4.1. Therapeutic indications

Treatment of patients with locally advanced, non-metastatic prostate cancer, as an alternative to surgical castration.

Treatment of metastatic prostate cancer.

As adjuvant treatment to radiotherapy in patients with high-risk localised or locally advanced prostate cancer.

As neoadjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced prostate cancer.

As adjuvant treatment to radical prostatectomy in patients with locally advanced prostate cancer at high risk of disease progression.

Treatment of central precocious puberty (CPP) in children 2 years and older with an onset of CPP before 8 years in girls and 10 years in boys).

4.2. Posology and method of administration

Posology

The recommended dose of Decapeptyl SR 22.5 mg is 22.5 mg of triptorelin (1 vial) administered every six months (twenty four weeks) as a single intramuscular injection.

In patients treated with GnRH analogues for metastatic prostate cancer, treatment is usually continued upon development of castrate-resistant prostate cancer.

Reference should be made to relevant guidelines.

Decapeptyl is also available as a 1-month treatment (Decapeptyl SR 3 mg) and as a 3-month treatment (Decapeptyl SR 11.25 mg).

Patients with renal or hepatic impairment

No dosage adjustment is necessary for patients with renal or hepatic impairment.

Paediatric population

Central precocious puberty (before 8 years in girls and 10 years in boys)

The treatment of children with Decapeptyl SR 22.5 mg should be under the overall supervision of a paediatric endocrinologist or of a paediatrician or an endocrinologist with expertise in the treatment of central precocious puberty.

Treatment should be stopped around the physiological age of puberty in boys and girls and should not be continued in girls with a bone maturation of more than 12-13 years. There are limited data available in boys relating to the optimum time to stop treatment based on bone age, however it is advised that treatment is stopped in boys with a bone maturation age of 13-14 years.

Method of administration

As with other medicinal products administered by injection, the injection site should be varied periodically.

Once reconstituted, the suspension of Decapeptyl SR 22.5 mg should be intramuscularly injected relatively rapidly and uninterrupted manner in order to avoid any potential blockage of the needle.

Precautions to be taken before handling or administering the medicinal product

Decapeptyl SR 22.5 mg is only intended for intramuscular use.

Since Decapeptyl SR 22.5 mg is a suspension of microparticles, inadvertent intravascular injection must be strictly avoided.

Decapeptyl SR 22.5 mg must be administered under the supervision of a physician.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to GnRH, its analogues or to any of the excipients listed in section 6.1 (see also section 4.8).

Triptorelin is contraindicated during pregnancy and lactation (see section 4.6).

4.4. Special warnings and precautions for use

The use of GnRH agonists may cause a reduction in bone mineral density. In men, preliminary data suggest that the use of a bisphosphonate in combination with a GnRH agonist may reduce bone mineral loss. No specific data is available for patients with established osteoporosis or with risk factors for osteoporosis (e.g. chronic alcohol abuse, smokers, long-term therapy with drugs that reduce bone mineral density, e.g. anti-convulsants or corticosteroids, family history of osteoporosis, malnutrition, e.g. anorexia nervosa). Particular caution is therefore necessary since reduction in bone mineral density is likely to be more detrimental in these patients. Treatment with Decapeptyl SR should be considered on an individual basis and only be initiated if the benefits of treatment outweigh the risk following a very careful appraisal. Consideration should be given to additional measures in order to counteract loss of bone mineral density.

Rarely, treatment with GnRH agonists may reveal the presence of a previously unknown gonadotroph cell pituitary adenoma. These patients may present with a pituitary apoplexy characterised by sudden headache, vomiting, visual impairment and ophthalmoplegia.

In patients undergoing treatment with GnRH agonists, an increased risk of depression was reported (which may be severe and includes rare case reports of suicidal ideation from post-marketing experience, including reports of positive dechallenge and reversible symptoms, and with the majority of reports occurring in patients with a background history of depression). Patients should be informed accordingly to contact a doctor as soon as possible if worsening depression occurs, and if suicidal ideation develops and treated as appropriate if symptoms occur. Patients with known depression should be monitored closely during therapy.

Caution is required with intramuscular injection in patients treated with anticoagulants, due to the potential risk of haematomas at the site of injection. The efficacy and safety of Decapeptyl SR 22.5 mg has been established via intramuscular route only. The subcutaneous administration is not recommended.

Convulsions have been reported with GnRH analogues, particularly in children. Some of these patients had risk factors for seizures (such as a history of epilepsy, intracranial tumors or co-medication with drugs known to present a risk of seizure reactions). Convulsions have also been reported in patients in the absence of such risk factors.

This medicine contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially 'sodium free'.

This medicine contains 2 mg of polysorbate 80 in each vial. Polysorbates may cause allergic reactions.

In men

Initially, triptorelin, like other GnRH agonists, causes a transient increase in serum testosterone levels. As a consequence, isolated cases of transient worsening of signs and symptoms of prostate cancer may occasionally develop during the first weeks of treatment. During the initial phase of treatment, consideration should be given to the additional administration of a suitable anti-androgen to counteract the initial rise in serum testosterone levels and the worsening of clinical symptoms.

A small number of patients may experience a temporary worsening of signs and symptoms of their prostate cancer (tumour flare) and temporary increase in cancer related pain (metastatic pain), which can be managed symptomatically.

As with other GnRH agonists, isolated cases of spinal cord compression or urethral obstruction have been observed. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted, and in extreme cases, an immediate orchidectomy (surgical castration) should be considered. Careful monitoring is indicated during the first weeks of treatment, particularly in patients suffering from vertebral metastases, at risk of spinal cord compression, and in patients with urinary tract obstruction.

After surgical castration, triptorelin does not induce any further decrease in serum testosterone levels. Once the castration levels of testosterone have been achieved by the end of the first month, serum testosterone levels are maintained for as long as the patients receive their injection every 6 months (twenty four weeks).

Long-term androgen deprivation either by bilateral orchidectomy or administration of GnRH agonists is associated with increased risk of bone loss and may lead to osteoporosis and increased risk of bone fracture.

Androgen deprivation therapy may prolong the QT interval.

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Decapeptyl SR 22.5 mg.

In addition, from epidemiological data, it has been observed that patients may experience metabolic changes (e.g. glucose intolerance, fatty liver), and an increased risk of cardiovascular disease during androgen deprivation therapy. However, prospective data did not confirm the link between treatment with GnRH analogues and an increase in cardiovascular mortality. Patients at high risk of metabolic or cardiovascular diseases should be carefully assessed before commencing treatment and their glucose, cholesterol and blood pressure adequately monitored during androgen deprivation therapy.

Metabolic changes may be more severe in these high-risk patients. Patients at high risk of metabolic or cardiovascular disease and receiving androgen deprivation therapy should be monitored at appropriate intervals not exceeding 3 months.

Administration of triptorelin in therapeutic doses results in suppression of the pituitary gonadal system. Normal function is usually restored after treatment is discontinued. Diagnostic tests of pituitary gonadal function conducted during treatment and after discontinuation of therapy with GnRH agonists may therefore be misleading.

Due to androgen deprivation, treatment with analogues of the GnRH can increase the risk of anaemia. This risk should be assessed in treated patients and monitored appropriately.

In paediatric population

Precocious puberty

Treatment of children with progressive brain tumours should follow a careful individual appraisal of the risks and benefits.

Pseudo-precocious puberty (gonadal or adrenal tumour or hyperplasia) and gonadotropin-independent precocious puberty (testicular toxicosis, familial Leydig cell hyperplasia) should be precluded.

In girls, initial ovarian stimulation at treatment initiation, followed by the treatment-induced oestrogen withdrawal, may lead, in the first month, to vaginal bleeding of mild or moderate intensity.

The therapy is a long-term treatment, adjusted individually. Decapeptyl SR 22.5mg should be administered as precisely as possible in regular 6 monthly periods. An exceptional delay of the injection date for a few days (169 ± 3 days) does not influence the results of the therapy.

After discontinuation of treatment the development of puberty characteristics will occur.

Information with regards to future fertility is still limited but future reproductive function and fertility appears to be unaffected by GnRH treatment. In most girls, regular menses will start on average one year after ending the therapy.

Bone mineral density may decrease during GnRH agonist therapy for central precocious puberty due to the expected effects of oestrogen suppression. However, after cessation of treatment subsequent bone mass accrual is preserved and peak bone mass in late adolescence does not seem to be affected by treatment.

Slipped capital femoral epiphysis can be seen after withdrawal of GnRH agonist treatment. The suggested theory is that the low concentrations of oestrogen during treatment with GnRH agonists weaken the epiphysial plate. The increase in growth velocity after stopping the treatment subsequently results in a reduction of the shearing force needed for displacement of the epiphysis.

Idiopathic intracranial hypertension

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in paediatric patients receiving triptorelin. 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 triptorelin should be considered.

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

Drugs which raise prolactin levels should not be prescribed concomitantly as they reduce the level of GnRH receptors in the pituitary.

When Decapeptyl SR 22.5 mg is co-administered with drugs affecting pituitary secretion of gonadotropins, caution should be exercised and it is recommended that the patient's hormonal status should be supervised

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Decapeptyl SR 22.5 mg with 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).

Paediatric Population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

Decapeptyl SR 22.5 mg is indicated for adult men and children. There are very limited data on the use of triptorelin in pregnant women. It should be confirmed that the patient is not pregnant before prescription of Decapeptyl SR 22.5 mg.

Triptorelin must not be used during pregnancy since concurrent use of GnRH agonists is associated with a theoretical risk of abortion or fetal abnormality. Prior to treatment, potential fertile women should be examined carefully to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy until menses return.

Animal studies have shown effects on reproductive parameters (see section 5.3 Preclinical safety data).

Lactation

Decapeptyl SR 22.5 mg is not indicated in lactating women.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, the ability to drive and use machines may be impaired should the patient experience dizziness, somnolence and visual disturbances (being possible undesirable effects of treatment), or resulting from the underlying disease.

4.8. Undesirable effects

General tolerance in Men (see section 4.4)

Since patients suffering from locally advanced or metastatic, hormone-dependent prostate cancer are generally old and have other diseases frequently encountered in this aged population, more than 90 % of the patients included in clinical trials reported adverse events, and often the causality is difficult to assess. As seen with other GnRH agonist therapies or after surgical castration, the most commonly observed adverse events related to triptorelin treatment were due to its expected pharmacological effects: These effects included hot flushes and decreased libido.

With the exception of immuno-allergic (rare) and injection site (< 5%) reactions, all adverse events are known to be related to testosterone changes.

The following adverse reactions, considered as at least possibly related to triptorelin treatment, were reported. Most of these events are known to be related to biochemical or surgical castration.

The frequency of the adverse reactions is classified as follows: very common (≥1/10); common (≥1/100, < 1/10); uncommon (≥1/1000, < 1/100); rare (≥1/10 000, < 1/1000); not known (cannot be estimated from the available data).

System Organ Class

Very Common

Common

Uncommon

Rare

Additional post-marketing

Frequency not known

Infections and infestations

Nasopharyngitis

Blood and lymphatic system disorders

Thrombocytosis

Anaemia

Immune system disorders

Hypersensitivity

Anaphylactic reaction

Anaphylactic shock

Endocrine disorders

Pituitary apoplexy**

Metabolism and nutrition disorders

Anorexia

Diabetes mellitus

Gout

Hyperlipidaemia

Increased appetite

Psychiatric disorders

Libido decreased

Loss of libido

Depression*

Mood changes*

Insomnia

Irritability

Confusional state

Decreased activity

Euphoric mood

Anxiety

Nervous system disorders

Paraesthesia in lower limbs

Dizziness

Headache

Paraesthesia

Memory impairment

Convulsions***

Eye disorders

Visual impairment

Abnormal sensation in eye

Visual disturbance

Ear and labyrinth disorders

Tinnitus

Vertigo

Cardiac disorders

Palpitations

QT prolongation* (see sections 4.4 and 4.5)

Vascular disorders

Hot flush

Hypertension

Hypotension

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Epistaxis

Orthopnoea

Gastrointestinal disorders

Dry mouth

Nausea

Abdominal pain

Constipation

Diarrhoea

Vomiting

Abdominal distension

Dysgeusia

Flatulence

General disorders and administration site conditions

Asthenia

Injection site reaction (including erythema inflammation and pain)

Oedema

Lethargy

Oedema peripheral

Pain

Rigours

Somnolence

Chest pain

Dysstasia

Influenza-like illness

Pyrexia

Malaise

Skin and subcutaneous tissue disorders

Hyperhidrosis

Acne

Alopecia

Erythema

Pruritus

Rash

Urticaria

Blister

Purpura

Angioneurotic oedema

Musculoskeletal and connective tissue disorders

Back pain

Musculoskeletal pain

Pain in extremity

Arthralgia

Bone pain

Muscle cramp

Muscular weakness

Myalgia

Joint stiffness

Joint swelling

Musculoskeletal stiffness

Osteoarthritis

Renal and urinary disorders

Nocturia

Urinary retention

Urinary incontinence

Reproductive system and breast disorders

Erectile dysfunction (including ejaculation failure, ejaculation disorder)

Pelvic pain

Gynaecomastia

Breast pain

Testicular atrophy

Testicular pain

Investigations

Weight increase

Alanine aminotransferase increased

Aspartate aminotransferase increased

Blood creatinine increased

Blood pressure increased

Blood urea increased

Gamma-glutamyl transferase increased

Weight decreased

Blood alkaline phosphatase increased

* This frequency is based on class-effect frequencies common for all GnRH agonists

**Reported following initial administration in patients with pituitary adenoma

***During post market experience convulsions have been reported in patients receiving GnRH analogues, including triptorelin.

Triptorelin causes a transient increase in circulating testosterone levels within the first week after the initial injection of the sustained release formulation. With this initial increase in circulating testosterone levels, a small percentage of patients (≤ 5 %) may experience a temporary worsening of signs and symptoms of their prostate cancer (tumour flare), usually manifested by an increase in urinary symptoms (< 2 %) and/or metastatic pain (5 %), which can be managed symptomatically. These symptoms are transient and usually disappear in one to two weeks.

Isolated cases of exacerbation of disease symptoms, either urethral obstruction or spinal cord compression by metastasis have occurred. Therefore, patients with metastatic vertebral lesions and/or with upper or lower urinary tract obstruction should be closely observed during the first few weeks of therapy (see section 4.4 Special warnings and precautions for use).

The use of GnRH agonists to treat prostate cancer may be associated with increased bone loss and may lead to osteoporosis and increase the risk of bone fracture. This may also lead to an incorrect diagnosis of bone metastases.

Patients receiving long-term treatment with GnRH analogue in combination with radiation therapy may have more side effects, mostly gastrointestinal and related to radiotherapy.

General tolerance in Children (see section 4.4)

The frequency of the adverse reactions is classified as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000, < 1/100); not known (cannot be estimated from the available data).

System Organ Class

Very Common Treatment related AEs

Common Treatment related AEs

Uncommon Treatment related AEs

Additional post-marketing

Frequency not known

Immune system disorders

Hypersensitivity

Anaphylactic shock

Metabolism and nutrition disorders

Obesity

Psychiatric disorders

Mood altered

Lability affected

Depression

Nervousness

Nervous system disorders

Headache

Idiopathic intracranial hypertension (pseudotumor cerebri) (see section 4.4)

Convulsions*

Eye disorders

Visual impairment

Visual disturbance

Vascular disorders

Hot flush

Hypertension

Respiratory, thoracic and mediastinal disorders

Epistaxis

Gastrointestinal disorders

Abdominal pain

Vomiting

Constipation

Nausea

Skin and subcutaneous tissue disorders

Acne

Pruritus

Rash

Urticaria

Angioneurotic oedema

Musculoskeletal and connective tissue disorders

Neck pain

Myalgia

Reproductive system and breast disorders

Vaginal bleeding (including vaginal haemorrhage, withdrawal bleeding, uterine haemorrhage, vaginal discharge, vaginal bleeding including spotting)

Breast pain

General disorders and administration site conditions

Injection site reaction (including injection site pain, injection site erythema and injection site inflammation)

Malaise

Investigations

Weight increased

Blood pressure increased

Blood prolactin increased

*During post market experience convulsions have been reported in patients receiving GnRH analogues, including triptorelin.

General

Increased lymphocyte count has been reported with patients undergoing GnRH agonist treatment. This secondary lymphocytosis is apparently related to GnRH induced castration and seems to indicate that gonadal hormones are involved in thymic involution.

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

4.9. Overdose

The pharmaceutical properties of Decapeptyl SR 22.5 mg and its mode of administration make accidental or intentional overdose unlikely. There is no experience of overdose from clinical trials. Animal tests suggest that no effect other than the intended therapeutic effects on sex hormone concentration and on the reproductive tract will be evident with higher doses of Decapeptyl SR 22.5 mg. If overdose occurs, this should be managed symptomatically.