ZOLADEX 10,8 mg Implant inj in prefilled syringe SC B/1

Goserelin base ......................................................................................................................... 10,80 mg

(As goserelin acetate)

For an implant.

Zoladex is indicated in adults for:

• Treatment of metastatic prostate cancer.
• Adjuvant treatment to external radiotherapy in locally advanced prostate cancer (stage T3-T4 of the TNM classification or stage C of the AUA classification).

Precautions must be taken when injecting Zoladex 10,8 mg into the anterior abdominal wall due to the proximity of the underlying inferior epigastric artery and its branches.

Particular caution must be observed when administering Zoladex 10,8 mg to patients with a low BMI and/or receiving anticoagulant treatment (see section Warnings and precautions).

For correct administration, refer to the diagram of the method of administration enclosed in the box.

Dosage

Reserved for adult males.

One goserelin acetate implant dosed at 10,8 mg will be injected subcutaneously into the anterior abdominal wall every 3 months.

In the indication: "adjuvant treatment to external radiotherapy in locally advanced prostate cancer," the duration of hormone therapy is set at 3 years.

Method of administration

Before injection, it should be ensured that part of the implant is visible in the syringe window.

Precautions to take before handling or administering the medicine:

The plunger must not be removed when the needle is in place, and it is essential to push it fully to inject the implant into the subcutaneous tissue.

Hypersensitivity to the active substance or to any of the excipients listed in section Composition or to any of the components of the implant.

The use of Zoladex 10,8 mg is not indicated in children because the safety and efficacy of this product have not been established for this patient group.

Injection site injuries have been reported with Zoladex 10,8 mg, including pain, hematomas, hemorrhages, and vascular injuries. Patients showing signs or symptoms of abdominal hemorrhage should be monitored. In very rare cases, administration errors have caused vascular injury and hemorrhagic shock requiring blood transfusions and surgical intervention. Particular caution must be observed when administering Zoladex 10,8 mg to patients with a low BMI and/or receiving anticoagulant treatment (see section Dosage and administration).

There is an increased risk of incident depression (which may be severe) in patients treated with GnRH agonists, such as goserelin. Patients should be informed accordingly and treated appropriately if symptoms appear.

The use of Zoladex 10,8 mg in men at particular risk of ureteral obstruction or spinal cord compression should be considered with caution, and these patients must be closely monitored during the first month of treatment.

Initial use of an anti-androgen (e.g. cyproterone acetate 300 mg per day for three days before and three weeks after starting treatment with Zoladex) should be considered when initiating treatment with an LHRH analogue, as it has been reported to prevent possible sequelae of the initial increase in serum testosterone. In the presence of spinal cord compression or renal insufficiency due to ureteral obstruction, standard treatment specific to these complications must be initiated.

The use of LHRH agonists may lead to a decrease in bone mineral density. Preliminary data obtained in men indicate that the use of a bisphosphonate in combination with an LHRH agonist could reduce the loss of bone mineral density.

Particular caution is required in patients with additional risk factors for osteoporosis (e.g. chronic excessive alcohol consumption, smoking, long-term treatment with anticonvulsants or corticosteroids, family history of osteoporosis).

Mood disturbances, including depression, have been reported. Depressed patients and hypertensive patients should be closely monitored.

A decrease in glucose tolerance has been observed in men receiving LHRH agonists. It may manifest as diabetes or, in patients who already have diabetes mellitus, as a loss of glycaemic control. Monitoring of blood glucose should therefore be considered.

An increase in cases of heart failure and myocardial infarction has been observed in an epidemiological study in patients treated with LHRH agonists for prostate cancer. The risk appears to be increased when LHRH agonists are combined with anti-androgens.

Monitoring measures targeted at cardiovascular risk factors are necessary. In patients presenting these risk factors and/or pre-existing cardiovascular disease, management and treatment of the risk factors is necessary. See Section Adverse effects.

Androgen deprivation therapy may prolong the QT interval.

For patients with a history or risk factors of QT interval prolongation, and for patients receiving medicinal products that may prolong the QT interval (see section Interactions), physicians should assess the benefit-risk balance, taking into account the risk of torsade de pointes before initiating Zoladex.

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

Associations requiring precautions for use

As androgen deprivation therapy may result in prolongation of the QT interval, the concomitant use of Zoladex with medicinal products known to prolong the QT interval or medicinal products that can induce torsade de pointes such as class Ia antiarrhythmics (e.g. quinidine, disopyramide) or class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, antipsychotics, etc., should be carefully evaluated (see section Warnings and precautions)

Zoladex 10,8 mg has no or negligible influence on the ability to drive and use machines.

The following frequency categories are based on all adverse reactions from clinical studies, post-marketing studies and spontaneous reports.

In this section, adverse reactions are defined as follows: 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), and very rare (< 1/10 000), not known (cannot be estimated from the available data).

^a A decrease in glucose tolerance has been observed in men receiving LHRH agonists. It may manifest as diabetes or, in patients who already have diabetes mellitus, as loss of glycaemic control.

^b Pharmacological effects that rarely require discontinuation of treatment. Hot flushes and sweating may continue after stopping Zoladex.

^c May manifest as hypotension or hypertension and are sometimes observed in patients who have received goserelin. These changes are usually transient, disappearing during treatment or after discontinuation of goserelin treatment. In rare cases, these changes have been severe enough to require medical intervention, including discontinuation of goserelin treatment.

^d Generally mild, often regressing without requiring discontinuation of treatment.

^e Initially, patients with prostate cancer may experience a temporary increase in bone pain, which can be managed with symptomatic treatment.

^f An increase in cases of heart failure and myocardial infarction was observed in an epidemiological study in patients treated with LHRH agonists for prostate cancer.

The risk appears to be increased when LHRH agonists and anti-androgens are combined.

^g Particularly loss of body hair, which is an expected effect of the decrease in androgen levels.

Post-marketing experience

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/

Experience with overdose is limited in humans. In cases where Zoladex was administered before the scheduled date, or when a dose of goserelin higher than the planned dose was administered, no clinically significant adverse effects were observed. Tests performed in animals suggest that, at higher doses of goserelin, no effects other than the desired therapeutic effects on sex hormone concentrations and the reproductive organs will be visible. In case of overdose, treatment should be symptomatic.

Pharmacotherapeutic class: GONADOTROPHIN-RELEASING HORMONE ANALOGUE, ATC code: L02AE03

Goserelin is a synthetic decapeptide analogue and agonist of natural LH-RH. Chronic administration of goserelin acetate leads to a strong reduction in pituitary LH and plasma testosterone levels to the level usually observed in men who have undergone surgical castration.

This is maintained throughout the duration of treatment.

In men, at the start of treatment with goserelin acetate, the initial stimulation of LH secretion causes a transient rise in plasma testosterone.

However, about three weeks after the first injection, the plasma testosterone concentration falls back to the castration level and remains at this level with treatment administered every three months. If, exceptionally, the injection were not renewed at three months, studies have shown that testosterone concentrations remain below the castration threshold for up to 16 weeks in 85 % of patients.

Zoladex 10.8 mg can be administered every three months without significant clinical accumulation being observed.

Goserelin has a serum elimination half-life of 2 to 4 hours in subjects with normal renal function. The half-life of goserelin increases in subjects with renal impairment to approximately 12 hours without, however, resulting in accumulation in these patients.

In hepatically impaired patients, maximum concentrations and areas under the curve are significantly higher compared with healthy subjects.

Upon long-term administration, an increase in the incidence of benign pituitary tumours was observed in male rats, comparable to that already noted in this species following surgical castration. No link has been established with use in humans.

In mice, long-term administration of doses higher than the therapeutic dose in humans resulted in hyperplasia of the islet cells of the Islets of Langerhans and benign pyloric proliferation, a phenomenon spontaneous in this species.

The possible clinical implication is unknown.

3 years

Store at a temperature not exceeding +25 °C.

For correct administration, refer to the diagram of the method of administration enclosed in the box.

Check the integrity of the pouch before use.

The goserelin implant is used as soon as the pouch is opened. Particular caution must be exercised when administering Zoladex 10,8 mg to patients with a low BMI and/or receiving anticoagulant treatment (see section Warnings and precautions).

The presence of the safety system (Safesystem^TM) is intended to protect healthcare personnel against the risk of accidental needlestick injury.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.