4.1. Therapeutic indications

(i) Metastatic prostate cancer.

(ii) Locally advanced prostate cancer, as an alternative to surgical castration.

(iii) As an adjuvant treatment to radiotherapy in patients with high-risk localized or locally advanced prostate cancer.

(iv) As an adjuvant to radical prostatectomy in patients with locally advanced prostate cancer at high risk of disease progression.

(v) As a neo-adjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced prostate cancer.

4.2. Posology and method of administration

Posology

Administer one implant once every three months.

Method of administration

Staladex should be administered only by healthcare professionals.

Staladex is injected subcutaneously under the abdominal skin.

Animal study findings (thrombosis of small vessels distal to the administration site) indicate that accidental intra-arterial injection must be avoided.

Response to Leuprorelin therapy should be monitored by clinical parameters and by measuring prostate-specific antigen (PSA) serum levels. Clinical studies with leuprorelin acetate have shown that testosterone levels increased during the first 4 days of treatment in the majority of non-orchidectomised patients. They then decreased and reached castrate levels by 2-4 weeks.

Once attained, castrate levels were maintained as long as drug therapy continued. If a patient's response appears to be sub-optimal, then it would be advisable to confirm that serum testosterone levels have reached or are remaining at castrate levels.

In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of castrate-resistant prostate cancer. Reference should be made to relevant guidelines.

Treatment of advanced, hormone-dependent prostate cancer with Leuprorelin is usually a long-term treatment.

Clinical data have shown that 3 years of androgen deprivation therapy used concomitantly with and after radiotherapy is preferable to a 6-month course of androgen deprivation therapy in locally advanced, hormone-dependent prostate cancer (see also section 5.1). Medical guidelines recommend a 2- to 3-year course of androgen deprivation therapy for patients (T3 - T4) receiving radiotherapy.

4.3. Contraindications

• Hypersensitivity to leuprorelin or other GnRH analogues, or to any of the implant excipients listed in section 6.1.

• Patients who previously underwent orchiectomy.

• As the sole treatment in prostate cancer patients with spinal cord compression or evidence of spinal metastases.

• In women or paediatric patients.

4.4. Special warnings and precautions for use

Transient testosterone flare:

In the initial stages of therapy, a transient rise in levels of testosterone, dihydrotestosterone and acid phosphatase may occur. In some cases, this may be associated with a "flare" or exacerbation of the tumour growth resulting in temporary deterioration of the patient's condition. These symptoms usually subside on continuation of therapy. "Flare" may manifest itself as systemic or neurological symptoms in some cases.

In order to reduce the risk of “flare”, an anti-androgen may be administered beginning 3 days prior to leuprorelin therapy and continuing for the first two to three weeks of treatment. This has been reported to prevent the sequelae of an initial rise in serum testosterone.

Following surgical castration, Leuprorelin does not lead to a further decrease in serum testosterone levels in male patients.

Therapeutic success should be monitored regularly (but particularly if there is evidence of progression despite appropriate treatment) by means of clinical examinations (digital rectal examination of the prostate, ultrasound, skeletal scintigraphy, computed tomography) and by checking phosphatases and/or PSA and serum testosterone.

Cases of ureteral obstruction and spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with GnRH agonists. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted.

Patients with vertebral and/or brain metastases as well as patients with urinary tract obstruction should be closely monitored during the first few weeks of therapy.

Patients with hypertension should be carefully monitored.

Bone density:

Long-term androgen deprivation either by bilateral orchiectomy or administration of GnRH analogues is associated with increased risk of bone loss which, in patients with additional risk factors, may lead to osteoporosis and increased risk of bone fracture..

Apart from long lasting testosterone deficiency, increased age, smoking and consumption of alcoholic beverages, obesity and insufficient exercise may have an influence on the development of osteoporosis.

Pituitary apoplexy:

During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of GnRH-agonists, with a majority occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy was presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention is required.

Depression

There is an increased risk of incident depression (which may be serious) in patients undergoing treatment with GnRH agonists, such as leuprorelin.

Patients should be informed of this risk and treated as appropriate if symptoms occur.

Convulsions

There have been post-marketing reports of convulsions observed in patients treated with leuprorelin acetate and these events have been reported in both children and adults with or without a history of epilepsy, seizure disorders or risk factors for seizures.

The use of Leuprorelin can produce positive results in doping tests.

Metabolic changes and cardiovascular risk:

Epidemiological data have shown that during androgen-deprivation therapy, changes in metabolism (e.g. reduction in glucose tolerance or aggravation of pre- existing diabetes mellitus) as well as an increased risk for cardiovascular diseases may occur. However, prospective data did not confirm the link between treatment with GnRH analogues and an increase in cardiovascular mortality. Patients with diabetes and those at increased risk of metabolic or cardiovascular diseases should be appropriately monitored. Metabolic changes associated with GnRH agonist may also include fatty liver disease.

As would be expected with this class of drug, development or aggravation of diabetes may occur, therefore diabetic patients may require more frequent monitoring of blood glucose during treatment with Staladex.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), and Toxic epidermal necrolysis (TEN) which can be life-threatening or fatal, have been reported in association with leuprorelin treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for severe skin reactions. If signs and symptoms suggestive of these reactions appear, leuprorelin should be withdrawn immediately and an alternative treatment considered (as appropriate).

Androgen deprivation therapy may prolong the QT interval.

In patients with a history of or risk factors for QT interval prolongation and in patients receiving concomitant medicinal products known to prolong the QT interval (see section 4.5) physicians should carefully assess the benefit/risk ratio including the potential for developing torsade de pointes prior to initiating therapy with Staladex.

Hepatic dysfunction:

Hepatic dysfunction and jaundice with elevated liver enzyme levels have been reported with the use of leuprorelin acetate. Therefore, close observation should be made and appropriate measures taken if necessary.

Injection site abscesses

Abscesses at the injection site occur rarely. In one report of an abscess at the injection site, the absorption of leuprorelin from the depot appeared to be decreased. It is therefore advised to determine testosterone levels in such cases.

Idiopathic intracranial hypertension

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in patients receiving leuprorelin. Patients should be warned for signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, vision disturbances and tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of leuprorelin should be considered.

4.5. Interaction with other medicinal products and other forms of interaction

No pharmacokinetic drug-drug interaction studies have been performed with Staladex. There have been no reports of any interactions of leuprorelin acetate with other medicinal products.

Since androgen deprivation therapy may prolong the QT interval, the concomitant use of Staladex with other medicinal products known to prolong the QT interval or medicinal products able to induce torsade de pointes, such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics etc, should be carefully evaluated (see section 4.4).

4.6. Fertility, pregnancy and lactation

Staladex is not indicated for use in women and is generally contraindicated during pregnancy and lactation.

4.7. Effects on ability to drive and use machines

No studies on the effects of Leuprorelin on the ability to drive and use machines have been performed. However, the ability to drive and use machines may be impaired due to visual disturbances and dizziness.

Fatigue is common, particularly during initiation of therapy, and may also be due to the underlying malignancy

4.8. Undesirable effects

Adverse reactions seen with Staladex are due mainly to the specific pharmacological action, namely increases and decreases in certain hormone levels.

In cases where a "tumour flare" occurs after therapy, an exacerbation may occur in any symptoms or signs due to disease, for example bone pain, urinary obstruction, weakness of the lower extremities and paraesthesia). These symptoms usually subside on continuation of therapy.

The following tables list adverse reactions with leuprorelin based on experience from clinical trials as well as from post-marketing experience. Adverse reactions are grouped by MedDRA System Organ Classes and frequency classification. Frequencies are defined as:

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),

not known (cannot be estimated from the available data).

Table 1. Undesirable effects

Blood and lymphatic system disorders

Not known

Anaemia (reported in medicinal products of this class), thrombocytopaenia, leucopenia

Immune system disorders

Not known

Hypersensitivity reactions (including rash. pruritus, urticaria and rarely, wheezing and interstitial pneumonitis, anaphylactic reactions)

Metabolism and nutrition disorders

Very common

Weight fluctuation

Common

Decreased appetite, l

Not known

Lipids abnormal, glucose tolerance abnormal

Psychiatric disorders

Common

Insomnia, depression (see section 4.4), mood changes (long-term use)**

Nervous system disorders

Common

Headache (occasionally severe)

Uncommon

Dizziness, paraesthesia

Very rare

Pituitary apoplexy has been reported following initial administration in patients with pituitary adenoma.

Not known

Paralysis (see section 4.4), seizure, idiopathic intracranial hypertension (pseudotumor cerebri) (see section 4.4)

Eye disorders

Not known

Visual impairment

Cardiac disorders

Not known

QT interval prolonged (see sections 4.4 and 4.5), palpitations

Vascular disorders

Very common

Hot flushes

Not known

Pulmonary embolism, hypertension, hypotension (see section 4.4)

Gastrointestinal disorders

Common

Nausea

Uncommon

Diarrhoea, vomiting

Hepatobiliary disorders

Uncommon

Hepatic function abnormal, liver function test abnormal (usually transient)

Not known

Jaundice

Skin and subcutaneous tissue disorders

Very common

Hyperhidrosis

Not known

Stevens-Johnson syndrome/Toxic Epidermal Necrolysis (SJS/TEN) (see section 4.4), Toxic Skin Eruption, Erythema Multiforme

Musculoskeletal and connective tissue disorders

Very common

Muscle weakness, bone pain

Common

Athralgia,

Uncommon

Myalgia, weakness of lower extremities

Not known

Spinal fracture (see section 4.4), reduction in bone mass which may occur with the use of GnRH agonists

Renal and urinary disorders

Not known

Urinary tract obstruction

Reproductive system and breast disorders

Very common

Libido decreased, erectile dysfunction, testiculars atrophy

Common

Gynaecomastia

Respiratory, thoracic and mediastinal disorders

Not known

Interstitial lung disease

General disorders and administration site conditions

Very common

Fatigue, injection site reactions e.g. induration, erythema, pain, abscesses, swelling, nodules, ulcers and necrosis.

Common

Peripheral oedema

Not known

Pyrexia

** mood changes (long term use: frequency of 'common' and short term use: frequency of 'uncommon'

Special notes:

It is advisable the response to Leuprorelin therapy is monitored by measuring serum concentrations of testosterone 28 days after each injection carried out and before each re-administration of Staladex and additionally on the basis of other laboratory tests like acid phosphatase and PSA. For example, testosterone levels show an initial surge upon initiation of therapy, only to decrease thereafter over a period of two weeks. After two to four weeks, testosterone concentrations reach levels similar to those observed following bilateral orchiectomy and remain at that level throughout the treatment period.

An increase in acid phosphatase levels may be seen in the initial phase of treatment and is transient in nature. Acid phosphatase usually returns to normal levels or near- normal levels after a few weeks.

Abscesses at the injection site occur rarely. In one report of an abscess at the injection site, the absorption of leuprorelin from the depot appeared to be decreased. It is therefore advised to determine testosterone levels in such cases.

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No case of overdose has been reported.

Even when administering doses of up to 20 mg leuprorelin acetate per day for two years ( the dose levels used in early clinical studies), no other or new adverse reactions differing from those seen after daily administration of 1 mg or three- monthly administration of 11.25 mg were observed.

In cases of overdose, the patients should be monitored closely and management should be symptomatic and supportive.