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The use of GnRH agonists may cause 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. Particular caution is necessary in patients with additional risk factors for osteoporosis (e.g. chronic alcohol abuse, smokers, long-term therapy with drugs that reduce bone mineral density, e.g. anticonvulsants or corticoids, family history of osteoporosis, malnutrition).
It should be confirmed that the patient is not pregnant before prescription of Diphereline P.R.
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 agonist, such as triptorelin. Patients should be informed accordingly and treated appropriate if symptoms occur. Patients with known depression should be monitored closely during therapy.
Diphereline P.R. contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially "sodium-free".
Caution should be given to patients treated with anti-coagulants as haematoma may potentially appear at the injection site.
In men: 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 orchiectomy (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. For the same reason, particular care should be taken when beginning treatment in patients with premonitory signs of spinal cord compression.
After surgical castration, triptorelin does not induce any further decrease in serum testosterone levels.
Long-term androgen deprivation either by bilateral orchiectomy or administration of GnRH analogues 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 Interactions) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Diphereline P.R. 11.25 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 adequately monitored during androgen deprivation therapy.
Due to androgen deprivation, treatment with analogues of the GnRH can increase the risk of anaemia. This risk should be assessed in treated patients and monitored appropriately.
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 analogues may therefore be misleading.
A transitory increase in acid phosphatases may be observed at the beginning of the treatment.
3.75 mg: 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.
It may be advantageous to check blood testosterone levels periodically with an accurate method.
11.25 mg: It may be advantageous to check blood testosterone levels periodically with an accurate method as these should not exceed 1 ng/ml.
In women: It should be confirmed that patient is not pregnant before prescription of Diphereline P.R.
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.
No specific data is available for patients with established osteoporosis or with risk factors for osteoporosis (e.g. chronic alcohol abuses, 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.
11.25 mg: The administration, of Diphereline P.R. 11.25 mg results in constant hypogonadotrophic amenorrhoea. If genital 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.
Since menses should stop during triptorelin treatment, the patient should be instructed to notify her physician if regular menstruation persists. A non-hormonal method of contraception should be used throughout treatment including for 3 months after the last injection.
After withdrawal of treatment, ovarian function resumes and ovulation occurs approximately 5 months after the last injection.
In paediatric population: Central precocious puberty: 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.
After discontinuation of treatment the development of puberty characteristics will occur.
Bone mineral density (BMD) may decrease during GnRH therapy for central precocious puberty. 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 treatment.
3.75 mg: In girls initial gonadal stimulation may lead, in the first month, to vaginal bleeding of mild or moderate intensity.
Information with regards to fertility in patients treated with GnRH analogues during childhood is limited. In most girls, regular menses will start on average one year after ending the therapy.
11.25 mg: 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.
Information with regards to future fertility is still limited. In most girls, regular menses will start on average one year after ending the therapy.
Diphereline P.R. 11.25 mg is not indicated in transient precocious puberty as well as the normal variants of pubertal development (premature thelarche, pubarche and menarche) and isolated menstruation associated, or not, with breast development with inconsistent response to the LHRH test and presence of functioning cysts of the ovary.
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.
Endometriosis and pre-surgery treatment of uterine fibromyomas: 3.75 mg: Regular administration, every four weeks, of one vial of Diphereline P.R. 3.75 mg results in constant hypogonadotrophic amenorrhoea. If genital 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.
Since menses should stop during triptorelin treatment, the patient should be instructed to notify her physician if regular menstruation persists.
A non-hormonal method of contraception should be used throughout treatment including for 1 month after the last injection. After withdrawal of treatment, ovarian function resumes and ovulation occurs approximately 2 months after the last injection.
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: 3.75 mg: 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, premenopausal 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 (28 days 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.
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. 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.
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 by dizziness, somnolence and visual disturbances which are possible undesirable effects of treatment, or resulting from the underlying disease.
