Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Ipsen Limited, 190 Bath Road, Slough SL1 3XE, United Kingdom
Hypersensitivity to GnRH, its analogues or to any of the excipients of the medicinal product listed in section 6.1 (see also section 4.8).
Triptorelin is contraindicated during pregnancy and lactation (see section 4.6).
The use of GnRH agonists may cause a reduction in bone mineral density. In men, preliminary data suggest that the use of a bisphosphonate in combination with a GnRH agonist may reduce bone mineral loss. No specific data is available for patients with established osteoporosis or with risk factors for osteoporosis (e.g. chronic alcohol abuse, smokers, long-term therapy with drugs that reduce bone mineral density, e.g. anti-convulsants or corticosteroids, family history of osteoporosis, malnutrition, e.g. anorexia nervosa). Particular caution is therefore necessary since reduction in bone mineral density is likely to be more detrimental in these patients. Treatment with Decapeptyl SR should be considered on an individual basis and only be initiated if the benefits of treatment outweigh the risk following a very careful appraisal. Consideration should be given to additional measures in order to counteract loss of bone mineral density.
Rarely, treatment with GnRH agonists may reveal the presence of a previously unknown gonadotroph cell pituitary adenoma. These patients may present with a pituitary apoplexy characterised by sudden headache, vomiting, visual impairment and ophthalmoplegia.
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.
Caution is required with intramuscular injection in patients treated with anticoagulants, due to the potential risk of haematomas at the site of injection. The efficacy and safety of Decapeptyl SR 22.5 mg has been established via intramuscular route only. The subcutaneous administration is not recommended.
Decapeptyl SR 22.5 mg contains less than 1 mmol (23 mg) sodium per dose i.e it is essentially ‘sodum free’.
Initially, triptorelin, like other GnRH agonists, causes a transient increase in serum testosterone levels. As a consequence, isolated cases of transient worsening of signs and symptoms of prostate cancer may occasionally develop during the first weeks of treatment. During the initial phase of treatment, consideration should be given to the additional administration of a suitable anti-androgen to counteract the initial rise in serum testosterone levels and the worsening of clinical symptoms.
A small number of patients may experience a temporary worsening of signs and symptoms of their prostate cancer (tumour flare) and temporary increase in cancer related pain (metastatic pain), which can be managed symptomatically.
As with other GnRH agonists, isolated cases of spinal cord compression or urethral obstruction have been observed. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted, and in extreme cases, an immediate orchidectomy (surgical castration) should be considered. Careful monitoring is indicated during the first weeks of treatment, particularly in patients suffering from vertebral metastases, at risk of spinal cord compression, and in patients with urinary tract obstruction.
After surgical castration, triptorelin does not induce any further decrease in serum testosterone levels. Once the castration levels of testosterone have been achieved by the end of the first month, serum testosterone levels are maintained for as long as the patients receive their injection every 6 months (twenty four weeks).
Long-term androgen deprivation either by bilateral orchidectomy or administration of GnRH agonists is associated with increased risk of bone loss and may lead to osteoporosis and increased risk of bone fracture.
Androgen deprivation therapy may prolong the QT interval.
In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Decapeptyl SR 22.5 mg.
In addition, from epidemiological data, it has been observed that patients may experience metabolic changes (e.g. glucose intolerance), 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 of metabolic or cardiovascular diseases should be carefully assessed before commencing treatment and their glucose, cholesterol and blood pressure adequately monitored during androgen deprivation therapy.
Metabolic changes may be more severe in these high-risk patients. Patients at high risk of metabolic or cardiovascular disease and receiving androgen deprivation therapy should be monitored at appropriate intervals not exceeding 3 months.
Administration of triptorelin in therapeutic doses results in suppression of the pituitary gonadal system. Normal function is usually restored after treatment is discontinued. Diagnostic tests of pituitary gonadal function conducted during treatment and after discontinuation of therapy with GnRH agonists may therefore be misleading.
Treatment of children with progressive brain tumours should follow a careful individual appraisal of the risks and benefits.
Pseudo-precocious puberty (gonadal or adrenal tumour or hyperplasia) and gonadotropin-independent precocious puberty (testicular toxicosis, familial Leydig cell hyperplasia) should be precluded.
In girls, initial ovarian stimulation at treatment initiation, followed by the treatment-induced oestrogen withdrawal, may lead, in the first month, to vaginal bleeding of mild or moderate intensity.
The therapy is a long-term treatment, adjusted individually. Decapeptyl SR 22.5mg should be administered as precisely as possible in regular 6 monthly periods. An exceptional delay of the injection date for a few days (169 ± 3 days) does not influence the results of the therapy.
After discontinuation of treatment the development of puberty characteristics will occur.
Information with regards to future fertility is still limited but future reproductive function and fertility appears to be unaffected by GnRH treatment. In most girls, regular menses will start on average one year after ending the therapy.
Bone mineral density may decrease during GnRH agonist therapy for central precocious puberty due to the expected effects of oestrogen suppression. However, after cessation of treatment subsequent bone mass accrual is preserved and peak bone mass in late adolescence does not seem to be affected by treatment.
Slipped capital femoral epiphysis can be seen after withdrawal of GnRH agonist treatment. The suggested theory is that the low concentrations of oestrogen during treatment with GnRH agonists weaken the epiphysial plate. The increase in growth velocity after stopping the treatment subsequently results in a reduction of the shearing force needed for displacement of the epiphysis.
Drugs which raise prolactin levels should not be prescribed concomitantly as they reduce the level of GnRH receptors in the pituitary.
When Decapeptyl SR 22.5 mg is co-administered with drugs affecting pituitary secretion of gonadotropins, caution should be exercised and it is recommended that the patient’s hormonal status should be supervised
Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Decapeptyl SR 22.5 mg with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).
Decapeptyl SR 22.5 mg is indicated for adult men and children. There are very limited data on the use of triptorelin in pregnant women. It should be confirmed that the patient is not pregnant before prescription of Decapeptyl SR 22.5 mg.
Triptorelin must not be used during pregnancy since concurrent use of GnRH agonists is associated with a theoretical risk of abortion or fetal abnormality. Prior to treatment, potential fertile women should be examined carefully to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy until menses return.
Animal studies have shown effects on reproductive parameters (see section 5.3 Preclinical safety data).
Decapeptyl SR 22.5 mg is not indicated in lactating women.
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 (≥1/10 000, <1/1000).
Rare: Nasopharyngitis
Uncommon: Thrombocytosis
Common: Hypersensitivity
Rare: Anaphylactic reaction
Frequency unknown: Anaphylactic shock
Uncommon: Anorexia, Diabetes mellitus, Gout, Hyperlipidaemia, Increased appetite
Very Common: Libido decreased
Common: Loss of libido, Depression*, Mood changes*
Uncommon: Insomnia, Irritability
Rare: Confusional state, Decreased activity, Euphoric mood
Frequency unknown: 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 unknown: 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: Asthenia
Common: Injection site reaction (including erythema inflammation and pain), Oedema
Uncommon: Lethargy, Oedema peripheral, Pain, Rigours, Somnolence
Rare: Chest pain, Dysstasia, Influenza-like illness, Pyrexia
Frequency unknown: Malaise
Very Common: Hyperhidrosis
Uncommon: Acne, Alopecia, Erythema, , Pruritus, Rash, Urticaria
Rare: Blister, Purpura
Frequency unknown: 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 unknown: Urinary incontinence
Very Common: Erectile dysfunction (including ejaculation failure, ejaculation disorder)
Common: Pelvic pain
Uncommon: Gynaecomastia, Breast pain, Testicular atrophy, Testicular pain
Common: Weight increase
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/or metastatic pain (5%), which can be managed symptomatically. These symptoms are transient and usually disappear in one to two weeks.
Isolated cases of exacerbation of disease symptoms, either urethral obstruction or spinal cord compression by metastasis have occurred. Therefore, patients with metastatic vertebral lesions and/or with upper or lower urinary tract obstruction should be closely observed during the first few weeks of therapy (see section 4.4 Special warnings and precautions for use).
The use of GnRH agonists to treat prostate cancer may be associated with increased bone loss and may lead to osteoporosis and increases the risk of bone fracture. This may also lead to an incorrect diagnosis of bone metastases.
The frequency of the adverse reactions is classified as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000, <1/100).
Common: Hypersensitivity
Frequency unknown: Anaphylactic shock
Uncommon: Obesity
Uncommon: Mood altered
Frequency unknown: Lability affected, Depression, Nervousness
Common: Headache
Uncommon: Visual impairment
Frequency unknown: Visual disturbance
Common: Hot flush
Frequency unknown: Hypertension
Uncommon: Epistaxis
Common: Abdominal pain
Uncommon: Vomiting, Constipation, Nausea
Common: Acne
Uncommon: Pruritus, Rash, Urticaria
Frequency unknown: Angioneurotic oedema
Uncommon: Neck pain
Frequency unknown: Myalgia
Very Common: Vaginal bleeding (including vaginal haemorrhage, withdrawal bleeding, uterine haemorrhage, vaginal discharge, vaginal bleeding including spotting)
Uncommon: Breast pain
Common: Injection site reaction (including injection site pain, injection site erythema and injection site inflammation)
Uncommon: Malaise
Common: Weight increased
Frequency unknown: Blood pressure increased, Blood prolactin increased
Increased lymphocyte count has been reported with patients undergoing GnRH agonist treatment. This secondary lymphocytosis is apparently related to GnRH induced castration and seems to indicate that gonadal hormones are involved in thymic involution.
Reporting 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
In the absence of compatibility studies, this medicinal product must not be reconstituted with other medicinal products.
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