Instructions Diferelin powder for preparation of suspension for injection 3.75 mg vial solvent 2 ml ampoule syringe 2 needles No. 1
Composition
active ingredient: triptorelin;
1 vial contains triptorelin acetate, equivalent to 3.75 mg of triptorelin;
excipients: D, L lactide coglycolide polymer, mannitol (E 421), carmellose sodium, polysorbate 80;
composition of the solvent: 1 ampoule contains mannitol (E 421), water for injections.
Dosage form
Powder and solvent for prolonged-release suspension for injection.
Main physicochemical properties: the contents of the vial are an almost white lyophilized powder. The general appearance of the reconstituted suspension is a homogeneous milky suspension.
Pharmacotherapeutic group
Gonadotropin-releasing hormone analogues. ATX code L02A E04.
Pharmacological properties
Pharmacodynamics
Triptorelin is a synthetic decapeptide analogue of gonadotropin-releasing hormone (GnRH). Studies in humans and animals have shown that, after initial stimulation, long-term administration of triptorelin inhibits gonadotropin secretion with subsequent suppression of testicular and ovarian function.
Further studies in animals showed a different mechanism of action – a direct effect on the gonads due to a decrease in the sensitivity of peripheral receptors to GnRH.
Prostate cancer
Administration of a daily dose of triptorelin may initially increase the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the blood and subsequently lead to an increase in the initial level of testosterone ("flash"). Continued therapy reduces the levels of LH and FSH to concentrations that cause a decrease in steroid levels to those observed after castration, within 2-3 weeks after injection and throughout the entire period of use of the drug.
Therapy may exacerbate functional and objective symptoms.
Several randomized, long-term clinical trials in patients with locally advanced prostate cancer have demonstrated the superiority of androgen deprivation therapy (ADT) combined with radiotherapy (RT) over RT alone (RTOG 85-31, RTOG 86-10, EORTC 22863, D'Amico et al., JAMA, 2008).
A randomized phase III trial (EORTC 22961) involving 970 patients with locally advanced prostate cancer (mostly T2c-T4 and a few patients with T1C-T2B cancer with pathological regional nodal involvement) investigated whether radiotherapy with short-term antiandrogen therapy (6 months, n = 483) was not inferior to radiotherapy with long-term antiandrogen therapy (3 years, n = 487). Triptorelin (62.2%) or other GnRH agonists were used as GnRH agonists. The study did not stratify by agonist type.
The 5-year overall mortality was 19.0% and 15.2% in the short-term and long-term hormonal treatment groups, respectively, with a relative risk of 1.42 (95.71% CI = 1.79; or 95.71% CI = [1.09; 1.85], p = 0.65 for non-inferiority and p = 0.0082 for difference between groups in study outcomes). The 5-year prostate cancer-related mortality was 4.78% and 3.2% in the short-term and long-term hormonal treatment groups, respectively, with a relative risk of 1.71 (95% CI [1.14 to 2.57], p = 0.002). Overall quality of life, as assessed by the QLQ–C30 questionnaire, did not differ significantly between the two groups (P = 0.37).
Analysis of the results in the triptorelin subgroup also showed an advantage of long-term treatment compared with short-term treatment in terms of overall mortality (relative risk – 1.28; CI 95.71% = [0.89; 1.84], p = 0.38 and p = 0.08, respectively, in the non-inferiority study for the results obtained and for the difference between treatment groups).
The evidence base for the use of this medicinal product in the treatment of high-risk localized prostate cancer is based on published data from studies of radiotherapy in combination with GnRH analogue therapy. Clinical data from five studies were analysed (EORTC 22863, RTOG 85–31, RTOG 92–02, RTOG 86–10 and D'Amico et al., JAMA, 2008). All of them demonstrated an advantage of the combination of GnRH analogue therapy and radiotherapy. The published data do not allow a clear differentiation of the relevant populations by indication - locally advanced prostate cancer and high-risk localized prostate cancer.
In patients with metastatic castration-resistant prostate cancer, clinical trials have demonstrated the benefit of adding abiraterone acetate as an inhibitor of androgen biosynthesis or enzalutamide as an inhibitor of androgen receptor function to GnRH analogues, such as triptorelin.
Precocious puberty
Suppression of pituitary gonadotropic hyperfunction in both sexes is expressed in the suppression of estradiol and testosterone secretion, a decrease in the maximum value of LH, and an improvement in height-for-age and bone age indicators.
Initial gonadal stimulation may cause minor bleeding, requiring the use of medroxyprogesterone or cyproterone acetate.
Endometriosis
Long-term treatment with triptorelin suppresses estradiol secretion and thus provides "quiescence" of the ectopic endometrium.
Long-term triptorelin therapy suppresses the secretion of gonadotropins (FSH and LH). Thus, the therapy provides suppression of the intercurrent endogenous LH peak, allowing for improved quality of folliculogenesis and accelerated follicle recovery.
Uterine fibroids
Studies have shown a sustained and significant reduction in the volume of uterine fibroids in certain cases. This reduction reaches its highest level in the third month of treatment.
Triptorelin therapy causes amenorrhea in most patients after the first month of therapy, which provides an opportunity to correct possible anemia resulting from menorrhagia and/or metrorrhagia.
Breast cancer
Clinical trials in premenopausal women with hormone-sensitive early-stage breast cancer have used triptorelin to suppress the secretion of estradiol in the ovaries, where estrogens are mainly produced. Studies in healthy women and women with endometriosis have shown that triptorelin takes 3–4 weeks to take effect.
Two phase III trials (SOFT and TEXT) examined the 5-year benefit of ovarian suppression therapy (OFS) in combination with tamoxifen (T) or an aromatase inhibitor (exemestane, E) in premenopausal women with hormone-sensitive early breast cancer.
Triptorelin was the primary treatment for achieving OFS (91.0% of randomized patients in SOFT and 100% in TEXT). The remaining 9% of women in SOFT underwent bilateral oophorectomy or bilateral ovarian irradiation.
SOFT study results
The SOFT study design aimed to answer questions about the added value of ovarian suppression in adjuvant tamoxifen therapy for premenopausal women with hormone-sensitive early breast cancer.
A total of 3047 women were analyzed (1015 women in the T+OFS group, 1018 women in the T monotherapy group, and 1014 women in the E+OFS group).
At a median follow-up of 67 months (5.6 years), treatment with T+OFS did not significantly reduce the risk of disease-free survival (DFS) compared with T alone (HR = 0.83; 95% CI, 0.66–1.04; p = 0.10). The estimated 5-year DFS rate was 86.6% (95% CI, 84.2–88.7%) in women in the T+OFS group compared with 84.7% (95% CI, 82.2–86.9%) in women in the T alone group.
However, after adjusting for prespecified covariates in a multivariate Cox model, women randomized to T+OFS had a significantly lower risk of a DFS event compared with women receiving T alone. The reduction was 22% (HR = 0.78; 95% CI, 0.62–0.98; p = 0.03).
Women assigned to T+OFS had a slightly reduced risk of breast cancer events compared with women receiving T alone (HR = 0.81; 95% CI, 0.63–1.03; p = 0.09). The estimated 5-year breast cancer-free interval (BCFI) was 88.4% (95% CI, 86.1%–90.3%) in women assigned to T+OFS compared with 86.4% (95% CI, 84.0%–88.5%) in women assigned to T alone.
However, after adjusting for prespecified covariates in a multivariate Cox model, women randomized to the T+OFS group had a significantly reduced risk of a BCFI event compared with women in the T monotherapy group. The risk reduction was 25% (HR = 0.75; 95% CI, 0.59–0.96; p = 0.02).
The absolute advantage was greater in women who received adjuvant chemotherapy. The 5-year DFS rate in women who received adjuvant chemotherapy was 80.7% in the T+OFS group and 77.1% in the T monotherapy group (HR = 0.82; 95% CI, 0.64–1.07), with an absolute advantage of 3.6% for the T+OFS regimen.
In particular, the benefit of adding OFS to the regimen was evident in 5-year DFS in a post hoc analysis in the subgroup of women <40 years of age (HR = 0.74; 95% CI, 0.53, 1.03) with an absolute advantage of 4.4% for the T+OFS regimen compared with the T monotherapy regimen.
In the SOFT trial, patients assigned to the E+OFS regimen had a statistically significant reduction in the risk of a DFS event compared with patients in the T monotherapy group (HR = 0.68, 95% CI, 0.53–0.86). The estimated 5-year DFS rate was 89.0% (95% CI, 86.8–90.9%) in the E+OFS group compared with 84.7% (95% CI, 82.2–86.9%) in the T monotherapy group.
Patients assigned to E+OFS had a statistically significant reduced risk of developing breast cancer compared with patients assigned to T alone (HR = 0.64; 95% CI, 0.49–0.83). The estimated 5-year BCFI was 90.9% (95% CI, 88.9–92.6%) in patients assigned to E+OFS compared with 86.4% (95% CI, 84.0–88.5%) in patients assigned to T alone.
Patients assigned to the E+OFS regimen had a statistically significantly reduced risk of distant recurrence compared with patients in the T monotherapy group (HR = 0.71; 95% CI, 0.52–0.96). The estimated 5-year distant recurrence-free interval (DRFI) was 93.0% (95% CI, 91.2–94.5%) in subjects assigned to the E+OFS regimen compared with 90.7% (95% CI, 88.6–92.4%).
The absolute advantage was greater in women who received adjuvant chemotherapy. The 5-year DFS rate in women who received adjuvant chemotherapy was 83.8% in the E+OFS group and 77.1% in the T monotherapy group (HR = 0.70, 95% CI, 0.53–0.92) with an absolute advantage of 6.7% for the E+OFS group.
In the 3-arm SOFT trial, women receiving chemotherapy had a higher proportion of clinical criteria for high-risk recurrence: 49.3% of women aged < 40 years, 56.9% of women with positive lymph nodes, 47.0% of women with breast tumor size > 2 cm, and 33.7% with stage 3 tumor.
The primary objective of the TEXT study was to evaluate the role of aromatase inhibitors (exemestane) in OFS therapy compared with the T+OFS regimen in all participants in the SOFT and TEXT studies. A total of 4690 women were analyzed: 2346 women in the E+OFS group and 2344 women in the T+OFS group.
At the median follow-up (68 months, 5.7 years), treatment with the E+OFS regimen significantly reduced the risk of a DFS event compared with the T+OFS regimen (HR = 0.72; 95% CI, 0.60–0.86; p = 0.0002). The estimated 5-year DFS was 91.1% (95% CI, 89.7–92.3%) in women assigned to the E+OFS regimen compared with 87.3% (95% CI, 85.7–88.7%) in women assigned to the T+OFS regimen.
Women assigned to the E+OFS regimen had a statistically significant reduced risk of developing breast cancer compared with women assigned to the T+OFS regimen (HR = 0.66; 95% CI, 0.55–0.80; P < 0.0001). The estimated 5-year BCFI improved to 92.8% (95% CI, 91.6–93.9%) in women assigned to the E+OFS regimen, compared with 88.8% (95% CI, 87.3–90.1%) in women assigned to the T+OFS regimen.
Pharmacokinetics
After intramuscular injection of this prolonged-release medicinal product, an initial phase of active substance release is observed, followed by a normal release over a period of 28 days.
After intramuscular injection of the drug Diferelin® (3.75 mg) in women with endometriosis and uterine fibroids, maximum levels of triptorelin in the blood are reached in the interval from 2 to 6 hours after injection, and the peak value is 11 ng/ml. There is no evidence of accumulation of the drug after monthly injections for six months.
Plasma trough concentrations were maintained between 0.1 and 0.2 ng/mL. The bioavailability of the sustained-release formulation is approximately 50%.
These data, which were observed in patients with endometriosis and uterine fibroids, can be extrapolated to patients with breast cancer, as this disease is not expected to have an impact on the properties of this medicinal product in the prolonged-release dosage form.
Indication
Prostate cancer
Treatment of high-risk localized or locally advanced prostate cancer, in combination with radiotherapy (see section "Pharmacodynamics").
Treatment of locally advanced or metastatic prostate cancer.
The favorable outcome of treatment is more pronounced and observed more often if the patient has not previously received any other hormonal therapy.
Precocious puberty in children (in girls under 8 years of age and in boys under 10 years of age). Genital and extragenital endometriosis (stages I–IV)
Therapy should not be continued for longer than 6 months (see section “Adverse reactions”). Repeated treatment with triptorelin or other gonadotropin-releasing hormone (GnRH) analogues is not recommended.
Female infertility
Additional treatment in combination with gonadotropins (human menopausal gonadotropin (MHG), follicle-stimulating hormone (FSH), human chorionic gonadotropin (hCG)), to artificially recreate ovulation conditions for the purpose of in vitro fertilization and subsequent embryo transplantation (IVFET).
Treatment of uterine fibroids before surgery
in connection with anemia (hemoglobin level below or equal to 8 g/dl); as an auxiliary and corrective drug in surgical treatment if it is necessary to reduce the size of fibroids: endoscopic surgery, transvaginal surgery.
The duration of treatment is limited to three months.
Breast cancer
As adjuvant therapy in combination with tamoxifen or an aromatase inhibitor for the treatment of hormone-sensitive early breast cancer at high risk of recurrence after completion of chemotherapy in women with confirmed premenopausal status (see sections "Contraindications", "Special instructions", "Adverse reactions" and "Pharmacodynamics").
Contraindication
Hypersensitivity to GnRH, its analogues or to any of the excipients of this medicinal product listed in the "Composition" section (see section "Adverse reactions").
Pregnancy or breastfeeding.
Premenopausal women with breast cancer: use of an aromatase inhibitor until adequate ovarian suppression with triptorelin is achieved (see sections “Method of administration and dosage” and “Special warnings and precautions for use”).
Special safety precautions
The suspension for injection should be reconstituted under aseptic conditions only using the ampoule with solvent for injection.
The following preparation instructions should be strictly followed:
Draw the solvent into the syringe provided using the reconstitution needle (20 G, without protection system) and transfer it to the vial with the powder. Dissolve by gently shaking the vial until a homogeneous milky suspension is formed. Do not invert the vial.
It is important to check that there are no agglomerates of powder in the vial. Then draw the resulting suspension back into the syringe without inverting the vial. Then replace the reconstitution needle with an injection needle (20 G, with protection system) for administration.
Since the drug is in the form of a suspension, the injection should be performed immediately after dissolution to prevent the formation of a precipitate.
For single use only.
Used needles, any unused suspension or other waste material should be disposed of in accordance with local requirements.
Interaction with other medicinal products and other types of interactions
=When using triptorelin with drugs that affect the secretion of pituitary gonadotropic hormones, precautions must be taken and careful monitoring of the patient's hormonal levels is recommended.
Since androgen deprivation therapy may prolong the QT interval, the simultaneous use of Diferelin® (3.75 mg) with drugs that prolong the QT interval or can induce torsades de pointes, such as class IA antiarrhythmics (quinidine, disopyramide, etc.) or class III (amiodarone, sotalol, dofetilide, ibutilide), as well as methadone, cisapride, moxifloxacin, antipsychotics, requires careful evaluation (see section "Special instructions").
Application features
Use of GnRH agonists may cause a decrease in bone mineral density. Preliminary data suggest that in men, the use of a bisphosphonate in combination with a GnRH agonist may reduce bone mineral loss. Particular attention should be paid to patients with additional risk factors for osteoporosis (such as alcohol abuse, smoking, long-term treatment with drugs that cause a decrease in bone mineral density, such as anticonvulsants or corticosteroids, a family history of osteoporosis, malnutrition).
Before prescribing Diferelin® (3.75 mg), it is necessary to confirm that the patient is not pregnant.
In rare cases, GnRH agonist therapy may reveal previously undetected pituitary gonadotropin-releasing adenomas. Such patients may present with pituitary apoplexy, characterized by sudden headaches, vomiting, visual disturbances, and ophthalmoplegia.
There is an increased risk of developing depression (which may be severe) in patients treated with GnRH agonists, including triptorelin. Therefore, patients should be informed accordingly and provided with appropriate treatment if symptoms occur. Patients who are depressed should be closely monitored during therapy.
Diferelin® (3.75 mg) contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially sodium-free.
This medicinal product should be administered with caution to patients treated with anticoagulants due to the risk of hematomas at the injection site.
Prostate cancer
At the beginning of treatment with triptorelin, like other GnRH agonists, a temporary increase in serum testosterone levels occurs. As a result, isolated cases of temporary worsening of prostate cancer symptoms may occur during the first weeks of treatment. During the initial phase of treatment, the additional administration of an appropriate antiandrogen should be considered to counteract the initial increase in serum testosterone levels and prevent worsening of clinical symptoms.
A small number of patients may experience a temporary worsening of prostate cancer symptoms and a temporary increase in cancer-related pain (metastatic pain), which is treated symptomatically.
As with other GnRH agonists, isolated cases of spinal cord compression or urethral obstruction have been reported. If spinal cord compression or renal dysfunction occurs, standard treatment for these complications should be used, and in extreme cases, immediate orchiectomy (surgical castration) should be considered. Close monitoring is indicated during the first weeks of treatment, especially in patients with vertebral metastases, at risk of spinal cord compression, and/or urinary tract obstruction. For the same reason, special caution should be exercised when treating patients with prodromal signs of spinal cord compression.
After surgical castration, triptorelin does not cause a further decrease in serum testosterone levels.
Prolonged androgen deprivation due to bilateral orchiectomy or administration of GnRH analogues increases the risk of bone loss and can lead to osteoporosis, and also increases the risk of bone fracture.
Androgen deprivation therapy may cause QT prolongation.
In addition, epidemiological data have suggested that patients may experience metabolic changes (e.g., impaired glucose tolerance) or an increased risk of cardiovascular disease during antiandrogen therapy. Although prospective data have not shown an association between GnRH analogue therapy and increased cardiovascular mortality, patients at high risk of metabolic and cardiovascular disease should be carefully evaluated before initiating treatment and should be closely monitored during antiandrogen therapy.
Due to prolonged androgen deprivation, treatment with GnRH analogues may increase the risk of anaemia. This risk should be assessed and patients should be appropriately monitored.
The administration of triptorelin in medicinal doses interferes with the function of the pituitary-gonadal system. As a rule, its normal functioning is restored after discontinuation of therapy. Therefore, the data of diagnostic tests for the function of the pituitary-gonadal system, which are performed during therapy with GnRH analogues and after its discontinuation, may be erroneous.
An increase in acid phosphatase activity is possible during the initial period of therapy.
It may be useful to periodically check your testosterone levels in your blood using an accurate method, as your level should not exceed 1 ng/ml.
In women
Before prescribing Diferelin® (3.75 mg), it is necessary to ensure that the patient is not pregnant.
There is a significant risk of bone mineral density loss with GnRH agonists, averaging 1% per month over a six-month course of therapy. A 10% decrease in bone mineral density increases the risk of bone fractures 2–3-fold.
According to available data, the decrease in bone density in most women stops after completion of therapy.
There is currently no specific information available for patients with established osteoporosis or risk factors for osteoporosis (e.g. alcohol abuse, smoking, long-term treatment with drugs that cause a decrease in bone mineral density, e.g. anticonvulsants or corticosteroids, hereditary predisposition to osteoporosis, malnutrition, e.g. anorexia nervosa). Since a decrease in bone mineral density may be detrimental in such patients, the decision to prescribe triptorelin should be made on an individual basis. Therapy should only be initiated if the benefit outweighs the risk, based on a careful assessment. Consideration should be given to additional measures to counteract the decrease in bone mineral density.
Female infertility
Follicular recovery may be significantly enhanced by the administration of triptorelin in combination with gonadotropins in susceptible patients, especially those with polycystic ovary syndrome. As with other GnRH analogues, ovarian hyperstimulation syndrome has been reported in association with the use of triptorelin in combination with gonadotropins.
The ovarian response to the use of triptorelin in combination with gonadotropic hormones may vary between patients taking the same dose, and in some cases within the same patient during different cycles.
It is necessary to ensure close medical supervision during induced ovulation with accurate and regular biological and clinical monitoring: rapid tests for estrogen levels in blood plasma, ultrasound (see the section "Adverse reactions").
In case of excessive ovarian response, it is recommended to interrupt the stimulation cycle by stopping the administration of gonadotropic hormones.
In patients with renal and hepatic insufficiency, the terminal half-life averages 7–8 hours, while in healthy women it averages 3–5 hours. Despite this long-lasting effect, triptorelin should no longer be present in the blood at the time of embryo transfer.
Endometriosis and uterine fibroid treatment before surgery
Regular use, every 4 weeks, of one vial of the drug Diferelin® (3.75 mg) causes permanent hypogonadotropic amenorrhea.
If genital bleeding occurs after the first month, plasma estradiol levels should be determined. If the level is less than 50 pg/mL, a study should be performed to determine possible organic lesions.
Since menstruation should cease during treatment with triptorelin, the patient should be advised to inform her doctor if her normal menstrual cycle resumes.
During the course of therapy and for 1 month after the last injection, non-hormonal methods of contraception must be used (see section "Use during pregnancy or breastfeeding").
After cessation of therapy, ovarian function is restored and ovulation occurs approximately 2 months after the last injection.
In the treatment of uterine fibroids, regular examination of the size of the fibroid is recommended. There have been a few cases of bleeding in patients with submucosal fibroids treated with a GnRH analogue. Bleeding usually occurs 6–10 weeks after the start of treatment.
To ensure adequate ovarian suppression in premenopausal women, triptorelin treatment should be initiated at least 6–8 weeks before the start of aromatase inhibitor therapy. Monthly triptorelin injections should be administered on a scheduled schedule and without interruption throughout the entire period of aromatase inhibitor therapy.
In premenopausal women diagnosed with breast cancer who have ceased menses following chemotherapy, ovarian estrogen production may or may not be maintained. Regardless of menstrual status, premenopausal status should be confirmed after chemotherapy and before initiation of triptorelin therapy by measuring serum estradiol and follicle-stimulating hormone (FSH) levels according to the reference range for premenopausal women in order to avoid unintended treatment with triptorelin in the event of chemotherapy-induced menopause. After initiation of triptorelin therapy, it is important to confirm adequate ovarian suppression (gonadotropin analogue-induced menopause) by performing circulating FSH and estradiol tests to establish true postmenopausal status if this subgroup of women is considered for aromatase inhibitor treatment according to current clinical practice guidelines. Accordingly, ovarian suppression should be confirmed by low FSH and estradiol blood concentrations before starting aromatase inhibitor therapy. Tests should be repeated every three months during this combination therapy with triptorelin and an aromatase inhibitor.
These measures are intended to avoid a rebound increase in circulating estrogen levels during aromatase inhibitor therapy with potential implications for breast cancer. It should be noted that circulating FSH levels decrease in response to gonadotropin analog-induced ovarian suppression (induced menopause), in contrast to natural menopause, in which FSH levels increase.
Triptorelin, when used as adjuvant therapy in combination with tamoxifen or an aromatase inhibitor, is associated with a higher risk of osteoporosis. Osteoporosis was reported more frequently after triptorelin was used in combination with an aromatase inhibitor than with tamoxifen (39% versus 25%).
Bone density should be assessed before initiating triptorelin therapy, especially in women with multiple risk factors for osteoporosis. These patients should be closely monitored and, if necessary, treated or prevented for osteoporosis.
In premenopausal women, treatment of hormone-sensitive early breast cancer with triptorelin in combination with tamoxifen or an aromatase inhibitor should be carried out after a careful individual assessment of the risks and benefits.
Patients who discontinue triptorelin treatment should also discontinue aromatase inhibitor therapy for 1 month after the last administration of triptorelin extended-release.
When triptorelin is used in combination with either an aromatase inhibitor or tamoxifen, the risk of developing musculoskeletal disorders (including joint pain and musculoskeletal pain) is 89% with the aromatase inhibitor and approximately 76% with tamoxifen.
When triptorelin is used in combination with either exemestane or tamoxifen (see section 4.8), hypertension has been reported as a very common and anticipated adverse event. In premenopausal women with breast cancer receiving triptorelin in combination with either exemestane or tamoxifen, it is advisable to ensure regular monitoring of cardiovascular risk factors and blood pressure.
Hyperglycaemia and diabetes have been reported as commonly anticipated adverse events when triptorelin is used in combination with either exemestane or tamoxifen (see section 4.8). In premenopausal women with breast cancer receiving triptorelin in combination with either exemestane or tamoxifen, it is advisable to ensure regular monitoring of risk factors for diabetes with regular monitoring of blood glucose and, if necessary, to prescribe appropriate antidiabetic therapy according to national guidelines.
Depression occurred in approximately 50% of patients receiving triptorelin in combination with either tamoxifen or exemestane in all treatment arms of the TEXT and SOFT studies, but less than 5% of patients experienced severe depression (grade 3–4). Patients should be informed of this and appropriate treatment should be initiated if symptoms occur. Patients with a diagnosis of depression or a history of depression should be closely monitored during treatment.
You should also carefully read the instructions for use of exemestane and tamoxifen for relevant safety information on the use of these agents in combination with triptorelin.
Chemotherapy may cause temporary amenorrhea or permanent cessation of ovarian function due to cytotoxic damage to gonadal tissue. The preservation of premenopausal status after completion of chemotherapy should be confirmed according to clinical guidelines by determining blood concentrations of estradiol and FSH and comparing the obtained values with reference values for premenopausal women.
Treatment of children with advanced brain tumors should be initiated after careful assessment of the risks and benefits of treatment.
In girls, initial gonadal stimulation may cause light to moderate vaginal bleeding during the first month.
After completion of therapy, the characteristics of puberty develop.
Information on reproductive status in children treated with GnRH analogues is limited. Most girls regained regular menstrual cycles on average one year after stopping therapy.
It is necessary to exclude the possibility of pseudoprecocious puberty (gonadal tumor and adrenal tumor, as well as hyperplasia) and gonadotropin-independent precocious puberty (testicular toxicosis, familial Leydig cell hyperplasia).
During treatment of central precocious puberty with GnRH agonists, bone mineral density may decrease. However, bone mass continues to accumulate after treatment is discontinued, and peak bone mass in late puberty is not affected by treatment.
Slipped capital femoral epiphysis may develop after discontinuation of GnRH agonist treatment. It is thought that the low estrogen concentration during GnRH agonist treatment weakens the epiphyseal plate. Accelerated growth after discontinuation of treatment results in a reduction in the force required to displace the epiphysis.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies have been conducted on the effect on the reaction rate when driving vehicles or using other mechanisms. However, the ability to drive vehicles and work with other mechanisms may be impaired due to dizziness, drowsiness and visual disturbances, which are possible undesirable effects of therapy or a result of the underlying disease.
Use during pregnancy or breastfeeding
Pregnancy
Triptorelin should not be used during pregnancy, as concomitant use of GnRH agonists is associated with a theoretical risk of abortion or malformations in the child. Before starting treatment, women of childbearing potential should undergo a careful examination to exclude the possibility of pregnancy. Non-hormonal methods of contraception should be used during treatment and until menstruation resumes.
Before prescribing Diferelin® (3.75 mg), in particular before treatment for infertility, it is necessary to ensure that the patient is not pregnant.
In this category of patients, there is no clinical evidence of a causal relationship between the use of triptorelin and any subsequent atypical oocyte development or pregnancy or its outcome.
Breast-feeding
Triptorelin is contraindicated during breastfeeding.
Method of administration and doses
Doses
Prostate cancer
One intramuscular injection of Diferelin® (3.75 mg) every 4 weeks.
Duration of treatment
In the treatment of high-risk localized or locally advanced hormone-dependent prostate cancer, when the drug is used as concomitant therapy and after radiotherapy, clinical data have demonstrated that radiotherapy followed by long-term antiandrogen therapy is preferable to radiotherapy followed by short-term antiandrogen therapy (see section "Pharmacodynamics").
The duration of antiandrogen therapy recommended by medical guidelines for patients with high-risk localized or locally advanced prostate cancer undergoing radiotherapy is 2–3 years.
Patients with metastatic castration-resistant prostate cancer who have not undergone surgical castration and are receiving a
