would result in impairment of ability to drive or operate machinery.

The following frequency categories for adverse drug reactions (ADRs) were calculated based on reports from Zoladex clinical trials and post-marketing sources. The most commonly observed adverse reactions include hot flushes, sweating and injection site reactions.

The following convention has been used for classification of frequency: Very common (1/10), Common (1/100 to <1/10), Uncommon (1/1,000 to <1/100), Rare (1/10,000 to <1/1,000), Very rare (<1/10,000) and Not known (cannot be estimated from the available data).

Table: Zoladex 3.6 mg adverse drug reactions presented by MedDRA System Organ Class

a A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes mellitus.

b These are pharmacological effects which seldom require withdrawal of therapy.

c These may 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.

d These are generally mild, often regressing without discontinuation of therapy.

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

f Observed in a pharmaco-epidemiology study of LHRH agonists used in the treatment of prostate cancer. The risk appears to be increased when used in combination with anti-androgens.

g Loss of head hair has been reported in females, including younger patients treated for benign conditions. This is usually mild but occasionally can be severe.

h Particularly loss of body hair, an expected effect of lowered androgen levels.

Post-marketing experience

A small number of cases of changes in blood count, hepatic dysfunction, pulmonary embolism and interstitial pneumonia have been reported in connection with Zoladex.

In addition, the following adverse drug reactions have been reported in women treated for benign gynaecological indications:

Acne, change of body hairs, dry skin, weight gain, increase in serum cholesterol, vaginitis, vaginal discharge, nervousness, sleep disorder, tiredness, peripheral oedema, myalgias, cramp in the calves, nausea, vomiting, diarrhoea, constipation, abdominal complaints, alterations of voice.

Rarely, breast cancer patients with metastases have developed hypercalcaemia on initiation of therapy. In the presence of symptoms indicative of hypercalcaemia (e.g. thirst), hypercalcaemia should be excluded.

Rarely, some women may enter the menopause during treatment with LHRH analogues and not resume menses on cessation of therapy. Whether this is an effect of Zoladex treatment or a reflection of their gynaecological condition is not known.

There is not much experience of overdose in humans. In cases where Zoladex has been given before the planned time of administration, or when a bigger dose of Zoladex than originally planned has been given, no clinically significant undesirable effects have been observed. 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. In case of overdosage, the condition should be managed symptomatically.

Zoladex (D-Ser(Bu^t)⁶ Azgly¹⁰ LHRH) is a synthetic analogue of naturally occurring LHRH. On chronic administration Zoladex results in inhibition of pituitary LH secretion leading to a fall in serum testosterone concentrations in males and serum estradiol concentrations in females.

Initially, Zoladex like other LHRH agonists, transiently increases serum testosterone concentration in men and serum estradiol concentration in women. During early treatment with Zoladex some women may experience vaginal bleeding of variable duration and intensity. Such bleeding probably represents oestrogen withdrawal bleeding and is expected to stop spontaneously.

In men, by around 21 days after the first depot injection, testosterone concentrations have fallen to within the castrate range and remain suppressed with continuous treatment every 28 days. This inhibition leads to prostate tumour regression and symptomatic improvement in the majority of patients.

In women, serum estradiol concentrations are suppressed by around 21 days after the first depot injection and remain suppressed at levels comparable with those observed in postmenopausal women with continuous treatment every 28 days. This suppression is associated with endometrial thinning, suppression of follicular development within the ovary, a response in hormone-dependent breast cancer (tumours that are ER-positive and/or PgR-positive), endometriosis and uterine fibroids and will result in amenorrhea in the majority of patients.

During treatment with LHRH analogues patients may enter the natural menopause. Rarely, some women do not resume menses on cessation of therapy.

The bioavailability of Zoladex is almost complete. Administration of a depot every four weeks ensures that effective concentrations are maintained with no 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 monthly in a depot formulation, this change will have minimal effect. Hence, no change in dosing is necessary in these patients. There is no significant change in pharmacokinetics in patients with hepatic failure.

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.

Lactide/glycolide 50/50 copolymer.

Not applicable.

3 years.

Do not store above 25°C.

Zoladex 3.6 mg Implant is supplied as a single dose SafeSystem™ syringe applicator with a protective sleeve in a sealed pouch which contains a desiccant. The syringe is moulded from polystyrene and high density polyethylene.

Use as directed by the prescriber. Use only if pouch is undamaged. Use immediately after opening pouch.

AstraZeneca UK Limited,

600 Capability Green,

Luton, LU1 3LU,

United Kingdom.

PA 970/25/1

02 February 1989 / 02 February 2004

27^th June 2011