Diphereline
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIPHERELINE® (DIPHERELINE®)
Composition:
Active substance: triptorelin;
1 vial contains triptorelin acetate equivalent to 3.75 mg of triptorelin;
Excipients: D, L-lactide glycolide copolymer, mannitol (E 421), sodium carmellose, polysorbate 80;
Solvent composition: 1 ampoule contains mannitol (E 421), water for injections.
Pharmaceutical form.
Powder and solvent for prolonged-release injectable suspension.
Main physicochemical properties: contents of the vial—almost white lyophilized powder. The appearance of the reconstituted suspension—homogeneous milky suspension.
Pharmacotherapeutic group.
Gonadotropin-releasing hormone analogues. ATC code L02A E04.
Pharmacological Properties
Mechanism of Action
Triptorelin is a synthetic decapeptide analogue of gonadotropin-releasing hormone (GnRH). Studies in humans and animals have shown that after an initial stimulation, prolonged administration of triptorelin suppresses gonadotropin secretion, leading to inhibition of testicular and ovarian function.
Further animal studies have demonstrated an additional mechanism of action—direct effects on the gonads due to reduced sensitivity of peripheral GnRH receptors.
Clinical Efficacy and Safety
Prostate Cancer
Administration of daily doses of triptorelin may initially increase serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), subsequently leading to a transient rise in testosterone levels ("flare"). Continued therapy reduces LH and FSH levels to concentrations that result in suppression of steroid levels to those observed after castration, typically within 2–3 weeks after injection and maintained throughout the treatment period.
Therapy may transiently exacerbate functional and objective symptoms.
In several randomized, long-term clinical trials involving patients with locally advanced prostate cancer, androgen deprivation therapy (ADT) combined with radiotherapy (RT) demonstrated superiority over RT alone (RTOG 85-31, RTOG 86-10, EORTC 22863, D’Amico et al., JAMA, 2008).
In a phase III randomized trial (EORTC 22961) involving 970 patients with locally advanced prostate cancer (predominantly T2c–T4, and several patients with T1c–T2b cancer and pathologically confirmed regional nodal involvement), short-term (6 months, n = 483) versus long-term (3 years, n = 487) antiandrogen therapy combined with radiotherapy was compared. GnRH agonists used included triptorelin (62.2%) or other GnRH agonists. The study did not stratify by type of agonist.
Five-year overall mortality was 19.0% and 15.2% in the short-term and long-term hormonal therapy 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 noninferiority analysis and p = 0.0082—for difference between groups in study outcomes). Five-year prostate cancer-specific mortality was 4.78% and 3.2% in the short-term and long-term hormonal therapy groups, respectively, with a relative risk of 1.71 (95% CI [1.14 to 2.57], p = 0.002). Overall quality of life, assessed using the QLQ–C30 questionnaire, did not differ significantly between the two groups (p = 0.37).
Subgroup analysis of patients treated with triptorelin also showed an advantage of long-term over short-term treatment in terms of overall mortality (relative risk = 1.28; 95.71% CI = [0.89; 1.84], p = 0.38 and p = 0.08 for noninferiority and difference between treatment groups, respectively).
The evidence base for using this medicinal product in the treatment of high-risk localized prostate cancer is based on published data from studies of radiotherapy combined with GnRH analogues. Clinical data from five trials (EORTC 22863, RTOG 85–31, RTOG 92–02, RTOG 86–10, and D’Amico et al., JAMA, 2008) were analyzed. All demonstrated the benefit of combining GnRH analogue therapy with radiotherapy. Published data do not allow clear differentiation of the respective populations by indication—locally advanced prostate cancer versus high-risk localized prostate cancer.
In patients with metastatic castration-resistant prostate cancer, clinical studies have demonstrated benefit from adding abiraterone acetate (an androgen biosynthesis inhibitor) or enzalutamide (an androgen receptor function inhibitor) to GnRH analogues such as triptorelin.
Central Precocious Puberty
Suppression of pituitary gonadotropin hyperfunction in both sexes results in reduced secretion of estradiol and testosterone, decreased peak LH levels, and improved height-age and bone age parameters.
Initial gonadal stimulation may cause minor bleeding, which may require treatment with medroxyprogesterone or cyproterone acetate.
Endometriosis
Prolonged treatment with triptorelin suppresses estradiol secretion, thereby inducing a state of "quiescence" in ectopic endometrial tissue.
Female Infertility
Prolonged therapy with triptorelin suppresses gonadotropin (FSH and LH) secretion. Thus, treatment prevents the mid-cycle endogenous LH surge, allowing improved folliculogenesis and accelerated follicular recruitment.
Uterine Fibroids
Studies have demonstrated consistent and pronounced reduction in uterine fibroid volume in certain cases. This reduction reaches its maximum by the third month of treatment.
Triptorelin therapy induces amenorrhea in most patients after the first month of treatment, allowing correction of anemia resulting from menorrhagia and/or metrorrhagia.
Breast Cancer
Clinical trials in premenopausal women with early-stage hormone-sensitive breast cancer involved the use of triptorelin to suppress ovarian estradiol secretion, the primary source of estrogens. Based on studies in healthy women and women with endometriosis, the effect of triptorelin is achieved within 3–4 weeks after administration.
Two phase III trials (SOFT and TEXT) evaluated the 5-year benefit of ovarian function suppression (OFS) combined with tamoxifen (T) or an aromatase inhibitor (exemestane, E) in premenopausal women with early-stage hormone-sensitive breast cancer.
Triptorelin was the primary agent used to achieve OFS (91.0% of randomized patients in the SOFT trial and 100% in the TEXT trial). The remaining 9% of women in the SOFT trial underwent bilateral oophorectomy or bilateral ovarian irradiation.
SOFT Trial Results
The SOFT trial was designed to evaluate the additional benefit of ovarian function suppression when added to tamoxifen as adjuvant therapy in premenopausal women with early-stage hormone-sensitive breast cancer.
Data from a total of 3,047 women were analyzed (1,015 in the T+OFS group, 1,018 in the tamoxifen monotherapy group, and 1,014 in the E+OFS group).
With a median follow-up of 67 months (5.6 years), treatment with T+OFS did not significantly improve disease-free survival (DFS) compared to tamoxifen 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 the T+OFS group versus 84.7% (95% CI, 82.2–86.9%) in the tamoxifen monotherapy group.
However, after adjustment for prespecified covariates in a multivariate Cox model, women randomized to the T+OFS group had a significantly lower risk of DFS events compared to those receiving tamoxifen alone, with a 22% reduction (HR = 0.78; 95% CI, 0.62–0.98; p = 0.03).
Women treated with T+OFS had a modestly reduced risk of breast cancer events compared to those on tamoxifen monotherapy (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 the T+OFS group versus 86.4% (95% CI, 84.0–88.5%) in the tamoxifen group.
After adjustment for prespecified covariates in the multivariate Cox model, women in the T+OFS group had a significantly reduced risk of BCFI events compared to the tamoxifen group, with a 25% risk reduction (HR = 0.75; 95% CI, 0.59–0.96; p = 0.02).
The absolute benefit 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 tamoxifen group (HR = 0.82; 95% CI, 0.64–1.07), resulting in an absolute benefit of 3.6% for the T+OFS regimen.
Notably, the benefit of adding OFS was particularly evident in a post hoc analysis of women aged 40 years or younger, with a 5-year DFS HR of 0.74 (95% CI, 0.53–1.03) and an absolute benefit of 4.4% for T+OFS versus tamoxifen monotherapy.
In the SOFT trial, patients receiving E+OFS showed a statistically significant reduction in DFS events compared to those on tamoxifen monotherapy (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 versus 84.7% (95% CI, 82.2–86.9%) in the tamoxifen group.
Patients receiving E+OFS also showed a statistically significant reduction in the risk of breast cancer events compared to the tamoxifen group (HR = 0.64; 95% CI, 0.49–0.83). The estimated 5-year BCFI was 90.9% (95% CI, 88.9–92.6%) in the E+OFS group versus 86.4% (95% CI, 84.0–88.5%) in the tamoxifen group.
Patients receiving E+OFS had a statistically significant reduction in the risk of distant recurrence compared to the tamoxifen 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 the E+OFS group versus 90.7% (95% CI, 88.6–92.4%) in the tamoxifen group.
The absolute benefit 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 tamoxifen group (HR = 0.70, 95% CI, 0.53–0.92), resulting in an absolute benefit of 6.7% for the E+OFS group.
Kaplan–Meier DFS estimates in women who received prior chemotherapy
| Recurrence-free survival, prior chemotherapy |
| Number of years since randomization Number of patients in the risk group |
In the SOFT trial, which was conducted in three groups, women who received chemotherapy had a higher proportion of clinical criteria indicating a high risk of recurrence: 49.3% of women under 40 years of age, 56.9% of women with positive lymph nodes, 47.0% of women with tumor size > 2 cm, and 33.7% with grade 3 tumors.
Combined results of the SOFT and TEXT trials
The primary objective of the TEXT trial was to evaluate the role of aromatase inhibitors (exemestane) in combination with ovarian function suppression (OFS) compared to tamoxifen plus OFS (T+OFS) in all participants of the SOFT and TEXT trials. Overall, data from 4,690 women were analyzed: 2,346 women in the E+OFS group and 2,344 women in the T+OFS group.
At the time of reaching median follow-up (68 months, 5.7 years), treatment with E+OFS significantly reduced the risk of a DFS event compared to T+OFS (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 to 87.3% (95% CI, 85.7–88.7%) in those assigned to the T+OFS regimen.
Kaplan–Meier estimates of DFS in the OFS+E and OFS+T groups
| Number of years since randomization Number of patients at risk |
Women who received the E+OFS regimen had a statistically significant reduction in the risk of developing breast cancer compared to women who received the T+OFS regimen (HR = 0.66; 95% CI, 0.55–0.80; P <0.0001). The estimated 5-year BCFI rate improved to 92.8% (95% CI, 91.6–93.9%) in women on the E+OFS regimen, compared to 88.8% (95% CI, 87.3–90.1%) in women on the T+OFS regimen.
Pharmacokinetics.
After intramuscular injection of this prolonged-release medicinal product, an initial release phase of the active substance is observed, followed by a sustained release over 28 days.
After intramuscular injection of Diphereline® (3.75 mg) in women with endometriosis and uterine fibroids, maximum plasma levels of triptorelin are reached within 2 to 6 hours after injection, with peak levels of 11 ng/mL. There was no evidence of drug accumulation after monthly injections for six months.
Minimum plasma concentrations were maintained in the range of 0.1 to 0.2 ng/mL. The bioavailability of the sustained-release formulation is approximately 50%.
These data observed in patients with endometriosis and uterine fibroids can be extrapolated to patients with breast cancer, as it is not expected that this disease will influence the properties of this medicinal product in its prolonged-release formulation.
Clinical characteristics.
Indications.
- 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 therapeutic effect is more pronounced and observed more frequently if the patient has not previously received any other hormonal therapy.
- Central precocious puberty in children (in girls under 8 years of age and in boys under 10 years of age).
- Genital and extragenital endometriosis (Stage I–IV)
Treatment should not exceed 6 months (see section "Adverse reactions"). Repeated treatment courses with triptorelin or another gonadotropin-releasing hormone (GnRH) analogue are not recommended.
- Female infertility
Adjunctive treatment in combination with gonadotropins (human menopausal gonadotropin (hMG), follicle-stimulating hormone (FSH), human chorionic gonadotropin (hCG)), for artificial induction of ovulation conditions for in vitro fertilization and subsequent embryo transfer (I.V.F.E.T).
- Treatment of uterine fibroids prior to surgery
- in cases associated with anaemia (haemoglobin level ≤ 8 g/dL);
- as an adjunctive and corrective medicinal agent prior to surgical intervention when reduction of fibroid size is required: endoscopic surgery, transvaginal surgery.
Treatment duration 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-stage breast cancer with a high risk of recurrence after completion of chemotherapy in women with confirmed premenopausal status (see sections "Contraindications", "Special precautions", "Adverse reactions", and "Pharmacodynamics").
Contraindications.
- 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.
- In premenopausal women with breast cancer: administration of an aromatase inhibitor prior to achieving adequate ovarian function suppression by triptorelin (see sections "Method of administration and dosage" and "Special precautions").
Special safety precautions.
The injectable suspension must be reconstituted under aseptic conditions using only the solvent vial provided for injection.
The following reconstitution instructions must be strictly followed:
Draw the solvent into the provided syringe through the reconstitution needle (20 G, without safety system) and transfer it into the vial containing the powder. Reconstitute by gently shaking the vial until a homogeneous milky-colored suspension is formed. Do not invert the vial.
It is important to check for the absence of powder aggregates in the vial. Then, draw the resulting suspension back into the syringe without inverting the vial. Afterwards, replace the reconstitution needle with the injection needle (20 G, with safety system) for administration.
Since the medicinal product is in the form of a suspension, the injection must be administered immediately after reconstitution to prevent sedimentation.
For single use only.
Used needles, any unused suspension, or other waste must be disposed of in accordance with local requirements.
Interaction with other medicinal products and other types of interactions.
Caution is required when triptorelin is used concomitantly with medicinal products affecting the secretion of pituitary gonadotropic hormones, and careful monitoring of the patient's hormonal levels is recommended.
Since androgen deprivation therapy may prolong the QT interval, concomitant use of triptorelin with medicinal products that prolong the QT interval or may induce torsades de pointes ventricular tachycardia, such as class IA antiarrhythmics (quinidine, disopyramide, etc.) or class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide), as well as methadone, cisapride, moxifloxacin, and antipsychotics, requires careful assessment (see section "Special precautions").
Special precautions for use.
Administration of GnRH agonists in adult patients may lead to a decrease in bone mineral density, increasing the risk of osteoporosis. Preliminary data suggest that in men, co-administration of bisphosphonates with GnRH agonists may reduce bone demineralization. Particular attention should be paid to patients with additional risk factors for osteoporosis (such as alcohol abuse, smoking, long-term treatment with agents causing decreased bone mineral density, e.g., anticonvulsants or corticosteroids, hereditary predisposition to osteoporosis, inadequate nutrition).
In rare cases, therapy with GnRH agonists may reveal previously undiagnosed gonadotroph adenoma of the pituitary gland. In such patients, pituitary apoplexy may occur, characterized by sudden headache, vomiting, visual disturbances, and ophthalmoplegia.
There is an increased risk of depression (which may be severe) in patients undergoing treatment with GnRH agonists, particularly triptorelin. Therefore, patients should be appropriately informed and provided with adequate treatment if symptoms occur. Patients with existing depression require careful monitoring throughout therapy.
This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., the product is essentially sodium-free.
This medicinal product should be administered with caution to patients receiving anticoagulant therapy due to the risk of injection-site hematoma.
In men
At the beginning of therapy, triptorelin, like other GnRH agonists, causes a transient increase in serum testosterone levels. As a result, during the first weeks of treatment, isolated cases of temporary worsening of symptoms of prostate cancer (transient aggravation of tumor clinical manifestations) may occur. During the initial treatment phase, consideration should be given to additional administration of an appropriate antiandrogen to neutralize the initial rise in serum testosterone levels and prevent clinical symptom deterioration.
A small number of patients may experience temporary worsening of prostate cancer symptoms (tumor flare) and temporary intensification of cancer-related pain (pain due to metastatic involvement), which should be managed symptomatically.
As with other GnRH agonists, isolated cases of spinal cord compression or ureteral obstruction have been observed. In the event of spinal cord compression or renal dysfunction, standard treatment methods for these complications should be applied, and in emergency cases, immediate orchiectomy (surgical castration) should be considered. Close monitoring is recommended during the first weeks of treatment, especially in patients with vertebral metastases at risk of spinal cord compression and/or patients with urinary tract obstruction. For this reason, particular caution should be exercised when prescribing treatment to patients with prodromal signs of spinal cord compression.
Following surgical castration, triptorelin does not further reduce serum testosterone levels.
Prolonged androgen deficiency due to bilateral orchiectomy or administration of GnRH analogs increases the risk of bone mass loss and may lead to osteoporosis, as well as an increased risk of bone fractures.
Androgen deprivation therapy may prolong the QT interval.
For patients with a history of QT interval prolongation or relevant risk factors, as well as patients receiving concomitant medicinal products that may prolong the QT interval (see section "Interaction with other medicinal products and other forms of interaction"), physicians should evaluate the benefit-risk ratio, including the potential risk of torsades de pointes ventricular tachycardia, before prescribing Diphereline® (3.75 mg).
Additionally, according to epidemiological data, metabolic changes (e.g., impaired glucose tolerance, hepatic steatosis) or increased risk of cardiovascular diseases may occur in patients during antiandrogen therapy. Although prospective data have not confirmed a link between GnRH analog therapy and increased cardiovascular mortality, patients at high risk of metabolic and cardiovascular disorders should be thoroughly evaluated before initiating treatment and require appropriate monitoring during antiandrogen therapy.
Due to prolonged androgen deficiency, treatment with GnRH analogs may increase the risk of anemia. This risk should be assessed, and such patients should be appropriately monitored.
Administration of triptorelin at therapeutic doses suppresses the function of the hypothalamic–pituitary–gonadal system. Normal function usually recovers after discontinuation of therapy. Therefore, diagnostic test results assessing hypothalamic–pituitary–gonadal function performed during and after therapy with GnRH analogs may be misleading.
Increased activity of acid phosphatase may occur during the initial period of therapy.
Therapeutic efficacy should be monitored regularly. Periodic measurement of serum testosterone levels using an accurate method may be useful, as levels should not exceed 1 ng/mL, as well as measurement of prostate-specific antigen (PSA).
In women
Before prescribing Diphereline® (3.75 mg), it must be confirmed that the patient is not pregnant.
Use of GnRH agonists carries a significant risk of decreased bone mineral density, averaging 1% per month during a six-month treatment course. A 10% reduction in bone mineral density increases the risk of bone fractures by 2–3 times.
There is currently no specific information regarding patients with diagnosed osteoporosis or risk factors for osteoporosis (e.g., alcohol abuse, smoking, long-term treatment with agents causing decreased bone mineral density, such as anticonvulsants or corticosteroids, hereditary predisposition to osteoporosis, inadequate nutrition, e.g., anorexia nervosa). Since bone demineralization may be detrimental in such patients, the decision to prescribe triptorelin should be made individually. Therapy may be initiated only if the positive effect outweighs the risk based on a thorough benefit-risk assessment. Additional measures to counteract decreased bone mineral density should be considered.
- Female infertility
Before prescribing Diphereline® (3.75 mg), it must be confirmed that the patient is not pregnant.
Follicular recruitment may significantly increase in predisposed patients, particularly those with polycystic ovary syndrome, when triptorelin is administered together with gonadotropins. As with other GnRH analogs, cases of ovarian hyperstimulation syndrome (OHSS) associated with gonadotropin use in combination with triptorelin have been reported.
Ovarian response to triptorelin combined with gonadotropins may vary among patients receiving the same dose and even in the same patient during different cycles.
In patients with renal or hepatic impairment, the terminal half-life averages 7–8 hours, compared to 3–5 hours in healthy women. Despite this prolonged duration, triptorelin should no longer be present in the blood at the time of embryo transfer.
Close medical supervision is required during induced ovulation, including precise and regular biological and clinical monitoring: plasma estrogen level tests, ultrasound (see section "Adverse reactions").
In cases of excessive ovarian response, it is recommended to interrupt the stimulation cycle by discontinuing gonadotropin administration.
- Endometriosis and preoperative treatment of uterine fibroids
Use of GnRH agonists is not recommended in patients under 18 years of age. Particular attention should be paid to adolescents and young women (especially under 16 years of age), in whom peak bone density may not yet have been achieved.
It has been demonstrated that in patients receiving GnRH analogs for endometriosis, add-on hormone replacement therapy (daily administration of estrogen and progestogen) reduces bone mineral density loss and the severity of vasomotor symptoms (see section "Ad游戏副本
Method of Administration and Dosage
Dosage
- 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 medicinal product is used as adjuvant therapy and after radiotherapy, clinical data have demonstrated that radiotherapy followed by long-term antiandrogen therapy is more favorable than radiotherapy followed by short-term antiandrogen therapy (see section "Pharmacodynamics").
The duration of antiandrogen therapy recommended by clinical guidelines for patients with high-risk localized or locally advanced prostate cancer undergoing radiotherapy is 2–3 years.
For patients with metastatic castration-resistant prostate cancer who have not undergone surgical castration and are receiving a GnRH agonist such as triptorelin, and for whom treatment with abiraterone acetate—an androgen biosynthesis inhibitor—or enzalutamide—an androgen receptor inhibitor—is appropriate, GnRH agonist therapy should be continued.
- Central Precocious Puberty
Treatment of children with triptorelin should be conducted under careful supervision by a pediatric endocrinologist, pediatrician, or endocrinologist experienced in managing central precocious puberty.
Children with body weight up to 20 kg: half (1/2) of the dose intramuscularly every 4 weeks (28 days), i.e., administration of half the volume of the prepared suspension.
Children with body weight from 20 to 30 kg: two thirds (2/3) of the dose intramuscularly every 4 weeks (28 days), i.e., administration of two thirds of the volume of the prepared suspension.
Children with body weight over 30 kg: one full dose intramuscularly every 4 weeks (28 days), i.e., administration of the complete volume of the prepared suspension.
Treatment should be discontinued upon attainment of physiological sexual maturity in both boys and girls. Continuing treatment in girls beyond the age of 12–13 years with advanced bone maturation is not recommended. Data in boys are limited. The optimal time to discontinue treatment in boys with advanced bone age is when they reach 13–14 years of age.
- Endometriosis
One intramuscular injection of Diferelin® (3.75 mg) every 4 weeks.
Treatment should be initiated within the first five days of the menstrual cycle.
The duration of treatment depends on the initial severity of endometriosis and the reduction of clinical manifestations (functional and anatomical) during therapy. The treatment course should not exceed 6 months (see section "Adverse Reactions"). Initiating a second course of treatment with triptorelin or another GnRH analogue is not recommended. In women treated with GnRH analogues for endometriosis, add-back hormone therapy (HT)—i.e., daily administration of estrogen and progestogen preparations—has been shown to reduce bone mineral density loss and the severity of vasomotor symptoms. Therefore, concomitant add-back HT with a GnRH analogue should be considered on an individual basis and initiated only if the benefit outweighs the risk, following a thorough risk-benefit assessment.
- Female Infertility
The standard therapeutic regimen involves administration of one vial of Diferelin® (3.75 mg) intramuscularly on the second day of the menstrual cycle. Combination with gonadotropins should be initiated after achieving pituitary desensitization (plasma estrogen level not exceeding 50 pg/mL), usually on day 15 after injection of Diferelin® (3.75 mg).
- Treatment of Uterine Fibroids Prior to Surgery
One intramuscular injection of Diferelin® (3.75 mg) every 4 weeks.
Treatment should be initiated within the first five days of the menstrual cycle.
The duration of treatment is limited to 3 months.
- Breast Cancer
One intramuscular injection every 4 weeks in combination with tamoxifen or an aromatase inhibitor.
Triptorelin therapy should be initiated after completion of chemotherapy and immediately after confirmation of premenopausal status (see section "Special Instructions").
Triptorelin treatment must be started at least 6–8 weeks before initiating aromatase inhibitor therapy. At least two triptorelin injections (with a 4-week interval between injections) must be administered before starting aromatase inhibitor therapy.
Triptorelin therapy must not be interrupted during aromatase inhibitor treatment to avoid a "rebound" increase in circulating estrogen levels in premenopausal women.
The recommended duration of treatment in the adjuvant setting, in combination with other hormonal therapy, is up to 5 years.
Care must be taken to avoid accidental intravascular injection, as Diferelin® (3.75 mg) is a microsphere suspension for injection.
WARNING! It is essential that the prolonged-release medicinal product injection be administered strictly according to the recommendations provided in the medicinal product's instructions for medical use. Any failed injection, after which more medicinal product remains in the syringe than specified in the instructions, must be documented.
THE FOLLOWING INFORMATION IS INTENDED FOR HEALTHCARE PROFESSIONALS ONLY
Instructions for Use of the Medicinal Product
|
|||||||
| Disinfect the injection site in advance, as the medicinal product must be administered immediately after reconstitution. |
|||||||
|
|||||||
| The pack contains 2 needles: |
|||||||
|
|||||||
|
|||||||
| The presence of bubbles in the upper part of the lyophilisate is a normal appearance of the medicinal product. |
|||||||
| 2a
|
|||||||
| 2b
|
|||||||
| 2c
Important: Ensure there are no powder aggregates in the vial (if powder clumps are present, continue mixing until they disappear). |
|||||||
| 2d
|
|||||||
|
|||||||
| To prevent sedimentation, administer the injection immediately into a previously disinfected site. |
|||||||
|
|||||||
Two options for activating the safety system
or
Used needles, any unused suspension, and other waste must be disposed of according to local requirements. |
Method A or
Method B
|
||||||
Children.
Decapeptyl® 3.75 mg is indicated for the treatment of precocious puberty in children (onset of the condition in girls under 8 years of age and in boys under 10 years of age) under close supervision by a pediatric endocrinologist, pediatrician, or endocrinologist experienced in managing central precocious puberty.
Overdose.
In case of overdose, symptomatic treatment is recommended.
Adverse reactions.
General tolerability in men (see section "Dosage and administration")
Since patients with locally advanced or metastatic hormone-dependent prostate cancer are typically elderly individuals with comorbidities common in this age group, adverse events were observed in more than 90% of patients participating in clinical studies, and it was often difficult to establish causal relationships.
Based on observations from treatment with other GnRH agonists or surgical castration, the most common adverse reactions associated with triptorelin therapy are consequences of its expected pharmacological effect. These included hot flushes and decreased libido.
With the exception of immunologic and allergic reactions (rare) and injection site reactions (< 5%), all known adverse effects are related to changes in testosterone levels.
The frequency of 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). The frequency of adverse reactions identified during the post-marketing period cannot be estimated reliably and is therefore listed as "not known".
The adverse reactions listed below were considered at least possibly related to triptorelin therapy. The occurrence of most of them is associated with biochemical or surgical castration.
| Class / Organ System |
Very common |
Common |
Uncommon |
Rare |
Frequency not known |
| Infections and infestations |
Nasopharyngitis |
||||
| Blood and lymphatic system disorders |
Anaemia |
Thrombocytosis |
|||
| Immune system disorders |
Hypersensitivity |
Anaphylactic reaction |
Anaphylactic shock |
||
| Metabolism and nutrition disorders |
Anorexia, diabetes mellitus, gout, hyperlipidaemia, increased appetite |
||||
| Psychiatric disorders |
Decreased libido |
Depression, loss of libido, mood alterations* |
Insomnia, irritability |
Confusion, decreased activity, euphoric state |
Anxiety |
| Nervous system disorders |
Paraesthesia of lower limbs |
Dizziness, headache |
Paraesthesia |
Memory impairment |
|
| Endocrine disorders |
Pituitary apoplexy** |
||||
| Eye disorders |
Blurred vision |
Ocular sensitivity disorders, visual disturbances |
|||
| Ear and labyrinth disorders |
Tinnitus, vertigo |
||||
| Cardiac disorders |
Palpitations |
QT interval prolongation (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction") |
|||
| Vascular disorders |
Hot flushes |
Arterial hypertension |
Arterial hypotension |
||
| Respiratory, thoracic and mediastinal disorders |
Dyspnoea, epistaxis |
Orthopnoea |
|||
| Gastrointestinal disorders |
Dry mouth, nausea |
Abdominal pain, constipation, diarrhoea, vomiting |
Abdominal distension, dysgeusia, flatulence |
||
| Skin and subcutaneous tissue disorders |
Hyperhidrosis |
Acne, alopecia, erythema, pruritus, rash, urticaria |
Blisters, purpura |
Angioneurotic oedema |
|
| Musculoskeletal and connective tissue disorders |
Back pain |
Musculoskeletal pain, limb pain |
Arthralgia, bone pain, muscle spasms, muscle weakness, myalgia |
Joint stiffness, joint swelling, musculoskeletal stiffness, osteoarthritis |
|
| Renal and urinary disorders |
Nocturia, urinary retention |
Urinary incontinence |
|||
| Reproductive system and breast disorders |
Erectile dysfunction (including ejaculation disorder, impaired ejaculation) |
Pelvic pain |
Gynaecomastia, breast pain, testicular atrophy, testicular pain |
||
| General disorders and administration site conditions |
Asthenia |
Injection site reactions (including erythema, inflammation and pain), oedema |
Lethargy, peripheral oedema, pain, chills, somnolence |
Chest pain, malaise, influenza-like illness, pyrexia |
Feeling unwell |
| Investigations |
Weight increased |
Increased alanine aminotransferase, increased aspartate aminotransferase, increased blood creatinine, increased blood pressure, increased blood urea, increased gamma-glutamyltransferase, weight decreased |
Increased alkaline phosphatase activity in blood |
* This frequency is based on the adverse reaction rate common to all GnRH agonists.
** Pituitary apoplexy has been reported after initial administration of the medicinal product to patients with pituitary adenoma.
Triptorelin causes a temporary increase in circulating testosterone levels during the first week after administration of the first prolonged-release injection. During this initial rise in circulating testosterone levels, some patients (≤ 5%) may experience a worsening of symptoms of existing prostate cancer ("flare"), typically manifested as urinary symptoms (< 2%) and pain from metastatic disease (5%), which can be managed symptomatically. These symptoms are transient and usually resolve within 1–2 weeks.
Isolated cases of disease flare-ups, urethral obstruction, or spinal cord compression due to metastases have been reported. Therefore, patients with spinal metastases and/or obstruction of upper or lower urinary tract should be closely monitored during the first few weeks of therapy (see section "Special precautions for use").
The use of GnRH agonists in the treatment of prostate cancer increases the risk of bone loss and may lead to osteoporosis, as well as an increased risk of bone fractures.
An increase in lymphocyte count has been observed in patients treated with GnRH analogues. This secondary lymphocytosis appears to be related to the castration induced by GnRH and indicates the involvement of gonadal hormones in thymic involution.
Patients receiving long-term GnRH analogue therapy in combination with radiation therapy may experience a higher incidence of adverse effects, particularly gastrointestinal effects associated with radiotherapy.
General tolerability in women (see section "Special precautions for use")
As a consequence of reduced estrogen levels, the most commonly reported adverse effects (expected in more than 10% of women) were headache, decreased libido, sleep disturbances, mood changes, dyspareunia, dysmenorrhea, genital bleeding, ovarian hyperstimulation syndrome, ovarian hypertrophy, pelvic pain, abdominal pain, vulvovaginal dryness, hyperhidrosis, hot flushes, and asthenia.
The frequency of adverse reactions is classified as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000). The frequency of adverse reactions identified during the post-marketing period cannot be determined and is therefore listed as "not known."
The adverse reactions listed below were considered at least possibly related to triptorelin therapy. The occurrence of most of these is associated with biochemical or surgical castration.
| System Organ Class |
Very common |
Common |
Uncommon |
Frequency not known |
| Immune system disorders |
Hypersensitivity |
Anaphylactic shock |
||
| Metabolism and nutrition disorders |
Decreased appetite, fluid retention |
|||
| Psychiatric disorders |
Sleep disorders (including insomnia), mood changes, decreased libido |
Depression*, nervousness |
Affective lability, anxiety, depression**, confusion |
Confusional state |
| Nervous system disorders |
Headache |
Dizziness |
Dysgeusia, hypoesthesia, loss of consciousness, memory disorders, attention disturbances, paraesthesia, tremor |
|
| Endocrine disorders |
Pituitary apoplexy*** |
|||
| Eye disorders |
Dry eyes, blurred vision |
Visual disturbances |
||
| Ear and labyrinth disorders |
Vertigo |
|||
| Cardiac disorders |
Palpitations |
|||
| Vascular disorders |
Hot flushes |
Arterial hypertension |
||
| Respiratory, thoracic and mediastinal disorders |
Dyspnea, nosebleeds |
|||
| Gastrointestinal disorders |
Nausea, abdominal pain, abdominal discomfort |
Abdominal distension, dry mouth, flatulence, ulcerative stomatitis, vomiting |
Diarrhea |
|
| Skin and subcutaneous tissue disorders |
Acne, hyperhidrosis, seborrhea |
Alopecia, dry skin, hirsutism, onycholysis, pruritus, rash |
Angioedema, urticaria |
|
| Musculoskeletal and connective tissue disorders |
Arthralgia, muscle spasms, limb pain |
Back pain, myalgia |
Muscle weakness |
|
| Reproductive system and breast disorders |
Breast disorders, dyspareunia, genital haemorrhage (including vaginal haemorrhage, withdrawal bleeding), ovarian hyperstimulation syndrome, ovarian hypertrophy, pelvic pain, vulvovaginal dryness |
Breast pain |
Bleeding during intercourse, cystocele, menstrual irregularities (including dysmenorrhoea, metrorrhagia and menorrhagia), ovarian cyst, vaginal discharge |
Amenorrhoea |
| General disorders and administration site conditions |
Asthenia |
Injection site reactions (including pain, swelling, erythema and inflammation), peripheral oedema |
Fever, malaise |
|
| Investigations |
Weight increased |
Weight decreased |
Increased blood alkaline phosphatase, increased blood pressure |
* Long-term use: This frequency is based on the common adverse reaction profile shared by all GnRH agonists.
** Short-term use: This frequency is based on the common adverse reaction profile shared by all GnRH agonists.
*** Pituitary apoplexy has been reported after initial administration of the drug in patients with pituitary adenoma.
At the beginning of treatment, during the transient increase in blood estradiol levels, exacerbation of symptoms typical of endometriosis, such as pelvic pain and dysmenorrhea, occurs very commonly (≥ 10%). These symptoms are temporary in nature and usually resolve within 1–2 weeks.
Genital bleeding, including metrorrhagia and menorrhagia, may occur within one month after the first injection.
When treating infertility with gonadotropins, ovarian hyperstimulation syndrome may occur. Ovarian hypertrophy, dyspnea, pelvic pain, and/or abdominal pain may be observed.
Prolonged use of GnRH analogs may lead to loss of bone mass and is a risk factor for the development of osteoporosis.
Breast cancer
The most common adverse reactions observed during triptorelin therapy over a period of up to 5 years, in combination with either tamoxifen or an aromatase inhibitor in the TEXT and SOFT trials, were hot flushes, musculoskeletal disorders, fatigue, insomnia, hyperhidrosis, vulvovaginal dryness, and depression.
Adverse reactions reported during treatment with triptorelin in combination with tamoxifen (N=2325) or in combination with exemestane (N=2318) are presented in the following table and classified according to frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000).
| System organ class |
Very common |
Common |
Uncommon |
Rare |
| Immune system disorders |
Hypersensitivity |
|||
| Endocrine system disorders |
Diabetes mellitus (glucose intolerance), hyperglycaemia |
|||
| Psychiatric disorders |
Insomnia, decreased libido, depression |
|||
| Nervous system disorders |
Cerebral ischaemia, haemorrhage into the central nervous system |
|||
| Cardiac disorders |
Myocardial ischaemia |
QT interval prolongation |
||
| Vascular disorders |
Hot flushes, arterial hypertension |
Embolism |
||
| Gastrointestinal disorders |
Nausea |
|||
| Skin and subcutaneous tissue disorders |
Hyperhidrosis |
|||
| Musculoskeletal and connective tissue disorders |
Disorders of musculoskeletal system, osteoporosis |
Fracture |
||
| Renal and urinary disorders |
Urinary incontinence |
|||
| Reproductive system and breast disorders |
Dyspareunia, vulvovaginal dryness |
|||
| General disorders and administration site conditions |
Fatigue |
Injection site reactions |
The adverse reactions listed above should be considered in addition to the information on adverse reactions of triptorelin in men and women in the previous tables for a complete description of the adverse reaction profile when using a gonadal function suppressor in combination with either exemestane or tamoxifen.
Osteoporosis was observed at a higher frequency with triptorelin in combination with exemestane than with tamoxifen (39% compared to 25%) (see section "Particular patient populations").
Musculoskeletal disorders and fractures were also more frequently reported in patients receiving triptorelin in combination with exemestane than with tamoxifen (89% compared to 76%, and 6.8% compared to 5.2%, respectively).
Arterial hypertension has been reported as an expected adverse reaction occurring very commonly when triptorelin is used in combination with either exemestane or tamoxifen (23% and 22%, respectively).
Hyperglycaemia and diabetes mellitus occurred commonly as expected adverse reactions during treatment with triptorelin in combination with either exemestane or tamoxifen (hyperglycaemia: 2.6% and 3.4%, respectively; diabetes mellitus: 2.3% and 2.3%, respectively).
General tolerability in children (see section "Particular patient populations")
The frequency of occurrence of 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). The frequency of adverse reactions observed during the post-marketing period cannot be determined and therefore is listed as "unknown".
| Class / Organ System |
Very common |
Common |
Uncommon |
Frequency unknown |
| Immune system disorders |
Hypersensitivity |
Anaphylactic shock |
||
| Metabolism and nutrition disorders |
Obesity |
|||
| Psychiatric disorders |
Mood lability |
Affective lability, depression, nervousness |
||
| Nervous system disorders |
Headache |
Idiopathic intracranial hypertension (pseudotumor cerebri) (see section "Special warnings and precautions for use") |
||
| Eye disorders |
Blurred vision |
Visual disturbance |
||
| Vascular disorders |
Hot flushes |
Arterial hypertension |
||
| Respiratory, thoracic and mediastinal disorders |
Nasal haemorrhage |
|||
| Gastrointestinal disorders |
Abdominal pain |
Vomiting, constipation, nausea |
||
| Skin and subcutaneous tissue disorders |
Acne |
Pruritus, rash, urticaria |
Angioneurotic oedema |
|
| Musculoskeletal and connective tissue disorders |
Neck pain |
Myalgia |
||
| Reproductive system and breast disorders |
Vaginal bleeding (including vaginal haemorrhage), withdrawal bleeding, uterine haemorrhage, vaginal discharge, spotting |
Breast pain |
||
| General disorders and administration site conditions |
Injection site reactions (including injection site pain, irritation and inflammation at injection site) |
Malaise |
||
| Investigations |
Increased body weight |
Increased blood prolactin, increased blood pressure |
Reporting of Adverse Reactions
Reporting adverse reactions following the registration of a medicinal product is important. It enables continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through the national reporting system.
Shelf life. 3 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of the reach of children.
Incompatibilities.
The powder should be mixed with the solvent immediately before injection. Only the solvent supplied in the package should be used.
Packaging. 1 vial of powder together with 2 ml solvent (mannitol (E 421), water for injections) in an ampoule, a single-use syringe and two needles (in a blister pack), in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
IPSEN PHARMA BIOTECH.
Manufacturer's address and place of business.
Parc d'Activité du Plateau de Signes, Départementale Road No. 402, 83870 SIGNES, France.
Marketing Authorization Holder.
IPSEN PHARMA.
Address of the Marketing Authorization Holder.
65, Quai Georges Gorse, 92100 Boulogne-Billancourt, France.