This information is intended for use by health professionals

1. Name of the medicinal product

Decapeptyl SR 3 mg, powder for suspension for injection.

2. Qualitative and quantitative composition

Triptorelin (I.N.N.) 4.2 mg, as triptorelin acetate.

The vial contains an overage to ensure that a dose of 3 mg is administered to the patient.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder for suspension for injection, sustained release formulation.

4. Clinical particulars
4.1 Therapeutic indications

Treatment of patients with locally advanced, non-metastatic prostate cancer, as an alternative to surgical castration (see section 5.1).

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 endometriosis.

Treatment of uterine fibroids prior to surgery or when surgery is not appropriate.

As adjuvant treatment in combination with tamoxifen or an aromatase inhibitor, of endocrine responsive early stage breast cancer in women at high risk of recurrence who are confirmed as pre-menopausal after completion of chemotherapy (see sections 4.3, 4.4, 4.8 and 5.1).

4.2 Posology and method of administration

Prostate cancer

One intramuscular injection should be administered every 4 weeks (28 days). No dosage adjustment is necessary in the elderly.

Decapeptyl is also available as a 3-month treatment (Decapeptyl SR 11.25 mg) and as a 6-month treatment (Decapeptyl SR 22.5 mg) for prostate cancer.

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.

Endometriosis and uterine fibroids

One intramuscular injection every 28 days. For the treatment of endometriosis and uterine fibroids the treatment must be initiated in the first five days of the cycle. The maximum duration of treatment should be 6 months. For patients with uterine fibroids Decapeptyl SR 3 mg should be administered for a minimum of 3 months.

A further course of treatment by Decapeptyl SR 3 mg or by other GnRH agonists beyond 6 months should not be undertaken due to concerns about bone density losses.

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

Breast cancer

One intramuscular injection every 4 weeks in combination with tamoxifen or an aromatase inhibitor.

Triptorelin should be commenced after completion of chemotherapy, once pre-menopausal status has been confirmed (see section 4.4).

The treatment with triptorelin must be initiated at least 6-8 weeks before starting aromatase inhibitor treatment. A minimum of two injections of triptorelin (with an interval of 4 weeks between injections) should be administered before commencement of aromatase inhibitor treatment.

During treatment with an aromatase inhibitor, triptorelin must not be interrupted to avoid rebound increases in circulating oestrogens in premenopausal women.

The recommended treatment duration for adjuvant treatment in combination with other hormonotherapy is up to 5 years.

Since triptorelin P.R. 3 mg is a suspension of microparticles, inadvertent intravascular injection must be strictly avoided.

4.3 Contraindications

Hypersensitivity to GnRH (gonadotropin releasing hormone), its analogues or to any of the excipients listed in section 6.1.

Pregnancy and lactation.

In the pre-menopausal breast cancer setting: Initiation of aromatase inhibitor treatment before adequate ovarian suppression with triptorelin has been achieved (see sections 4.2 and 4.4).

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. anticonvulsants 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 3 mg 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.

It should be confirmed that the patient is not pregnant before prescription of triptorelin.

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.

There is an increased risk of incident depression (which may be severe) in patients undergoing treatment with GnRH agonists, such as triptorelin. Patients should be informed accordingly and treated as appropriate if symptoms occur. Patients with known depression should be monitored closely during therapy.

Prostate cancer

Initially, Decapeptyl SR 3 mg, 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 metastasis, at the risk of spinal cord compression, and in patients with urinary tract obstruction.

After surgical castration, Decapeptyl SR 3 mg does not induce any further decrease in serum testosterone levels.

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 3 mg.

In addition, from epidemiological data, it has been observed that patients may experience metabolic changes (e.g. glucose intolerance), or 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 for 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.

Endometriosis and Uterine Fibromyomas

The use of GnRH 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.

Used at the recommended dose, Decapeptyl SR 3 mg causes constant hypogonadotropic amenorrhoea. If vaginal haemorrhage occurs after the first month, plasma oestradiol levels should be measured and if levels are below 50 pg/mL, possible organic lesions should be investigated.

After withdrawal of treatment, ovarian function resumes and ovulation occurs approximately 2 months after the last injection. A non-hormonal method of contraception should be used throughout treatment including for 1 month after the duration of the last injection.

Since menses should stop during Decapeptyl SR 3 mg treatment, the patient should be instructed to notify her physician if regular menstruation persists.

It is recommended that during treatment of uterine fibroids, the size of the fibroid is determined regularly. There have been a few reports of bleeding in patients with submucous fibroids following GnRH agonist therapy. Typically, the bleeding has occurred 6 - 10 weeks after the initiation of therapy.

Breast cancer:

In order to ensure adequate ovarian suppression in premenopausal women, treatment with triptorelin should be administered for at least 6-8 weeks prior to commencement of an aromatase inhibitor, and monthly triptorelin injections should be administered on schedule and without interruption throughout aromatase inhibitor treatment.

Women who are premenopausal at breast cancer diagnosis and who become amenorrhoeic following chemotherapy may or may not have continued oestrogen production from the ovaries. Irrespective of menstrual status, pre-menopausal status should be confirmed following chemotherapy and before commencement of triptorelin, by blood concentrations of oestradiol and FSH within the reference ranges for pre-menopausal women, in order to avoid unnecessary treatment with triptorelin in the event of a chemotherapy-induced menopause. Following commencement of triptorelin, it is important to confirm adequate ovarian suppression (gonadotrophin analogue- induced menopause) by serial assessment of circulating FSH, and oestradiol if this subset of women is to be considered for therapy with an aromatase inhibitor, in accordance with current clinical practice recommendations. Accordingly, ovarian suppression should be confirmed by low blood concentrations of FSH and oestradiol prior to starting aromatase inhibitor treatment and measurements should be repeated every three months during combination therapy with triptorelin and an aromatase inhibitor. This is to avoid aromatase inhibitor-induced rebound increase in circulating oestrogen, with consequential implications for the breast cancer. Of note, circulating FSH levels are lowered in response to gonadotrophin analogue-induced ovarian suppression (induced menopause), unlike in a natural menopause where FSH levels are elevated.

Triptorelin, when used as adjuvant therapy in combination with tamoxifen or an aromatase inhibitor, is associated with a high risk of osteoporosis. Osteoporosis has been reported with a higher frequency following the use of triptorelin in combination with an aromatase inhibitor than in combination with tamoxifen (39% vs 25%).

Bone mineral density should be assessed before starting treatment with triptorelin, especially in women who have multiple risk factors for osteoporosis. These patients should be closely monitored and treatment for, or prophylaxis of, osteoporosis should be initiated when appropriate.

Treatment of premenopausal women with endocrine responsive early stage breast cancer with triptorelin in combination with tamoxifen or an aromatase inhibitor should follow a careful individual appraisal of the risks and benefits.

Patients who have discontinued triptorelin treatment should also discontinue aromatase inhibitors within 1 month of the last triptorelin administration (1 month formulation).

The risk of musculoskeletal disorders (including joint or musculoskeletal pain) when triptorelin is used in combination with either an aromatase inhibitor or tamoxifen is approximately 89% with the AI and approximately 76% with tamoxifen.

Hypertension was reported as a targeted adverse event at a very common frequency with triptorelin in combination with either exemestane or tamoxifen (see section 4.8).

Premenopausal women with breast cancer receiving triptorelin in combination with either exemestane or tamoxifen should have regular monitoring of cardiovascular risk factors and blood pressure.

Hyperglycaemia and diabetes were reported as targeted adverse events at a common frequency with triptorelin in combination with either exemestane or tamoxifen (see section 4.8). Premenopausal women with breast cancer receiving triptorelin in combination with either exemestane or tamoxifen should have regular monitoring of risk factors for diabetes with blood glucose monitoring on a regular basis and appropriate anti-diabetic treatment initiated, if appropriate, according to national guidelines.

Depression occurred in approximately 50% of patients treated with triptorelin in combination with either tamoxifen or exemestane in all treatment groups in the TEXT and SOFT studies, but less than 5% of patients had severe depression (grade 3-4). Patients should be informed accordingly and treated as appropriate if symptoms occur. Patients with known depression or depression history should be carefully monitored during therapy.

Particular attention should also be paid to the exemestane and tamoxifen prescribing information for relevant safety information when administered in combination with triptorelin.

Chemotherapy can induce temporary amenorrhoea or a permanent loss of ovarian function due to cytotoxic damage of gonadal tissue. Retention of pre-menopausal status following completion of chemotherapy should be confirmed as recommended by clinical guidelines by blood concentrations of oestradiol and FSH within the reference ranges for pre-menopausal women.

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 3 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 be supervised.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Decapeptyl SR 3 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).

4.6 Pregnancy and lactation

Triptorelin should 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, potentially fertile women should be examined to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy until menses resume.

Reproductive studies in primates have shown no maternal toxicity or embryotoxicity, and there was no effect on parturition. Inadvertent administration of triptorelin during human pregnancy has not demonstrated a teratogenic or other fetal risk. However, it is recommended that Decapeptyl SR 3 mg should not be used during pregnancy or lactation.

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

Clinical trials experience

General tolerance in men

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 ( 1/10000, < 1/1000).

System Organ Class

Very Common

Common

Uncommon

Rare

Additional post-marketing AEs

Frequency not known

Infections and infestations

Nasopharyngitis

Blood and lymphatic system disorders

Thrombocytosis

Immune system disorders

Hypersensitivity

Anaphylactic reaction

Anaphylactic shock

Metabolism and nutrition disorders

Anorexia

Diabetes mellitus

Gout

Hyperlipidaemia

Increased appetite

Psychiatric disorders

Libido decreased

Depression*

Loss of libido

Mood change*

Insomnia

Irritability

Confusional state

Decreased activity

Euphoric mood

Anxiety

Nervous system disorders

Paraesthesia in lower limbs

Dizziness

Headache

Paraesthesia

Memory impairment

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

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

Breast pain

Gynaecomastia

Testicular atrophy

Testicular pain

General disorders and administration site conditions

Asthenia

Injection site reaction (including erythema, inflammation and pain)

Oedema

Lethargy

Oedema peripheral

Pain

Rigors

Somnolence

Chest pain

Dysstasia

Influenza like illness

Pyrexia

Malaise

Investigations

Weight increased

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

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 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).

The use of GnRH agonists, to treat prostate cancer may be associated with increased bone loss and may lead to osteoporosis and increases the risk of bone fracture.

General tolerance in women (see section 4.4)

As a consequence of decreased oestrogen levels, the most commonly reported adverse events (expected in 10% of women or more) were headache, libido decreased, sleep disorder, mood changes, dyspareunia, dysmenorrhoea, genital haemorrhage, ovarian hyperstimulation syndrome, ovarian hypertrophy pelvic pain, abdominal pain, vulvovaginal dryness, hyperhidrosis, hot flushes and asthenia.

The following adverse reactions, considered as at least possibly related to triptorelin treatment, were reported. Most of these 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 (1/10000, < 1/1000)

System Organ Class

Very Common

Common

Uncommon

Additional post-marketing AEs

Frequency not known

Immune system disorders

Hypersensitivity

Anaphylactic shock

Metabolism and nutrition disorders

Decreased appetite

Fluid retention

Psychiatric disorders

Libido decreased

Mood disorder

Sleep disorder (including insomnia)

Depression*

Nervousness

Affect lability

Anxiety

Depression**

Disorientation

Confusional state

Nervous system disorders

Headache

Dizziness

Dysgeusia

Hypoasthesia

Syncope

Memory impairment

Disturbance in attention

Paraesthesia

Tremor

Eye disorders

Dry eye

Visual Impairment

Visual disturbance

Ear and labyrinth disorders

Vertigo

Cardiac Disorders

Palpitations

Vascular disorders

Hot flush

Hypertension

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Epistaxis

Gastrointestinal disorders

Abdominal pain

Abdominal discomfort

Nausea

Abdominal distension

Dry mouth

Flatulence

Mouth ulceration

Vomiting

Diarrhoea

Skin and subcutaneous tissue disorders

Acne

Hyperhidrosis

Seborrhoea

Alopecia

Dry skin

Hirsutism

Onychoclasis

Pruritus

Rash

Angioneurotic oedema

Urticaria

Musculoskeletal and connective tissue disorders

Arthralgia

Muscle spasms

Pain in extremities

Back pain

Myalgia

Muscular weakness

Reproductive system and breast disorders

Breast disorder

Dyspareunia

Genital bleeding (including vaginal bleeding withdrawal bleed)

Ovarian hyperstimulation syndrome

Ovarian hypertrophy

Pelvic pain

Vulvovaginal dryness

Breast pain

Coital bleeding

Cystocele

Menstrual disorder (including dysmenorrhoea, metrorrhagia and menorrhagia)

Ovarian cyst

Vaginal discharge

Amenorrhoea

General disorders and administration site conditions

Asthenia

Injection site reaction (including pain, swelling, erythema and inflammation) Oedema peripheral

Malaise

Pyrexia

Investigations

Weight increased

Weight decreased

Blood alkaline phosphatase increased

Blood pressure increased

*Long term use: This frequency is based on class-effect frequencies common for all GnRH agonists

** Short term use: This frequency is based on class-effect frequencies common for all GnRH agonists

At the beginning of treatment, the symptoms of endometriosis including pelvic pain and dysmenorrhoea may be very commonly exacerbated (≥ 10%) during the initial transient increase in plasma oestradiol levels. These symptoms are transient and usually disappear in one or two weeks.

Genital haemorrhage including menorrhagia, metrorrhagia may occur in the month following the first injection.

General

Increased lymphocytes 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.

Breast Cancer

The most commonly observed adverse reactions associated with triptorelin treatment for up to 5 years in combination with either tamoxifen or an aromatase inhibitor in the TEXT and SOFT studies were hot flush, musculoskeletal disorder, fatigue, insomnia, hyperhidrosis, vulvovaginal dryness and depression.

The frequencies of the adverse reactions reported with triptorelin in combination with tamoxifen (N = 2325) or exemestane (N = 2318) are shown in the following table. The classifications are as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000).

System Organ Classes

Very Common

≥1/10

Common

≥1/100 to <1/10

Uncommon

≥1/1000 to <1/100

Rare

≥1/10,000 to <1/1000

Cardiac disorders

Myocardial Ischaemia

QT prolongation

Endocrine disorders

Diabetes mellitus (glucose intolerance)

Hyperglycaemia

Gastrointestinal disorders

Nausea

General disorders and administration site conditions

Fatigue

Injection site reaction

Immune system disorders

Hypersensitivity

Musculoskeletal and connective tissue disorders

Musculoskeletal disorder

Osteoporosis

Fracture

Nervous system disorders

Cerebral ischaemia

Central nervous system haemorrhage

Psychiatric disorders

Insomnia

Libido decreased

Depression

Renal and urinary disorders

Urinary incontinence

Reproductive system and breast disorders

Dyspareunia

Vulvovaginal dryness

Skin and subcutaneous tissue disorders

Hyperhidrosis

Vascular disorders

Hot flushes

Hypertension

Embolism

The ADRs identified above should be used in addition to the triptorelin ADRs identified in men and women in tables above to fully describe the ADR profile for the use of OFS in combination with either exemestane or tamoxifen.

Osteoporosis has been reported with a higher frequency with the use of triptorelin in combination with exemestane than in the combination with tamoxifen (39% versus 25%) (see section 4.4).

Musculoskeletal disorder and fractures were also more commonly reported in the combination with exemestane than in the combination with tamoxifen (89% versus 76% and 6.8% versus 5.2%, respectively)

Hypertension has been reported as a targeted adverse event at a very common frequency with triptorelin in combination with either exemestane or tamoxifen (23% and 22% respectively). Hyperglycaemia and diabetes have been reported as targeted adverse events at a common frequency with triptorelin in combination with either exemestane or tamoxifen (hyperglycaemia: 2.6% and 3.4% respectively; diabetes: 2.3% and 2.3% respectively).

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

4.9 Overdose

There is no human experience of overdosage. Animal data do not predict any effects other than those on sex hormone concentration and consequent effect on the reproductive tract. If overdosage occurs, symptomatic management is indicated.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Gonadotropin-Releasing Hormone analogue

L02AE04: Antineoplastic and immunomodulator

Triptorelin is a decapeptide analogue of GnRH which initially stimulates release of pituitary gonadotropins.

Patients with prostate cancer

This results in an increase in peripheral circulating levels of testosterone and dihydrotestosterone. Continued administration (over 7 days) however, leads to suppression of gonadotropins and a consequent fall in plasma testosterone. In patients with prostate cancer, plasma testosterone levels fall to castrate levels after 2 - 3 weeks of treatment, frequently resulting in an improvement of function and objective symptoms.

The efficacy and safety of triptorelin has been determined in clinical studies involving 645 patients with locally advanced or metastatic prostate cancer.

Of these, three long term controlled studies compared the efficacy and safety of triptorelin to bilateral orchidectomy as an initial therapy in patients with locally advanced or metastatic prostate cancer (stage C or D). In one of these three long term studies, 7 patients in the triptorelin group and 7 patients in the orchidectomy group had also undergone prostatectomy. Triptorelin induced biochemical castration at least as rapidly as surgical pulpectomy and was as effective as surgical castration in the long term palliative treatment of locally advanced or metastatic prostate cancer. Both the triptorelin and orchidectomy groups showed improvements in dysuria and pain, and reduction in volume of prostate. Analysis after six and eight years in two of the studies showed that there was no significant difference in the median survival rates in the triptorelin group versus the orchidectomy group.

A study assessing the pharmacodynamic equivalence between triptorelin 3-month and 28-day prolonged release formulations in patients with locally advanced or metastatic prostate cancer, found that equivalent testosterone suppression was achieved, whether 3 doses of Decapeptyl SR 3 mg (n=68) or a single dose of Decapeptyl SR 11.25 mg (n=63) was given. The percentage of patients who achieved a testosterone castrate level ≤ 0.5 ng/mL at D84 was similar in the two treatment groups (98% and 96% in the 3-month and 28-day formulation groups, respectively). The time to achieve chemical castration was not significantly different between the two groups.

In a phase III randomized clinical trial including 970 patients with locally advanced prostate cancer (mainly T2c-T4 with some T1c to T2b patients with pathological regional nodal disease) of whom 483 were assigned to short-term androgen suppression (6 months) in combination with radiation therapy and 487 to long-term therapy (3 years), a non-inferiority analysis compared the short-term to long-term concomitant and adjuvant hormonal treatment with triptorelin (62.2%) or goserelin (30.1%). The 5-year overall mortality was 19.0% and 15.2%, in the short-term and long-term groups, respectively. The observed Hazard Ratio of 1.42 with an upper one-sided 95.71% CI of 1.79 or two-sided 95.71% CI of 1.09; 1.85 (p = 0.65 for non inferiority), demonstrate that the combination of radiotherapy plus 6 months of androgen deprivation therapy provides inferior survival as compared with radiotherapy plus 3 years of androgen deprivation therapy. Overall survival at 5 years of long-term treatment and short-term treatment shows 84.8% survival and 81.0%, respectively.

Overall quality of life using QLQ-C30 did not differ significantly between the two groups (P= 0.37).

Neoadjuvant triptorelin prior to radiotherapy has been shown to significantly reduce prostate volume.

The use of a GnRH agonist may be considered after radical prostatectomy in selected patients considered at high risk of disease progression. There are no disease-free survival data or survival data with triptorelin in this setting.

Patients with endometriosis and uterine fibroids

Continued administration of Decapeptyl SR 3 mg induces suppression of oestrogen secretion and thus enables resting of ectopic endometrial tissue. In pre-operative therapy for uterine fibroids there appears to be a beneficial effect on the blood loss at surgery. Studies have demonstrated a consistent and marked reduction in uterine and/or fibroid volume becoming maximal in a three to six month treatment period. Clinical studies have shown that 90-100% of patients with fibroids become amenorrhoeic within two months of treatment and triptorelin provides relief from the symptoms of abdominal pain, dysmenorrhoea and menorrhagia associated with uterine fibroids.

Breast cancer

Clinical studies performed in premenopausal women with endocrine responsive early stage breast cancer have been conducted with triptorelin in order to suppress oestradiol ovarian secretion, the main source of oestrogens. Based on studies performed in healthy women and women with endometriosis, the effect of triptorelin is achieved 3-4 weeks after administration.

Two phase 3 studies (SOFT and TEXT) have explored the 5-year benefit of ovarian function suppression (OFS) in combination with tamoxifen (T) or an aromatase inhibitor (exemestane - E) in premenopausal women with endocrine responsive early stage breast cancer.

Triptorelin was the main treatment used to achieve OFS (91.0% of randomised subjects in the SOFT study, and 100% in the TEXT study). The remaining 9% of women in the SOFT study had bilateral oophorectomy or bilateral ovarian irradiation.

SOFT study results

The SOFT study was designed to answer the question of the added value of OFS to tamoxifen as adjuvant treatment of premenopausal women with endocrine responsive early stage breast cancer.

A total of 3047 women were analysed (1015 women in the T+OFS, 1018 women in the T alone and 1014 women in the E+OFS arm).

At a median follow-up of 67 months (5.6 years), treatment with T+OFS non-significantly reduced the hazard of a Disease Free Survival (DFS) event versus T alone (HR=0.83; 95% CI, 0.66 to 1.04; p=0.10). The estimated 5-year DFS was 86.6% (95% CI, 84.2% to 88.7%) among women assigned to T+OFS compared with 84.7% (95% CI, 82.2% to 86.9%) for women assigned to T alone.

However, after adjustment for prespecified covariates in the multivariate Cox model, women assigned treatment with T+OFS had a significantly reduced hazard of a DFS event compared with women assigned T alone, with a reduction of 22% (HR=0.78; 95% CI, 0.62 to 0.98; p=0.03).

Women assigned treatment with T+OFS had a non-significantly reduced hazard of a breast cancer event compared with women assigned T alone (HR=0.81; 95% CI, 0.63 to 1.03; p=0.09). The estimated 5-year Breast Cancer Free Interval (BCFI) was 88.4% (95% CI, 86.1% to 90.3%) for women assigned treatment with T+OFS compared with 86.4% (95% CI, 84.0% to 88.5%) for women assigned T alone.

However, after adjusting for pre-specified covariates in the multivariable Cox model, women assigned T+OFS had a significantly reduced hazard of a BCFI event compared with women assigned T with a reduction of 25% (HR=0.75; 95% CI, 0.59 to 0.96; p=0.02).

The absolute benefit is higher in women who received adjuvant chemotherapy. The DFS rate at 5 years for women who received adjuvant chemotherapy was 80.7% in the T + OFS arm and 77.1% in the T arm only (HR=0.82; 95% CI, 0.64 to 1.07) with an absolute benefit of 3.6% for T+OFS.

In particular, the benefit of adding OFS was apparent for 5-year DFS in a post-hoc analysis for the subgroup of women less than 40 years old (HR=0.74; 95% CI, 0.53, 1.03) with an absolute benefit of 4.4% for T+OFS compared to T alone.

In the SOFT study, subjects assigned E+OFS had a statistically significantly reduced hazard of a DFS event, as compared with subjects assigned T alone (HR=0.68, 95% CI, 0.53 to 0.86). The estimated 5-year DFS rate was 89.0% (95% CI, 86.8% to 90.9%) among subjects assigned to E+OFS as compared with 84.7% (95% CI, 82.2% to 86.9%) among subjects assigned T alone.

Subjects assigned E+OFS had a statistically significantly reduced hazard of a breast cancer event as compared with subjects assigned T alone (HR=0.64; 95% CI, 0.49 to 0.83). The estimated 5-year BCFI was 90.9% (95% CI, 88.9% to 92.6%) among subjects assigned E+OFS compared with 86.4% (95% CI, 84.0% to 88.5%) among subjects assigned T alone.

Subjects assigned E+OFS had a statistically significantly reduced hazard of a distant recurrence as compared with subjects assigned T alone (HR=0.71; 95% CI, 0.52 to 0.96). The estimated 5-year Distant Recurrence Free Interval (DRFI) was 93.0% (95% CI, 91.2% to 94.5%) among subjects assigned E+OFS compared with 90.7% (95% CI, 88.6% to 92.4%).

The absolute benefit is higher in women who received adjuvant chemotherapy. The DFS rate at 5 years for women who received adjuvant chemotherapy was 83.8% in the E + OFS arm and 77.1% in the T arm only (HR=0.70, 95%CI, 0.53 to 0.92) with an absolute benefit of 6.7% for E+OFS.

Kaplan-Meier Estimates of DFS in women who received prior chemotherapy

In the 3 arms SOFT study, women who received chemotherapy had a higher proportion of high risk clinical criteria of recurrence: 49.3% below age < 40, 56.9% with lymph nodes positive, 47.0% with breast tumour size > 2 cm and 33.7% with tumour grade 3.

Combined SOFT and TEXT study results

The primary objective of TEXT study was to evaluate the role of aromatase inhibitors (exemestane) in women treated with OFS compared with T+OFS including all women from SOFT and TEXT studies. A total of 4690 women were analysed: 2346 women in the E+OFS arm and 2344 women in the T+OFS arm.

At a median follow-up of 68 months (5.7 years), treatment with E+OFS statistically significantly reduced the hazard of a DFS event versus T+OFS (HR=0.72; 95% CI, 0. 60 to 0.86; p=0.0002). The estimated 5-year DFS was 91.1% (95% CI, 89.7% to 92.3%) for women assigned to E+OFS compared with 87.3% (95% CI, 85.7% to 88.7%) for women assigned T+OFS.

Kaplan-Meier Estimates of DFS OFS+E vs OFS +T

Women assigned E+OFS had a statistically significantly reduced hazard of a breast cancer event compared with women assigned T+OFS (HR=0.66; 95% CI, 0.55 to 0.80; P<0.0001). The estimated 5-year BCFI was improved at 92.8% (95% CI, 91.6% to 93.9%) for women assigned E+OFS compared with 88.8% (95% CI, 87.3% to 90.1%) for women assigned T+OFS.

5.2 Pharmacokinetic properties

SUBCUTANEOUS FORM

In healthy volunteers

Subcutaneously administered triptorelin (100 μg) is rapidly absorbed (Tmax = 0.63 ± 0.26 hr for peak plasma concentration = 1.85 ± 0.23 ng/mL). Elimination is effected with a biological half-life of 7.6 ± 1.6 hr, after a 3 to 4 hr distribution phase. Total plasma clearance is: 161 ± 28 mL/min. Distribution volume is 104.1 ± 11.7 litres.

In patients with prostate cancer

With subcutaneous administration (100 μg), triptorelin blood levels oscillate between maximum values of 1.28 ± 0.24 ng/mL (Cmax) obtained in general one hour after injection (Tmax) and minimum values of 0.28 ± 0.15 ng/mL (Cmin) obtained 24hrs after injection.

The biological half-life is on average 11.7 ± 3.4 hr but varies according to patients. Plasma clearance (118 ± 32 mL/min) reflects slower elimination in patients, whilst distribution volumes are close to those of healthy volunteers (113.4 ± 21.6 litres).

SUSTAINED RELEASE FORM

In patients with prostate cancer

Following intramuscular injection of the sustained release form, an initial phase of release of the active principle present on the surface of the microspheres is observed, followed by further fairly regular release (Cmax = 0.32 ± 0.12 ng/mL), with a mean rate of release of triptorelin of 46.6 ± 7.1 μg/day. The bioavailability of the microparticles is approximately 53% at one month.

In patients with endometriosis and uterine fibroids

After intramuscular injection of Decapeptyl SR 3 mg in women with endometriosis and uterine fibroids the maximum blood level of triptorelin is obtained between 2 to 6 hours after injection, the peak value reached is 11 ng/mL. There was no evidence of accumulation of the product following monthly injections over six months.

The minimum blood level oscillates between 0.1 and 0.2 ng/mL. The bioavailability of the sustained release product is approximately 50%.

Trough plasma concentrations are maintained between 0.1 and 0.2 ng/mL. The bioavailability of the sustained release product is approximately 50%. These data observed in endometriosis and uterine fibroma patients can be extrapolated to breast cancer patients as it is not expected that the disease has an impact on the prolonged release properties of the product.

5.3 Preclinical safety data

Preclinical findings were only those related to the expected pharmacological activity of triptorelin, namely down-regulation of the hypothalamic-pituitary-gonadal axis. These included atrophy of the testes and genital tract, with resultant suppression of spermatogenesis, together with decreased weight of the prostate gland. These findings were largely reversible within the recovery period. In a small number of rats, in a 24 months oncogenicity study, a low incidence of benign histological changes were seen in the non-glandular part of the fore stomach. Erosions, ulcers, necrosis and inflammation were seen at varying degrees of severity. The clinical relevance of these findings is unknown. The increased incidence of adenomatous tumours in the rat pituitary observed with Decapeptyl following long-term repeated dosing is thought to be a class specific action of GnRH analogues due to a hormonally-mediated mechanism and has not been found in the mouse nor has it been described in man.

Standard mutagenicity testing revealed no mutagenic activity of triptorelin.

6. Pharmaceutical particulars
6.1 List of excipients

D,L-lactide/glycolide copolymer

Mannitol

Carmellose sodium

Polysorbate 80

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in 6.6.

6.3 Shelf life

3 years.

The product should be used immediately after reconstitution.

6.4 Special precautions for storage

Do not store above 25°C. Keep the container in the outer carton.

6.5 Nature and contents of container

A type I, 5 mL capacity glass vial with an elastomer stopper and an aluminium cap containing the powder.

Type I, 3 mL capacity glass ampoule containing 2 mL of the suspension vehicle.

Box containing 1 vial and 1 ampoule with 1 syringe and 2 needles.

6.6 Special precautions for disposal and other handling

The suspension for injection must be reconstituted using an aseptic technique and only using the ampoule of solvent for injection.

The instructions for reconstitution hereafter and in the leaflet must be strictly followed.

The solvent should be drawn into the syringe provided using the reconstitution needle (20 G, without safety device) and transferred to the vial containing the powder. The suspension should be reconstituted by swirling the vial gently from side to side for long enough until a homogeneous, milky suspension is formed. Do not invert the vial.

It is important to check there is no unsuspended powder in the vial. The suspension obtained should then be drawn back into the syringe, without inverting the vial. The reconstitution needle should then be changed and the injection needle (20 G, with safety device) used to administer the product.

As the product is a suspension, the injection should be administered immediately after reconstitution to prevent precipitation.

For single use only.

Used needles, any unused suspension or other waste materials should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Ipsen Limited

190 Bath Road

Slough

Berkshire

SL1 3XE

United Kingdom.

8. Marketing authorisation number(s)

PL 34926/0002

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 29 December 1994

Date of last renewal: 13 September 2001

10. Date of revision of the text

8 September 2017