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.

In patients treated with GnRH analogues for endometriosis, the addition of an add-back therapy (ABT - an estrogen and progestogen) has been shown to reduce bone mineral density loss and vasomotor symptoms. Therefore, if appropriate, ABT should be co-administered with GnRH analogue taking into account the risks and benefits of each treatment.

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 Decapeptyl SR 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 (see section 4.8 Undesirable effects).

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.

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.

Convulsions have been reported with GnRH analogues, particularly in women. 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 sodium (23 mg) 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

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, 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 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.

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

In women

It should be confirmed that the patient is not pregnant before prescription of Decapeptyl SR 3 mg.

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.

No specific data are available for patients with established osteoporosis or with risk factors for osteoporosis (e.g. chronic alcohol abusers, smokers, long-term therapy with drugs that reduce bone mineral density, e.g. anticonvulsants or corticoids, family history of osteoporosis, malnutrition, e.g. anorexia nervosa). Since reduction in bone mineral density is likely to be more detrimental in these patients, treatment with triptorelin 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.

Endometriosis and Uterine Fibromyomas

GnRH agonist is not recommended for patients under the age of 18 years. Careful attention should be given to adolescent and young women (specially less than 16 years of age) who may not have reached maximum bone density.

In patients treated with GnRH analogues for endometriosis, the addition of ABT (an estrogen and progestogen) has been shown to reduce bone mineral density loss and vasomotor symptoms (see 'Posology and Method of Administration' section 4.2 for further information).

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. Fertility, pregnancy and lactation

Pregnancy

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.

Lactation

Triptorelin should not be used during 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 (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 to < 1/10); uncommon (≥1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000), not known, (cannot be estimated from the available data).

System Organ Class

Very common ≥ 1/10

Common ≥1/100 - <1/10

Uncommon ≥1/1000 - <1/100

Rare ≥1/10000 - <1/1000

Additional post-marketing AEs

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

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

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

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

** 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 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).

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

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 to < 1/10); uncommon (≥1/1000 to < 1/100); not known (cannot be estimated from the available data).

System Organ Class

Very common ≥ 1/10

Common ≥1/100 - <1/10

Uncommon ≥1/1000 - <1/100

Additional post-marketing AEs

Frequency not known

Immune system disorders

Hypersensitivity

Anaphylactic shock

Endocrine disorders

Pituitary apoplexy***

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

Hypoesthesia

Syncope

Memory impairment

Disturbance in attention

Paraesthesia

Tremor

Convulsions****

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

*** Reported following initial administration in patients with pituitary adenoma

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

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

Metabolism and nutrition 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

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

Injury, poisoning and procedural complications

Fracture

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

4.9. Overdose

If overdose occurs, symptomatic management is indicated.