Diferelin powder for preparation of prolonged-release suspension 11.25 mg bottle solvent 2 ml ampoule syringe 2 needles No. 1

Instructions Diferelin powder for preparation of prolonged-release suspension 11.25 mg bottle solvent 2 ml ampoule syringe 2 needles No. 1

Composition

active ingredient: triptorelin;

1 vial contains triptorelin pamoate, equivalent to triptorelin 11.25 mg*;

excipients: D, L lactide coglycolide polymer, mannitol (E 421), carmellose sodium, polysorbate 80;

*taking into account the characteristics of the dosage form, each vial contains triptorelin pamoate in an amount corresponding to 15 mg of triptorelin

solvent composition:

1 ampoule contains mannitol (E 421), water for injections.

Dosage form

Powder and solvent for prolonged-release suspension for injection (intramuscular or subcutaneous).

Main physicochemical properties:

Powder: is a friable, slightly yellowish mass.

General characteristics of the reconstituted suspension: homogeneous suspension.

Solvent: colorless, clear solution.

Pharmacotherapeutic group

Gonadotropin-releasing hormone analogues.

ATX code L02A E04.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Triptorelin is a synthetic decapeptide similar to natural GnRH (gonadotropin-releasing hormone).

The results of preclinical and clinical studies have shown that after primary stimulation, prolonged use of triptorelin inhibits the secretion of gonadotropins with subsequent suppression of testicular and ovarian function.

At the beginning of treatment with Diferelin® (11.25 mg), the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the blood may increase with a corresponding increase (flare) in testosterone levels in men and estradiol in women. With continued treatment, LH and FSH levels decrease, which is accompanied by a decrease in testosterone and estradiol levels to post-castration values, which were reached within approximately 20 days after injection and were maintained as long as the active substance was released.

Clinical efficacy and safety

Prostate cancer

An open-label, uncontrolled, multicenter, phase III clinical trial of 6 months duration was conducted in 126 patients to evaluate the efficacy of subcutaneous administration of Diferelin® (11.25 mg) (one injection every 3 months). After 4 weeks, 97.6% of participants achieved castrate testosterone levels (<50 ng/dL) (95% confidence interval (CI) 93.2 - 99.5), which were maintained for 6 months in 96.6% of participants (95% CI 91.6 - 99.1) (co-primary endpoints). The probability of achieving castrate levels during the first month of treatment and maintaining this level at each control time point for 6 months was 96% (95% CI 0.92 - 0.99) (see Figure 1).

Figure 1. Kaplan-Meier plot of the probability of achieving testosterone levels < 50 ng/dL from day 29 to day 183 after subcutaneous drug administration

During treatment with triptorelin, mean prostate-specific antigen (PSA) levels decreased by 64.2% at month 1 and by 96% at month 6 (secondary endpoint). Mean PSA values remained within the normal range (0–4 ng/mL) from month 2 to the end of the study. Several randomized clinical trials in patients with locally advanced prostate cancer have shown a benefit of androgen deprivation therapy (ADT) in combination with radiotherapy (RT) compared with RT alone (RTOG 85-31, RTOG 86-10, EORTC 22863, D'Amico et al., Journal of the American Medical Association [JAMA], 2008).

A randomized phase III trial (EORTC 22961) in 970 patients with locally advanced prostate cancer (mainly stage T2c-T4, with some patients from T1C to T2B with pathological regional nodal involvement) compared the efficacy of radiotherapy in combination with short-term androgen deprivation therapy (6 months, n = 483) with radiotherapy in combination with long-term androgen deprivation therapy (3 years, n = 487). The GnRH agonists used were triptorelin (62.2%) or other GnRH agonists (37.8%). The study was not stratified by agonist type.

The overall mortality at 5 years was 19.0% in the short-term hormone therapy group and 15.2% in the long-term hormone therapy group, with a relative risk of 1.42 (two-sided confidence interval [CI] 95.71% = 1.79; 95.71% CI = 1.09–1.85, p = 0.65 for noninferiority and p = 0.0082 for retrospective assessment of the difference between groups in study outcomes).

Retrospective analysis in the triptorelin subgroup also showed an advantage of long-term treatment over short-term treatment in terms of all-cause mortality (relative risk 1.28; 95.71% CI = 0.89–1.84, p = 0.38 and p = 0.08, respectively, for retrospective analysis of non-inferiority 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 studies of radiotherapy in combination with GnRH analogues. Clinical data from five published studies were analysed (EORTC 22863, RTOG 85-31, RTOG 92-02, RTOG 86-10 and D'Amico et al., JAMA, 2008). All data demonstrated an advantage of combining GnRH analogue therapy with radiotherapy. The published studies do not allow a clear differentiation of the relevant study populations according to the indications - 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.

Endometriosis

Long-term treatment with the drug Diferelin® (11.25 mg) inhibits the secretion of estradiol and thus ensures the "quiet" of the ectopic endometrium in women.

Central precocious puberty

Suppression of pituitary gonadotropic hyperfunction in children of 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.

Pharmacokinetics.

When Diferelin® (11.25 mg) is administered intramuscularly to patients (males and females), peak plasma triptorelin concentrations are observed approximately 3 hours after injection. After a phase of decreasing concentration lasting for the first month, the level of triptorelin circulating in the blood remains constant until the end of the third month after injection.

In a study conducted with subcutaneous administration of this medicinal product in men, peak plasma triptorelin concentrations were reached rapidly after injection (median Tmax = 4.5 h), with triptorelin release being constant over 91 days. 3 months after subcutaneous administration, the residual triptorelin concentrations (Cmin) were 0.063 ng/ml.

Indication

Prostate cancer

Treatment of locally advanced or metastatic prostate cancer.

Treatment of high-risk localized or locally advanced prostate cancer, in combination with radiotherapy (see section "Pharmacodynamics").

The favorable outcome of treatment is more pronounced and observed more often if the patient has not previously received any other hormonal therapy.

Genital and extragenital endometriosis (stages I – IV).

Therapy should not be continued for longer than 6 months. Repeated courses of triptorelin or other gonadotropin-releasing hormone (GnRH) analogues are not recommended.

Central precocious puberty of central genesis in children (in girls under 8 years of age and in boys under 10 years of age).

Contraindication

Hypersensitivity to gonadotropin-releasing hormone (GnRH) or to any of the excipients. Pregnancy or breast-feeding.

Interaction with other medicinal products and other types of interactions

When using triptorelin together with drugs that modify the secretion of pituitary gonadotropic hormones, precautions must be taken and careful monitoring of hormonal levels is recommended.

Since androgen deprivation therapy may prolong the QT interval, the appropriateness of the concomitant use of triptorelin with drugs that can prolong the QT interval and with drugs that can induce torsades de pointes, such as class IA (quinidine, disopyramide) and class III (amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmics, methadone, moxifloxacin, antipsychotics, etc., should be carefully assessed (see section "Special warnings and precautions for use").

Application features

In rare cases, GnRH agonist therapy may reveal previously undetected pituitary gonadotropin-releasing adenomas. Such patients may develop 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. Accordingly, patients should be informed and provided with appropriate treatment if symptoms occur. Patients who are depressed should be closely monitored during therapy.

This medicinal product 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.

In men

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 to prevent an increase in 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 prescribing treatment to patients with prodromal signs of spinal cord compression.

After surgical castration, triptorelin does not lead to 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 patients with a history of QT prolongation or risk factors, or in patients receiving concomitant medications that may prolong the QT interval (see Interactions), physicians should consider the benefit-risk ratio, including the potential for torsades de pointes, before initiating treatment with Diferelin® 11.25 mg.

In addition, epidemiological data have suggested that patients may experience metabolic changes (e.g., impaired glucose tolerance, fatty liver) 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 starting treatment and should be monitored closely during antiandrogen therapy.

Due to prolonged androgen deprivation, treatment with GnRH analogues may increase the risk of anemia. This risk requires assessment in patients receiving treatment and appropriate monitoring.

The use of triptorelin in therapeutic doses interferes with the work 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 may be observed during the initial period of therapy.

The therapeutic effect of treatment should be regularly checked by measuring serum testosterone and prostate-specific antigen (PSA) levels.

In women

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 use triptorelin should be made on an individual basis and therapy should only be initiated if the benefit outweighs the risk after a careful assessment. Consideration should be given to additional measures to counteract the decrease in bone mineral density.

Endometriosis

The use of a GnRH agonist is not recommended in patients under the age of 18. Particular attention should be paid to adolescents and young women (especially under the age of 16), who may not have reached peak bone density.

It has been demonstrated that in patients receiving GnRH analogues for endometriosis, additional hormone replacement therapy (daily estrogen and progestogen) reduced bone mineral density loss and the severity of vasomotor symptoms (see section “Adverse reactions”).

The use of the drug Diferelin® (11.25 mg) causes permanent hypogonadotropic amenorrhea.

If genital bleeding occurs after the first month, it is necessary to analyze the level of estradiol in the blood plasma, and if the indicator is less than 50 pg/ml, it is necessary to conduct a study for possible organic damage.

Since menstruation should cease during treatment with triptorelin, the patient should be advised to inform her physician if her normal menstrual cycle resumes.

After cessation of therapy, ovarian function is restored and ovulation occurs approximately 5 months after the last injection.

During the course of therapy and for 3 months after the last injection, non-hormonal methods of contraception must be used.

Pediatric population

Central precocious puberty

Before prescribing triptorelin to girls, it is necessary to make sure that the patient is not pregnant,

Treatment of children with advanced brain tumors should be initiated after careful assessment of the risks and benefits of treatment.

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, hereditary Leydig cell hyperplasia).

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 future fertility is still limited. In most girls, the onset of regular menstruation is established on average one year after stopping therapy.

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 therapy. It is theorized that the low estrogen concentration during GnRH agonist therapy weakens the epiphyseal plate. Accelerated growth after discontinuation of therapy results in a reduction in the shear force required to displace the epiphysis.

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in pediatric patients treated with triptorelin. Patients should be warned about the signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, visual disturbances, and tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of triptorelin should be considered.

Use during pregnancy or breastfeeding

Pregnancy

Pregnancy must be excluded before prescribing the drug Diferelin® 11.25 mg.

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.

Breast-feeding

Triptorelin is contraindicated for use during breastfeeding.

Fertility

There is no clinical evidence of a causal relationship between the use of triptorelin and any subsequent abnormalities in oocyte development, pregnancy course or outcome.

The ability to influence the reaction speed when driving or working with other mechanisms

No studies have been conducted on the effect on reaction speed when driving vehicles or using other mechanisms.

However, the ability to drive and use machines may be impaired due to dizziness, drowsiness and visual disturbances, which are possible side effects of treatment or the result of the underlying disease.

Method of administration and doses

Dosage

Prostate cancer

One intramuscular or subcutaneous injection of Diferelin® (11.25 mg) every 3 months.

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 more acceptable than radiotherapy followed by short-term antiandrogen therapy (see section "Pharmacodynamics").

The duration of antiandrogen therapy recommended by treatment protocols for patients with high-risk localized or locally advanced prostate cancer undergoing radiotherapy is 2–3 years.

In 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 as an inhibitor of androgen biosynthesis or enzalutamide as an inhibitor of androgen receptor function is acceptable, GnRH agonist therapy should be continued.

Endometriosis

One intramuscular injection of the drug Diferelin® (11.25 mg) every 3 months.

Subcutaneous administration of the drug has not been studied in women.

Treatment should be started within the first five days of the menstrual cycle.

The duration of treatment depends on the initial severity of endometriosis and the reduction in clinical manifestations (functional and anatomical) during treatment. The course of treatment should not exceed 6 months (see section “Adverse reactions”). A second course of treatment with triptorelin or another GnRH analogue is not recommended. In patients receiving GnRH analogues for endometriosis, additional hormone replacement therapy (HRT), i.e. daily administration of oestrogen and progestogen, has been shown to reduce bone mineral density loss and the severity of vasomotor symptoms. Therefore, the use of additional HRT concomitantly with a GnRH analogue should be considered on a case-by-case basis and should only be initiated if the benefits outweigh the risks, based on a careful assessment.

Central precocious puberty:

Treatment of children with triptorelin should be carried out under the close supervision of a pediatric endocrinologist, pediatrician, or endocrinologist with experience in the treatment of central precocious puberty.

Children weighing more than 20 kg: one intramuscular injection of the drug Diferelin® (11.25 mg) every 3 months.

Treatment should be discontinued when boys and girls reach physiological puberty and is not recommended for girls older than 12-13 years of age with bone maturation. Limited data are available for boys. Regarding the optimal time to discontinue treatment based on bone age, it has been reported that treatment should be discontinued in boys with bone maturation at 13-14 years of age.

The drug Diferelin® (11.25 mg) should not be administered intravascularly. Subcutaneous administration of the drug in children has not been studied.

Method of application

See above in the "Dosage" section.

The powder should be suspended in the supplied solvent immediately before injection by gently rocking the vial from side to side until a homogeneous milky suspension is obtained. For single use only.

Instructions for reconstituting the drug Diferelin® (11.25 mg) for use are provided in the "Instructions for Use" section.

WARNING! It is important that the injection of the extended-release drug is performed in accordance with all recommendations given in the instructions for medical use. Each unsuccessful injection, after which more drug remains in the syringe than specified in the instructions, must be recorded.

The following information is intended for healthcare professionals only.

Children

The drug is used to treat central precocious puberty in children (in girls under 8 years of age and in boys under 10 years of age).

Overdose

In case of overdose, symptomatic treatment is prescribed.

Side effects

Because patients with locally advanced or metastatic hormone-dependent prostate cancer are usually elderly and have comorbidities common in this age group, adverse events were observed in more than 90% of patients in clinical trials and it was often difficult to assess causality. Based on data from treatment with other GnRH agonists or after surgical castration, the most frequently observed adverse reactions associated with triptorelin therapy were due to the expected pharmacological action. These effects included hot flushes and decreased libido. With the exception of immunoallergic reactions (rare) and injection site reactions (< 5%), all adverse reactions are known to be related to changes in testosterone levels.

The following adverse reactions have been reported and are considered at least possibly related to triptorelin therapy. The majority of these events have been attributed to biochemical or surgical castration.

The frequency of adverse reactions is classified as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000). The frequency of adverse reactions that have been reported in the post-marketing period cannot be determined, therefore they are reported as "frequency unknown".

* This frequency is based on the frequency of class effects common to all GnRH agonists.

Triptorelin causes a temporary increase in circulating testosterone levels during the first week after the first injection of the sustained-release formulation. During the initial increase in circulating testosterone levels, some patients (≤ 5%) may experience an increase in symptoms of their existing prostate cancer (a "flare"), usually manifested by urinary symptoms (< 2%) and metastatic pain (5%), which are treated symptomatically. The symptoms are transient and usually resolve within 1 to 2 weeks.

Isolated cases of exacerbation of symptoms, urethral obstruction or spinal compression due to metastasis have been reported. Therefore, patients with metastatic spinal involvement and/or upper or lower urinary tract obstruction should be closely monitored during the first few weeks of therapy (see section 4.4).

The use of GnRH agonists in the treatment of prostate cancer increases the risk of bone loss and can lead to osteoporosis, and also increases the risk of bone fracture.

An increase in lymphocyte count has been reported in patients treated with GnRH analogues. This secondary lymphocytosis is apparently related to GnRH-induced castration and suggests the involvement of gonadal hormones in thymic involution.

Patients receiving long-term GnRH analogue therapy in combination with radiotherapy may experience an increased number of side effects, particularly gastrointestinal, associated with the use of radiotherapy.

General tolerability in women (see section "Special instructions")

As a consequence of the decrease in estrogen levels, the most common side 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 flashes, and asthenia.

The following adverse reactions have been reported and are considered at least possibly related to triptorelin therapy. Most of them are known to be associated with biochemical or surgical castration. The frequency of adverse reactions is classified as follows: very common (≥1/10); common (≥1/100, <1/10). The frequency of adverse reactions reported during post-marketing experience cannot be estimated and are therefore reported as "frequency not known".

Organ system class	Very often	Often	Infrequently	Frequency unknown
On the part of the immune system		Hypersensitivity		Anaphylactic shock
Metabolism and nutritional disorders			Decreased appetite, fluid retention
From the psyche	Sleep disorders (including insomnia), mood changes, decreased libido	Depression*, nervousness	Affective lability, anxiety, depression**, disorientation	Confusion of consciousness
From the nervous system	Headache	Dizziness	Dysgeusia, hypoaesthesia, syncope, memory impairment, disturbance in attention, paraesthesia, tremor
From the organs of vision			Dry eyes, blurred vision	Vision impairment
From the endocrine system				Bloodstroke pituitary gland***
Hearing and balance disorders			Vertigo
From the heart			Feeling of heart palpitations
From the vascular side	Hot flashes			Arterial hypertension
Respiratory, thoracic and mediastinal disorders			Dyspnea, epistaxis
Gastrointestinal tract		Nausea, abdominal pain, abdominal discomfort	Abdominal bloating, 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, pain in extremities	Back pain, mia Specifications Characteristics Active ingredient Triptorelin Adults Can ATC code L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS; L02 AGENTS USED FOR HORMONE THERAPY; L02A HORMONES AND RELATED SUBSTANCES; L02A E Gonadotropin-releasing hormone analogues; L02A E04 Triptorelin Country of manufacture France Diabetics Can Dosage 11,25 мг Drivers With caution For allergies With caution For children Can Form Vials with dry contents Method of application Injections Nursing It is impossible. Pregnant It is impossible. Producer IPSEN PHARMA Quantity per package 1 bottle Trade name Diferelin Vacation conditions By prescription Reviews There are no reviews for this product. + Add review Write a review Diferelin powder for preparation of prolonged-release suspension 11.25 mg bottle solvent 2 ml ampoule syringe 2 needles No. 1 My mark: Continue There are no reviews for this product, be the first to leave your review. Answers & questions Add your question and we will answer as soon as possible. + Ask a question Ask a question Add your question and we will answer as soon as possible. * Your question Continue No questions about this product, be the first and ask your question. You are watched new Hit Sold out Hygienic lipstick Home Doctor cranberry and lingonberry 3.6 g Распродано 0 41.90 грн.