Pharmacological properties
Pharmacodynamics. Triptorelin is a synthetic decapeptide, an analogue of natural gonadotropin-rg (releasing hormone). The data of the conducted studies have shown that after a short initial period of stimulation of the gonadotropic function of the pituitary gland, long-term use of triptorelin has an inhibitory effect on the secretion of gonadotropin with subsequent suppression of both female and male steroidogenesis.
Further studies suggest a different mechanism of action: a direct effect on the gonads by reducing the sensitivity of peripheral receptors to the influence of the factor responsible for the release of gonadotropin.
When using the drug, an initial increase in the level of LH and FSH in the blood and, accordingly, the level of testosterone in men and estradiol in women is possible. With prolonged treatment, the levels of LH and FSH decrease to an indicator corresponding to the state after surgical castration within 20 days after the first injection, which remains at this level throughout the entire period of use of the drug.
Pharmacokinetics
Diferelin 0.1 mg
After s / c administration of 0.1 mg of Diferelin is rapidly absorbed; time to reach C max of the drug in blood plasma - 0.63 ± 0.26 h; C max of the drug in blood plasma - 1.85 ± 0.23 ng / ml. T ½ biological - 7.6 ± 1.6 h after 3-4 h of the distribution phase. Total plasma clearance - 161 ± 28 ml / min. Conditional volume of distribution - 1,562 ± 158 ml / kg.
Diferelin 3.75 mg
It is a prolonged-release drug due to the microspherical structure of triptorelin deposition, which provides a clinically effective concentration for 28 days.
men
After intramuscular administration of the prolonged-release form of the drug, an initial stage of drug release occurs, followed by a normal release (Cmax - 0.32 ± 0.12 ng / ml), during which the average rate of triptorelin release is 46.6 ± 7.1 mg / day. Bioavailability after 1 month is 53%.
women
After i / m injection, the maximum level of triptorelin in the blood is noted between 2-6 hours after injection, C max - 11 ng / ml. There is no data on the accumulation of the drug after 6 months of use. C min in the blood varies between 0.1-0.2 ng / ml. The bioavailability of the drug in the prolonged release form is about 50%.
Diferelin 11.25 mg
After the / m administration of a dose of Diferelin 11.25 mg C max of triptorelin in plasma is recorded after approximately 3 hours. After the phase of decreasing concentration, which occurs during the 1st month, the level of circulating triptorelin remains constant for up to 90 days (about 0.03-0.06 ng / ml).
Indication
Diferelin 0.1 mg
Female infertility. Ovulation stimulation in combination with gonadotropins for the purpose of in vitro fertilization and embryo transfer (IVFET).
Diferelin 3.75 mg
Prostate cancer and its complications, in which suppression of testosterone secretion is indicated; genital and extragenital endometriosis: stages I-IV; endometrioid cysts; endometrial hyperplastic processes; female infertility; complex treatment in combination with gonadotropins, for artificial reproduction of ovulation conditions, for the purpose of in vitro fertilization and subsequent embryo transplantation; premature puberty in children (onset of the disease in girls under 8 years of age and in boys under 10 years of age); breast cancer, when hormone therapy is indicated; uterine fibroids.
Diferelin 11.25 mg
Prostate adenocarcinoma with metastases; breast cancer; genital and extragenital endometriosis; precocious puberty in children.
Application
Diferelin 0.1 mg
Used in combination with gonadotropins.
Subcutaneous injection once a day, starting from the 2nd day of the menstrual cycle (simultaneously with the start of ovarian stimulation) until the day preceding the planned ovulation induction, i.e. the average period of use is 10-12 days for each attempt.
Diferelin 3.75 mg
Prostate cancer and its complications: 1 intramuscular injection of Diferelin 3.75 mg prolonged-release every 4 weeks. The duration of administration of the drug is adjusted by the doctor individually for each patient.
Endometriosis, endometrioid cysts, endometrial hyperplastic processes: 1 intramuscular injection of Diferelin 3.75 mg every 4 weeks. Treatment should be started in the first 5 days of the menstrual cycle. The duration of treatment depends on the initial degree of endometriosis and the positive dynamics of clinical manifestations during treatment. The course of treatment is no more than 6 months. It is not recommended to start a second course of treatment with triptorelin or another analogue of gonadotropin-RG.
Female infertility: the usual therapeutic regimen is based on the use of 1 i.m. injection on day 2 of the cycle. The parallel use of gonadotropins should be started after pituitary desensitization is achieved (plasma estrogen level does not exceed 50 pg/ml), usually on day 15 after the Diferelin injection.
Uterine fibroids: treatment begins in the first 5 days of the menstrual cycle. Diferelin should be administered every 4 weeks. The duration of the treatment course is 3 months for patients preparing for surgery, and up to 6 months for patients who are not indicated for surgical treatment.
Breast cancer: 1 intramuscular injection of Diferelin 3.75 mg prolonged-release every 4 weeks. The duration of administration of the drug is adjusted by the doctor individually for each patient.
Precocious puberty: 1 IM injection at the rate of 50 mcg/kg body weight every 4 weeks.
Diferelin 11.25 mg
Endometriosis: 1 IM injection of 11.25 mg every 3 months. Treatment should be started in the first 5 days of the menstrual cycle. The treatment period depends on the initial degree of endometriosis and the presence of positive clinical dynamics during treatment. The course of treatment is no more than 6 months.
Breast cancer: 1 intramuscular injection of Diferelin 11.25 mg prolonged-release every 3 months. The duration of administration of the drug is adjusted by the doctor individually for each patient.
Precocious puberty: 1 intramuscular injection of 11.25 mg of Diferelin every 3 months.
WARNING! It is important that the injection of the prolonged-release drug is performed in compliance with all instructions. Each unsuccessful injection, after which the volume of the drug remaining in the syringe is greater than that specified in the instructions, should be recorded.
Contraindication
Hypersensitivity to the components of the drug; pregnancy and breastfeeding.
Side effects
Clinical trial data
Most adverse reactions reported during clinical trials are related to the pharmacological properties of the active substance and are the result of hypogonadotropic hypogonadism or, rarely, primary pituitary-gonadal stimulation caused by the drug.
General tolerability in adults. Hot flashes and sweating, which usually do not require discontinuation of therapy.
General tolerability in men. At the beginning of treatment, with an increase in plasma testosterone levels, there is an increase in urinary tract symptoms (dysuria and hematuria), increased bone pain of metastatic origin, and an exacerbation of symptoms associated with compression by spinal cord metastases (back pain, weakness, paresthesia of the upper extremities). These symptoms disappear after 1-2 weeks.
During treatment, the most frequently observed adverse reactions (decreased libido and impotence) are associated with a decrease in the level of testosterone in the blood plasma, which is a pharmacological effect of the active substance of the drug. A decrease in the volume of the testicles may also occur as a result of a decrease in the level of testosterone in the blood plasma.
Gynecomastia is occasionally possible.
General tolerability in women: At the beginning of treatment, symptoms associated with endometriosis (pelvic pain, dysmenorrhea) may increase during the initial and transient increase in plasma estradiol levels, which usually disappear within 1-2 weeks.
Genital bleeding (menorrhagia, metrorrhagia or spotting) may occur 1 month after the first injection.
In the treatment of infertility, the combination with gonadotropins may lead to ovarian hyperstimulation; ovarian hypertrophy, pelvic and/or abdominal pain are noted.
During treatment, sleep disturbances, headache, mood swings, vaginal dryness and diaphoresis, decreased libido associated with pituitary-ovarian blockade may occur. Cases of chest pain, muscle cramps, joint pain, weight gain, nausea, abdominal pain or discomfort, asthenia have been reported.
General tolerability in children. Cases of allergic reactions, headache, hot flashes have been reported. Initial ovarian stimulation may cause minor vaginal bleeding in girls. Occasionally, short-term pain, redness, and local inflammation at the injection site are noted.
According to post-marketing surveillance data
Adults: The following adverse reactions have been reported very rarely, classified by system organ class:
the body as a whole: fever, weakness, swelling.
Metabolic and nutritional disorders: anorexia.
Mental disorders: depression, personality changes.
CNS and peripheral nervous system: dizziness, paresthesia in men.
Organ of vision: blurred or impaired vision.
Cardiovascular system: increased blood pressure, tachycardia.
Respiratory system: shortness of breath.
Gastrointestinal tract: diarrhea, vomiting, constipation.
Skin: itching, urticaria, skin rash, angioedema, alopecia.
Musculoskeletal system: arthralgia, myalgia, muscle weakness, bone pain, risk of osteoporosis.
Reproductive system: after discontinuation of treatment, women may experience menstrual cycle disorders: amenorrhea, menorrhagia, or metrorrhagia.
Children. The following individual reactions have also been reported in children: allergic reactions such as urticaria, skin rash, angioedema, weight gain, hypertension, visual disturbances, discomfort, gastrointestinal pain and vomiting, nosebleeds, weakness, muscle pain, emotional lability, nervousness.
Special instructions
Diferelin 0.1 mg
It should be borne in mind that in some patients, especially with polycystic ovary syndrome, the use of Diferelin 0.1 mg in combination with gonadotropins may cause an increase in the number of mature follicles.
The ovarian response to the administration of Diferelin together with gonadotropins in equal doses may be individual for each patient, and even for the same patient in different cycles.
Warnings for use: Before starting treatment, it should be ensured that the patient is not pregnant.
Ovarian induction should be performed under strict medical supervision with regular biological and clinical monitoring: rapid determination of estrogens in blood plasma and ultrasound. If the ovarian response is excessive, it is recommended to stop the gonadotropin stimulation cycle.
In adults, long-term use of gonadotropin-RH analogues can lead to bone demineralization and is a risk factor for osteoporosis.
Patients receiving the drug may require adjustment of antihypertensive therapy. Before starting treatment with the drug, the absence of pregnancy should be confirmed.
Men. Prostate cancer: in some cases, an increase in clinical symptoms (e.g. bone pain) may occur. However, this effect is observed in a small number of patients and is usually transient. Such patients require medical supervision, especially in the presence of urinary tract obstruction and spinal cord metastases.
For the same reasons, patients with initial signs of medullary compression should also be monitored at the beginning of treatment.
During this period, a temporary increase in plasma phosphatase levels is possible.
Periodic monitoring of testosterone levels in the blood (1 ng/ml) is necessary.
Women. Female infertility: The drug should be used with caution in patients with polycystic ovary syndrome when undergoing an ovulation stimulation regimen. This is due to the fact that in a small number of patients the number of induced follicles may increase. The ovarian response to the same dose of triptorelin-gonadotropin may vary in different patients, and in some cases from one cycle to another in the same patient. It is necessary to carefully monitor the level of stimulation of the cycle during in vitro fertilization in order to identify patients at risk of developing ovarian hyperstimulation syndrome, since the degree and frequency of the syndrome may depend on the dosage regimen of gonadotropin. If ovarian hyperstimulation is suspected, it is recommended to cancel gonadotropin injections.
Endometriosis and uterine fibroids: the use of the drug Diferelin 3.75 mg causes persistent hypogonadotropic amenorrhea. The appearance of metrorrhagia after the end of the 1st month of treatment is an abnormal phenomenon and requires monitoring of the level of estradiol in the blood (50 pg / ml).
After discontinuation of treatment, ovarian function is restored and ovulation occurs on average on the 58th day after the last injection of the drug. The first menstruation occurs on the 70th day after the last injection. Thus, contraceptives can be prescribed on the 15th day after discontinuation of the drug, i.e. 1.5 months after the last injection.
Breast cancer: in patients with breast cancer, treatment with Diferelin 3.75 mg may be effective when other agents have failed or are less effective; if used as a first-line treatment, it does not reduce the effectiveness of other treatments if necessary.
Diferelin 11.25 mg
Mixing of the powder with the solvent should be carried out immediately before injection by shaking the vial with gentle movements to obtain a homogeneous milky suspension. The suspension should not be mixed with other drugs.
Prostate adenocarcinoma: periodic monitoring of testosterone levels in the blood (1 ng/ml) is required.
Endometriosis: Before starting treatment with the drug, the absence of pregnancy should be confirmed.
The use of the drug Diferelin 11.25 mg causes persistent hypogonadotropic amenorrhea. The appearance of metrorrhagia after the end of the 1st month of treatment is an abnormal phenomenon and requires monitoring of the level of estradiol in the blood (50 pg / ml).
After stopping treatment, ovarian function is restored and ovulation occurs on average on the 134th day after the last injection of the drug. Thus, contraceptives can be prescribed on the 15th day after drug withdrawal, i.e. 3.5 months after the last injection.
Use during pregnancy and breastfeeding. The use of the drug during pregnancy and breastfeeding is contraindicated.
Children. At the beginning of treatment, slight vaginal bleeding is possible in 1/3 of girls (after the first injection), indicating the need for additional therapy with medroxyprogesterone acetate (40 mg/day) or cyproterone acetate (40 mg/day), or cyproterone acetate (100 mg/day) during the 1st week of treatment.
The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Not detected. However, the ability to perform work requiring increased attention may be affected by dizziness or visual disturbances, which may be manifestations of a possible side effect or underlying disease.
Interactions
No clinically significant cases of interactions with other drugs have been reported.
The doctor decides on the possibility of simultaneous use of other medications.
Do not use simultaneously with drugs that increase prolactin levels, as they reduce the level of pituitary luteinizing hormone (LH) receptors.
Overdose
In case of overdose, side effects of the drug may occur.
Treatment is symptomatic.
Storage conditions
At a temperature not exceeding 25 °C.
