Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Ipsen Limited, 190 Bath Road, Slough, Berkshire, SL1 3XE, United Kingdom
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).
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.
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.
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.
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.
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).
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.
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.
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).
Rare: Nasopharyngitis
Uncommon: Thrombocytosis
Common: Hypersensitivity
Rare: Anaphylactic reaction
Frequency not known: Anaphylactic shock
Uncommon: Anorexia, Diabetes mellitus, Gout, Hyperlipidaemia, Increased appetite
Very Common: Libido decreased
Common: Depression*, Loss of libido, Mood change*
Uncommon: Insomnia, Irritability
Rare: Confusional state, Decreased activity, Euphoric mood
Frequency not known: Anxiety
Very Common: Paraesthesia in lower limbs
Common: Dizziness, Headache
Uncommon: Paraesthesia
Rare: Memory impairment
Uncommon: Visual impairment
Rare: Abnormal sensation in eye, Visual disturbance
Uncommon: Tinnitus, Vertigo
Uncommon: Palpitations
Frequency not known: QT prolongation (see sections 4.4 and 4.5)
Very Common: Hot flush
Common: Hypertension
Rare: Hypotension
Uncommon: Dyspnoea, Epistaxis
Rare: Orthopnoea
Common: Dry mouth, Nausea
Uncommon: Abdominal pain, Constipation, Diarrhoea, Vomiting
Rare: Abdominal distension, Dysgeusia, Flatulence
Very Common: Hyperhidrosis
Uncommon: Acne, Alopecia, Erythema, Pruritus, Rash, Urticaria
Rare: Blister, Purpura
Frequency not known: Angioneurotic oedema
Very Common: Back pain
Common: Musculoskeletal pain, Pain in extremity
Uncommon: Arthralgia, Bone pain, Muscle cramp, Muscular weakness, Myalgia
Rare: Joint stiffness, Joint swelling, Musculoskeletal stiffness, Osteoarthritis
Uncommon: Nocturia, Urinary retention
Frequency not known: Urinary incontinence
Very Common: Erectile dysfunction (including ejaculation failure, ejaculation disorder)
Common: Pelvic pain
Uncommon: Breast pain, Gynaecomastia, Testicular atrophy, Testicular pain
Very Common: Asthenia
Common: Injection site reaction (including erythema, inflammation and pain), Oedema
Uncommon: Lethargy, Oedema peripheral, Pain, Rigors, Somnolence
Rare: Chest pain, Dysstasia, Influenza like illness, Pyrexia
Frequency not known: Malaise
Common: Weight increased
Uncommon: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood creatinine increased, Blood pressure increased, Blood urea increased, Gamma-glutamyl transferase increased, Weight decreased
Rare: 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.
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)
Common: Hypersensitivity
Frequency not known: Anaphylactic shock
Uncommon: Decreased appetite, Fluid retention
Very Common: Libido decreased, Mood disorder, Sleep disorder (including insomnia)
Common: Depression*, Nervousness
Uncommon: Affect lability, Anxiety, Depression**, Disorientation
Frequency not known: Confusional state
Very Common: Headache
Common: Dizziness
Uncommon: Dysgeusia, Hypoasthesia, Syncope, Memory impairment, Disturbance in attention, Paraesthesia, Tremor
Uncommon: Dry eye, Visual Impairment
Frequency not known: Visual disturbance
Uncommon: Vertigo
Uncommon: Palpitations
Very Common: Hot flush
Frequency not known: Hypertension
Uncommon: Dyspnoea, Epistaxis
Common: Abdominal pain, Abdominal discomfort, Nausea
Uncommon: Abdominal distension, Dry mouth, Flatulence, Mouth ulceration, Vomiting
Frequency not known: Diarrhoea
Very Common: Acne, Hyperhidrosis, Seborrhoea
Uncommon: Alopecia, Dry skin, Hirsutism, Onychoclasis, Pruritus, Rash
Frequency not known: Angioneurotic oedema, Urticaria
Common: Arthralgia, Muscle spasms, Pain in extremities
Uncommon: Back pain, Myalgia
Frequency not known: Muscular weakness
Very Common: Breast disorder, Dyspareunia, Genital bleeding (including vaginal bleeding withdrawal bleed), Ovarian hyperstimulation syndrome, Ovarian hypertrophy, Pelvic pain, Vulvovaginal dryness
Common: Breast pain
Uncommon: Coital bleeding, Cystocele, Menstrual disorder (including dysmenorrhoea, metrorrhagia and menorrhagia), Ovarian cyst, Vaginal discharge
Frequency not known: Amenorrhoea
Very Common: Asthenia
Common: Injection site reaction (including pain, swelling, erythema and inflammation) Oedema peripheral
Frequency not known: Malaise, Pyrexia
Common: Weight increased
Uncommon: Weight decreased
Frequency not known: 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.
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.
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).
Uncommon: Myocardial Ischaemia
QT prolongation
Common: Diabetes mellitus (glucose intolerance), Hyperglycaemia
Very Common: Nausea
Very Common: Fatigue
Common: Injection site reaction
Common: Hypersensitivity
Very Common: Musculoskeletal disorder, Osteoporosis
Common: Fracture
Uncommon: Cerebral ischaemia, Central nervous system haemorrhage
Very Common: Insomnia, Libido decreased, Depression
Very Common: Urinary incontinence
Very Common: Dyspareunia, Vulvovaginal dryness
Very Common: Hyperhidrosis
Very Common: Hot flushes, Hypertension
Common: 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 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
This medicinal product must not be mixed with other medicinal products except those mentioned in 6.6.
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