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Ipsen Pharmaceuticals Ltd

Ipsen Pharmaceuticals Ltd

Summary of Product Characteristics last updated on medicines.ie: 18/5/2018

Decapeptyl (triptorelin) SR

1. NAME OF THE MEDICINAL PRODUCT

    Decapeptyl SR, 3 mg powder and solvent for suspension for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

    Each vial contains the quantity of triptorelin (as triptorelin acetate) to ensure that the minimum quantity injected is 3 mg.

A 2 mL ampoule of solvent for suspension is provided in each pack.

Once reconstituted, 1 ml of the suspension contains 1.5 mg triptorelin at a minimum.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for suspension for injection.

A sterile, white to off-white, lyophilised powder which, when reconstituted as directed with the clear, colourless, sterile liquid, yields a sterile suspension for injection.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Prostatic carcinoma

In the management of advanced prostatic carcinoma

Uterine fibromyomas

Treatment of uterine fibromyomas

Endometriosis

Genital and extragenital endometriosis

Breast cancer

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),

Female infertility

Complementary treatment in association with the gonadotropins (hMG, FSH and hCG) in the course of ovulation induction in view of in-vitro fertilisation and embryo transfer (I.V.F.E.T.).

4.2 Posology and method of administration

Prostatic cancer:

Male adults only:

One intramuscular injection of Decapeptyl SR (3 mg) every 28 days.

No special requirements are needed for the elderly.

In patients with metastatic castration resistant prostate cancer not surgically castrated receiving triptorelin and eligible for treatment with androgen biosynthesis inhibitors, treatment with triptorelin needs to be continued.

Uterine fibromyomas:

The treatment must be initiated in the first five days of the cycle. The recommended dose is one intramuscular injection every 28 days.

Injection schedule: this depends on the change in volume of the fibromyomas, assessed by ultrasonography.

In principle, fibromyomas should be treated for at least 4 months and for a maximum of 6 months. A second course of treatment by Decapeptyl SR or by other GnRH analogues should not be undertaken.

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 in order 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 Decapeptyl SR 3.75 mg is a suspension of microparticles, inadvertent intravascular injection must be strictly avoided.

Endometriosis:

The treatment must be initiated in the first five days of the cycle.

Injection schedule: one intramuscular injection of Decapeptyl SR every 28 days.

Duration of treatment: this depends on the initial severity of endometriosis and the change in clinical manifestations (functional and anatomical) during treatment.

In principle, endometriosis should be treated for at least 4 months and for a maximum of 6 months.

A second course of treatment by Decapeptyl SR or by other GnRH analogues should not be undertaken.

Female infertility:

One intramuscular injection of Decapeptyl SR administered on the second day of the cycle. In general, the stimulation by gonadotropins should be performed when the blood level of oestrogens are less than 50 pg/ml (usually around the 15th day of the cycle).

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 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.

Adjustment of antihypertensive therapy may be required in patients receiving such medication.

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.

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose and is considered essentially 'sodium-free'.

Prostate cancer

Initially, Decapeptyl SR, 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 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.

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 during androgen deprivation therapy.

Administration of triptorelin in therapeutic doses result 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 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 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 analogue 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 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.

Female infertility

The induction of ovulation should be monitored under rigorous medical supervision with strict and regular biological and clinical control by fast plasma oestrogen assay and ultrasonography. As with other GnRH analogues there have been reports of ovarian hyperstimulation syndrome (OHSS) associated with the use of triptorelin in combination with gonadotropins.

In cases of excessive ovarian response, interruption of the stimulation cycle by stopping the injections of gonadotropins is recommended.

The increase in the follicular retrieval induced by injection of Decapeptyl SR when associated with gonadotropins may be great in some predisposed patients and particularly in cases of polycystic ovarian disease. The ovarian response to the triptorelin-gonadotropin treatment may differ with the same doses from one patient to another, and in certain cases, from one cycle to another in the same patient.

In patients with renal or hepatic impairment, triptorelin has a mean terminal half life of 7-8 hours compared to 3-5 hours in healthy subjects. Despite this prolonged exposure, triptorelin is not expected to be present in circulation at the time of embryo transfer.

4.5 Interaction with other medicinal products and other forms of interaction

Hyperprolactinemic drugs should not be prescribed concomitantly as they reduce the level of GnRH receptors in the pituitary.

When Decapeptyl SR 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 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 Fertility, pregnancy and lactation

Pregnancy

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

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

Lactation

Decapeptyl SR should not be used during breast-feeding.

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 altered, 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.

When used to treat infertility, the combination with gonadotropins may result in ovarian hyperstimulation syndrome. Ovarian hypertrophy, pelvic and/or abdominal pain may be observed.

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 flushes, 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 at a higher frequency with the use of triptorelin in combination with exemestane than in combination with tamoxifen (39% versus 25%) (see section 4.4).

Musculoskeletal disorder and fractures were also more commonly reported in combination with exemestane than in 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).

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.

Reporting of suspected adverse reactions

Reporting of 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL-Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie, E-mail: medsafety@hpra.ie

4.9 Overdose

There is no human experience of overdosage. Animal data do not predict any effects other than those related to 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: Hormones and related agents,

ATC code: L02A EO4

Triptorelin is a synthetic decapeptide (D-Trp6 GnRH) analogue of natural GnRH. Studies in animals and man have shown that continued administration of triptorelin exerts, after a short initial stimulation, an inhibitory effect on the gonadotropin secretion with consequent suppression of testicular and ovarian functions.

Prostatic cancer

The first administration of Decapeptyl SR stimulates the release of pituitary gonadotropins with a resultant increase in peripheral circulating levels of testosterone and dihydrotestosterone. Prolonged administration (over 7 days) leads to a suppression of gonadotropins and a fall in plasma testosterone to castrate levels after approximately 20 days and which continues for as long as the product is administered.

A transient increase in acid phosphatases may be observed in men at the beginning of treatment.

In patients with metastatic castration-resistant prostate cancer, clinical studies have shown the benefit from the addition of androgen biosynthesis inhibitors, such as abiraterone acetate to GnRH analogues, such as triptorelin.

Uterine fibromyomas

The suppression of oestrogen secretion produces a significant reduction of the volume of the uterine fibromyomas.

Endometriosis

Continued administration of Decapeptyl SR induces suppression of the oestrogen secretion and thus enables resting of ectopic endometrial tissue.

Female infertility

The administration of Decapeptyl SR induces an initial phase of gonadotropin stimulation (FSH and LH) followed by an inhibition phase. The treatment ensures suppression of the intercurrent LH peak enabling enhanced folliculogenesis and increased follicular retrieval and as a consequence, a better rate of pregnancy per cycle.

Breast cancer

Clinical studies performed in premenopausal women with endocrine responsive early stage breast cancer have been conducted with triptorelin in order to suppress ovarian oestradiol 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 in 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 womenassigned 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 risk 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 analyzed: 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

In men:

Following intramuscular injection an initial phase of release of the active principle present on the surface of the microspheres is observed, followed by regular release of triptorelin at a mean rate of 46.6 ± 7.1 µg/day. The microsphere suspension bioavailability is approximately 53% at one month.

In women

After intramuscular injection of Decapeptyl in endometriosis and uterine fibroid women 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 after 6 months of monthly injections. 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.

Standard mutagenicity testing revealed no mutagenic activity of triptorelin.

Resorption of the microspheres is complete within 40 to 45 days following intramuscular injection in rats.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder

D,L-lactide/glycolide copolymer

Mannitol

Carmellose sodium

Polysorbate 80

Solvent for Suspension:

Mannitol

Water for Injections.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

Powder: 3 years

Solvent: 5 years

The product should be used immediately after opening/reconstitution.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Powder for suspension for injection:

Type I, clear, slightly tinted glass vial (4 ml)

Solvent for suspension for injection:

Type I, clear glass ampoule (2 ml)

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 Pharmaceuticals Ltd.

Blanchardstown Industrial Park

Blanchardstown

Dublin 15

Ireland.

8. MARKETING AUTHORISATION NUMBER(S)

PA 869/003/001

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 05 December 1989

Date of last renewal: 05 December 2009

10. DATE OF REVISION OF THE TEXT

12 September 2017

It is recommended that you also refer to http://www.medicines.ie as the Summary of Product Characteristics may have been updated since this copy was printed.