Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
The use of GnRH agonists may lead to reduced bone density. In men, preliminary data indicate that the use of a bisphosphonate in combination with a GnRH agonist may reduce the loss of bone mineral.
Special precautions are necessary in patients with additional risk factors for osteoporosis (e.g., chronic alcohol abuse, smoking, long-term therapy with drugs that reduce bone mineral density, e.g., anticonvulsants or corticoids, family history of osteoporosis, malnutrition).

In rare cases, treatment with GnRH agonists can lead to the discovery of a previously undetected gonadotroph cell pituitary adenoma. These patients may present with a pituitary apoplexy with sudden headache, vomiting, visual impairment and ophthalmoplegia.
There is an increased risk of depression (which may be severe) for patients who are being treated with GnRH agonists, such as triptorelin. The patients should be informed of this and treated appropriately if symptoms arise. Patients known to have depression should be monitored closely during therapy.

Caution should be exercised when intramuscular injections are administered in patients treated with anticoagulants, because of a potential risk of haematomas at the injection site.

This medicinal product contains less than 1 mmol (23 mg) sodium per injection vial, i.e., it is practically “sodium free”.


Prostate cancer
Like other GnRH agonists, triptorelin initially causes a transient increase in serum testosterone levels.
In isolated cases this can lead to temporarily worsened disease symptoms during the first weeks of treatment.
To counteract this initial increase in serum testosterone and worsening of clinical symptoms, additional administration of a suitable antiandrogen should be considered at the start of treatment.
A small number of patients may experience a temporary worsening of their prostate cancer symptoms (tumor flare) and a temporary increase in cancer related pain (metastatic pain), which can be managed symptomatically.
As with other GnRH agonists, isolated cases of medullary compression or urinary tract obstruction have been observed. If medullary compression or impaired renal function develops, conventional treatment of these complications should be instituted, and in extreme cases an immediate orchiectomy (surgical castration) should be considered. There should be close monitoring in the first weeks of treatment, especially of patients suffering from vertebral metastases, at the risk of spinal cord compression, and in patients with urinary tract obstruction.
Triptorelin does not result in any further reduction in serum testosterone concentration following surgical castration.
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 fractures.
Androgen deprivation therapy may prolong the QT interval.
For patients with QT prolongation in their medical history of with risk factors for QT prolongation, and in patients on concomitant treatment with other drugs that may prolong the QT interval (see section 4.5) prescribers should determine the benefit/risk balance including the risk of Torsades de pointes before commencing treatment with Decapeptyl depot.
In addition to this, it has been observed from epidemiological data that patients may experience metabolic changes (e.g., glucose intolerance, fatty liver), or an increased risk of cardiovascular disease during androgen deprivation therapy. Prospective data have not, however, confirmed the link between treatment with GnRH analogues and an increase in cardiovascular mortality. Patients with an increased risk for metabolic or cardiovascular diseases must be investigated thoroughly before commencing treatment and followed up during androgen deprivation therapy.
Administration of triptorelin in therapeutic doses results in suppression of the pituitary gland’s gonad function. Normal function is usually restored after completion of treatment. Diagnostic tests of pituitary gonadal function conducted during treatment and after completion of treatment with GnRH analogues may therefore be misleading.

Females
It should be confirmed that the patient is not pregnant before starting treatment with Decapeptyl depot 3.75mg.

Reduction in bone mineral density
The use of GnRH agonists entails a high probability of a reduction in bone mineral density. During a 6-month treatment period bone density can drop by approx. 1% a month. The risk of fracture increases two to three-fold for each 10% reduction in bone density.

No data are available for patients with clinically confirmed osteoporosis or risk factors for osteoporosis (e.g. chronic alcohol abuses, smoking, 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 harmful in these patients, treatment with triptorelin should be considered on an individual basis and only commenced if the benefits of treatment outweigh the risks. Additional measures to counteract a reduction in bone density should be considered.

Breast cancer
To achieve adequate ovarian function suppression in pre-menopausal women, treatment with triptorelin should be administered for at least 6-8 weeks before initiating an aromatase inhibitor, and monthly triptorelin injections should be administered on schedule and without interruption throughout aromatase inhibitor treatment.

Women who are pre-menopausal when they receive their breast cancer diagnosis and who experience amenorrhoea after chemotherapy may retain or lose continued oestrogen production from the ovaries.
Regardless of menstrual status, pre-menopausal status should be established after chemotherapy care and before initiating triptorelin, by checking that the blood concentrations of oestradiol and follicle- stimulating hormone (FSH) is within the reference interval for pre-menopausal women. This is to avoid unnecessary treatment with triptorelin in the event of chemotherapy-induced menopause. After initiating triptorelin, it is important to determine adequate ovarian function suppression (gonadotrophin analogue-induced menopause) through a series of measurements of circulating FSH and oestradiol if order to decide if aromatase inhibitor treatment in line with current clinical practice may be appropriate for this subgroup of women. Ovarian function suppression should consequently be determined through 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 an increase in circulating oestrogen through aromatase inhibitor-induced rebound effect, with subsequent consequences for the breast cancer. Note, that the circulating FSH levels are lowered in response to gonadotrophin analogue-induced ovarian function suppression (induced menopause), unlike in a natural menopause where FSH levels are elevated.

Triptorelin, used as adjuvant therapy in combination with tamoxifen or an aromatase inhibitor, is associated with a high risk of osteoporosis. A higher frequency of osteoporosis has been reported after use of triptorelin in combination with an aromatase inhibitor than in combination with tamoxifen (39% vs 25%).

Bone 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 with triptorelin in combination with tamoxifen or an aromatase inhibitor for premenopausal women with early stage hormone receptor-positive breast cancer should be monitored individually and closely by means of an assessment of the risks and benefits.

Patients who have stopped their triptorelin treatment should also stop their aromatase inhibitor treatment within a month of their final triptorelin injection (one-month formulation).

The risk of musculoskeletal disorders (including joint or musculoskeletal pain) is approx. 89% when triptorelin is used in combination with either an aromatase inhibitor or approximately 76% with tamoxifen.
Hypertension, which was studied closely, was reported to be a “very common” adverse reaction both when triptorelin was combined with exemestane and when it was combined with tamoxifen (see section 4.8). Premenopausal women with breast cancer who receive triptorelin in combination with either exemestane or with tamoxifen should have regular monitoring of their cardiovascular risk factors and blood pressure.

Hyperglycaemia and diabetes were reported as especially interesting "common" adverse reactions for both triptorelin in combination with either exemestane and triptorelin in combination with tamoxifen (see section 4.8). Pre-menopausal women with breast cancer who take triptorelin in combination with either exemestane or with tamoxifen should be monitored regularly to detect any risk factors for diabetes through regular blood glucose checks and appropriate anti-diabetic treatment should be 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, although fewer than 5% of patients had severe depression (grade 3-4). Patients should be informed of this and treated appropriately if symptoms arise. Patients with known depression or depression history should be monitored closely during treatment.

Particular attention should also be paid to the prescribing information exemestane and tamoxifen with regard to the safety of their use in combination therapy with triptorelin.

Chemotherapy can induce temporary amenorrhoea or a permanent loss of ovarian function due to cytotoxic damage of gonadal tissue. The preservation of pre-menopausal status after completion of chemotherapy care should be confirmed as recommended by clinical guidelines by determining that the blood concentrations of oestradiol and FSH are within the reference values for pre-menopausal women.

Endometriosis
GnRH agonists are not recommended for patients under the age of 18. Young girls and young women (especially those under the age of 16) who may not have reached maximum bone density should be monitored closely.
The addition of ABT (an oestrogen and progestogen) in patients treated with GnRH analogues for endometriosis has been shown to reduce the loss of bone density and vasomotor symptoms (see section 4.2 “Posology and method of administration” for more information).
Triptorelin causes constant hypogonadotropic amenorrhoea when used at the recommended dose,. If vaginal bleeding occurs after the first month, the oestrogen levels should be measured and if it is below 50 pg/ml, then any link with organic pathological changes should be investigated.
When the treatment is completed, the ovaries will regain their function and ovulation should take place approximately 2 months after the final injection. Non-hormonal contraception should be used through the treatment and for 1 month after the final injection.
Since menstruation is supposed to stop during triptorelin treatment, the patient should be instructed to notify her physician if regular menstruation persists.

Central Precocious puberty
In girls, it should be confirmed that the patient is not pregnant before prescribing triptorelin. A thorough and individual assessment of the risks and benefits should be carried out when treating children with progressive brain tumors
Pseudo-precocious puberty (gonadal or adrenal tumor, or hyperplasia) and gonadotropin-independent precocious puberty (testotoxicosis, familial Leydig cell hyperplasia) should be ruled out.

In girls initial stimulation of the ovaries, followed by the treatment-induced reduction of oestrogen may lead to mild to moderate vaginal bleeding in the first month.
The traits of puberty will develop once treatment is completed. Information on future fertility is still limited.
In most girls, regular menstruation begins around a year after treatment is completed.
Bone density may decrease during GnRH treatment for central precocious puberty. However, subsequent growth of bone mass after completion of treatment is not affected; maximum bone mass in late teenage years does not appear to be affected by the treatment.

Slipping of the femoral epiphysis may occur after completion of GnRH treatment. One explanation for this could be that the low concentrations of oestrogen during treatment with GnRH agonists weakens the epiphysial plate. The increase in rate of growth that occurs after completion of treatment results in a subsequent reduction of the shearing force required to displace the epiphysis.

Idiopathic intracranial hypertension
Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in paediatric patients receiving triptorelin. Patients should be warned for signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, vision disturbances and tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of triptorelin should be considered.


Effects on Driving

4.7   Effects on ability to drive and use machines
No studies have been carried out of the ability to drive and use machines. However the ability to drive and use machines may be impaired if the patient experiences dizziness, sleepiness and visual disturbances that are possible undesirable effects of the treatment or a result of the underlying disease.