Diphereline 3.75 storage conditions. Dipherelin - instructions for use. Side effects of Dipherelin

A drug Diphereline 11.25- antineoplastic agent, gonadotropin - hormone-releasing analogue.
Triptorelin is a synthetic decapeptide analogous to the natural gonadotropin-releasing hormone (GnRH).
After a short initial period of stimulation of the gonadotropic function of the pituitary gland, triptorelin has an inhibitory effect on the secretion of gonadotropins, followed by suppression of the function of the testicles and ovaries.
In the initial period of application, Diphereline 11.25 mg temporarily increases the concentration of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the blood, respectively, the concentration of testosterone in men and estradiol in women increases. Long-term treatment reduces the concentration of LH and FSH, which leads to a decrease in testosterone levels (to levels corresponding to the state after testiculectomy) and a decrease in estradiol indicators (to levels corresponding to the state of postovariectomy) - by about 20 days after the first injection and then remains unchanged throughout period of drug administration.
Long-term treatment with triptorelin suppresses the secretion of estradiol in women and, thus, prevents the development of endometrioid ectopias.
Pharmacokinetics:
With the intramuscular injection of Dipherelin at a dose of 11.25 mg, the maximum concentration of triptorelin in the blood plasma (in men and women) is determined approximately 3 hours after injection. After a phase of decrease in concentration, lasting during the first month, until day 90, the concentration of circulating triptorelin remains constant (about 0.04 to 0.05 ng / ml in the treatment of endometriosis and about 0.1 ng / ml in the treatment of prostate cancer).

Indications for use

A drug Diphereline 11.25 It is used to treat metastatic prostate cancer, genital and extragenital endometriosis (stages I - IV).

Mode of application

Prostate cancer: Diphereline 11.25 injected intramuscularly at a dose of 11.25 mg every 3 months.
Endometriosis: Diphereline is injected intramuscularly at a dose of 11.25 mg every 3 months.
Treatment should be started in the first five days of the menstrual cycle.
The duration of treatment depends on the severity of endometriosis and the observed clinical picture (functional and anatomical changes) during therapy.
As a rule, treatment is carried out for 3 to 6 months. Repeated treatment with triptorelin or GnRH is not recommended.
Suspension preparation rules:
The dissolution of the lyophilisate in the supplied solvent should be carried out immediately prior to administration. Stir the contents of the vial with caution until a homogeneous suspension is obtained.
Cases of incomplete injection, leading to the loss of more suspension than usually remains in the injection syringe, must be reported to the attending physician.
The introduction should be carried out in strict accordance with the instructions. The patient should be in the supine position. Disinfect the skin of your buttocks.
1. Break the neck of the ampoule (dot on the front side at the top).
2. Draw all of the solvent into the syringe and needle.
3. Remove the protective plastic cap from the top of the bottle.
4. Transfer the solvent to the lyophilisate vial
5. Pull the needle so that it remains in the vial, but does not touch the suspension.
6. Without turning the bottle, gently shake the contents until a homogeneous suspension is obtained.
7. Check the absence of agglomerates before drawing the suspension into the syringe (if there are agglomerates, shake until completely homogeneous).
8. Without turning the bottle over, draw the entire suspension into the syringe.
9. Remove the suspension needle and firmly attach the other needle to the tip of the syringe. Only hold on to the colored tip.
10. Remove air from the syringe.
11. Immediately inject into the gluteus muscle.
12. Dispose of needles in sharps containers.

Side effects

In men, at the beginning of treatment - Dysuric disorders (difficulty urinating, incomplete emptying Bladder, soreness), bone pain associated with metastases and compression by metastases of the spinal cord, which can be aggravated by a temporary increase in testosterone levels in the blood plasma at the beginning of treatment. These symptoms disappear in 1 to 2 weeks. Also during this period, there may be a temporary increase in the activity of liver enzymes in the blood plasma.
During treatment: hot flushes, decreased libido, gynecomastia, impotence, which is associated with a decrease in testosterone levels in the blood plasma.
In women, at the beginning of treatment. Symptoms associated with endometriosis (pelvic pain, dysmenorrhea), which may increase due to an initial transient increase in plasma estradiol concentration and disappear after 1 to 2 weeks.
One month after the first injection, metrorrhagia may occur.
During treatment.
Vaginal dryness, hot flashes, decreased libido, enlarged mammary glands, dyspareunia, which is associated with pituitary-ovarian blockade.
Rarely - headache, arthralgia, myalgia.
In men and women. Allergic reactions such as hives, rash, itching, and very rarely - Quincke's edema; mood disturbances, irritability, depression, fatigue, sleep disturbances, nausea, vomiting, weight gain, profuse sweat, hypertension, paresthesias, blurred vision, pain at the injection site and fever.
Long-term use of GnRH analogues can lead to bone demineralization and is a possible risk factor for osteoporosis.

Contraindications

:
Hypersensitivity to Diphereline, its components or other analogs of gonadotropin-releasing hormone.
In men, hormone-independent prostate cancer, a condition after a previous surgical testiculectomy.
In women - pregnancy, lactation and breastfeeding.
Use with caution in patients with osteoporosis, in women with polycystic ovary syndrome.

Pregnancy

:
It is contraindicated to use the drug Diphereline 11.25.
According to the available data, no teratogenic effects were found in animal studies. In isolated cases of the use of GnRH analogues (by negligence), no defects in fetal development and fetotoxicity were found.
Since there is no data on the penetration of the drug into breast milk and its possible effects on the breastfed baby should not be treated while breastfeeding.

Interaction with other medicinal products

Not described.

Overdose

:
Drug overdose cases Diphereline 11.25 are not known.

Storage conditions

At a temperature not exceeding 25 ° C, out of the reach of children.

Release form

Diphereline 11.25 - lyophilisate for the preparation of a suspension for intramuscular administration of prolonged action of 11.25 mg.
11.25 mg of triptorelin in a slightly darkened glass vial, sealed with a rubber stopper under an aluminum rim with a hole for a needle in the center and closed with a protective plastic cover for the first opening control.
2 ml of solvent in an ampoule.
One empty sterile disposable polypropylene syringe with a capacity of 3 ml, two hypodermic disposable needles measuring 0.90 x 40 mm with yellow tips in a PVC and laminated paper blister pack.
One bottle with the drug, one ampoule with a solvent, one blister pack with a syringe and two needles is placed in a cardboard box along with instructions for use.

Composition

:
Diphereline 11.25(1 bottle) contains: active ingredient: triptorelin pamoate, in terms of triptorelin 11.25 * mg.
Auxiliary components: copolymer of DL-lactic and glycolic acids 250.0 mg, mannitol 85.0 mg, sodium carmellose (sodium carboxymethyl cellulose) 30.0 mg, polysorbate-80 2.0 mg, solvent (1 ampoule), mannitol 16.0 mg, water for injection up to 2000.0 mg.
* Taking into account the characteristics of the dosage form, the preparation contains an excess active ingredient to ensure the administration of an effective dose.

Additionally

:
When treating endometriosis:
Pregnancy must be ruled out before starting treatment.
During the first month of therapy, non-hormonal contraceptives should be used. Intramuscular injection of the drug leads to persistent hypogonadotropic amenorrhea. Treatment should not be recommended for a period longer than 6 months. It is not recommended to repeat the course of therapy with triptorelin or another GnRH analog.
The occurrence of metrorrhagia during treatment, apart from the first month, is not the norm, and therefore it is necessary to determine the concentration of plasma estradiol. With a decrease in the concentration of estradiol less than 50 pg / ml, the presence of other organic lesions is possible.
Ovarian function is restored after completion of therapy. The first period occurs on average 134 days after the last injection. For this reason, contraceptive use should be started 15 days after discontinuation of treatment, that is, 3.5 months after the last injection.
When treating prostate cancer:
The most pronounced beneficial effect is observed in patients in the absence of other previous hormone therapy.
At the beginning of treatment, there may be the appearance and intensification of clinical symptoms (in particular, bone pain, dysuric disorders), which are of a transient nature.
This implies careful observation of these patients during the first few weeks of therapy (the level of testosterone in the blood plasma should not exceed 1 ng / ml).
Treatment with Dipherelin must be carried out in strict accordance with the instructions for use. Any change in the volume of the suspension administered intramuscularly should be recorded.

main parameters

Name:	DIFERELIN 11.25
ATX code:	L02AE04 -

One bottle contains triptorelin acetate ... It acts as an auxiliary substance. The solvent contains sodium chloride and water.

• Lyophilisate for manufacturing solution for subcutaneous administration- 1 vial Triptorelin (triptorelin acetate) - 0.1 mg... Mannitol 10 mg 1 ampoule of solvent - water for injection, sodium chloride.
• Lyophilisate for suspensions for intramuscular administration 3.75 mg... Auxiliary substances: sodium carmellose, copolymer of glycolic and DL-lactic acids, polysorbate-80, mannitol . 1 ampoule of solvent - water for injection, mannitol. Taking into account the peculiarities of this dosage form, the active ingredient is contained in the preparation in excess. The goal is to ensure that the optimal dose is administered.
• Lyophilisate for cooking suspensions for intramuscular administration prolonged action - 1 fl. Triptorelin (triptorelin acetate) - 11.25 mg... Auxiliary substances: sodium carmellose, copolymer of glycolic and DL-lactic acids, polysorbate-80, mannitol. 1 ampoule of solvent - water for injection, mannitol. Taking into account the peculiarities of this dosage form, the active ingredient is contained in the preparation in excess. The goal is to ensure that the optimal dose is administered.

Release form

Diphereline - 0.1 mg

Available in bottles. The kit includes ampoules with solvent. In a blister contour packaging there are 7 sets. There is one package in a cardboard box. Introduced p / c.

Diphereline - 3.75 mg

Diphereline - 11.25 mg

Available in bottles. The kit includes ampoules with a solvent, a syringe, two needles. There is one set in a cardboard box. Introduced in / m.

pharmachologic effect

Hormone analog drug gonadotropin-releasing hormone.

Pharmacodynamics and pharmacokinetics

Is an decapeptide synthetic , analogue of natural gonadotropin-releasing hormone which releases gonadotropin ... The drug is rapidly absorbed after administration. When administered intramuscularly, the active substance is quickly released.

Indications for use

Diphereline 0.1 mg

Rarely: increased blood pressure, nausea, vomiting, emotional lability, weight gain, visual impairment, pain in the area of ​​drug administration.

Very rare: joint and muscle pain, headache.

Additionally, Diphereline 3.75 mg

With prolonged use, it is possible that hypogonadotropic amenorrhea .

After the end of treatment, ovarian function is restored. Ovulation occurs approximately on the 58th day after the last injection. The first menstruation is on the 70th day. Important for contraception planning.

Additionally, Diphereline 11.25 mg

Men: at the beginning of admission possible dysuric disorders , bone pain. Symptoms resolve within one to two weeks.

During treatment: decreased libido, impotence , gynecomastia , flushes of blood to the face.

Women: at the beginning of taking the drug, pelvic pain is possible. Disappear within one to two weeks.

Possible occurrence metrorrhagia one month after the start of the injections.

Men and women: tiredness, , disturbed mood, irritability, sleep disturbance, blurred vision, paresthesias , profuse sweat, weight gain.

Instructions for Diphereline (Method and dosage)

Instructions on Diphereline 0.1 mg contains a short and long protocol. The drug is administered subcutaneously.

Short protocol: Taking the drug starts from the second day of the cycle. In this case, stimulation of the ovaries is carried out simultaneously. The treatment is completed one day before the introduction gonadotropin ... The general course of treatment is 10-12 days.

Long protocol on Diphereline: The drug is started on the second day of the cycle. Introduced daily. Approximately on the 15th day of taking the drug, stimulation with gonadotropins is carried out in parallel. The duration of treatment is individual and is adjusted by the doctor.

Preparation of the solution: Before the introduction of the drug, the solvent is introduced into the vial with the lyophilisate. Dissolve completely.

Diphereline 3.75. V / m... In case of illness prostate cancer - injected in the appropriate dose - 3.75 mg for a long time every 4 weeks. At premature puberty - 3.75 mg is administered every 28 days. In case of illness endometriosis Differelin depot drug is administered in the first five days of the cycle every month. At female infertility the drug is administered on the second day of the cycle.

Diphereline 11.25 injected in a volume of 11.25 mg every three months.

Preparation of the solution: Immediately before the administration of the drug, the solvent is introduced into the vial with the lyophilisate. Dissolve completely by gently shaking the contents of the bottle.

Overdose

So far, no information has been received about overdoses.

Interaction

Interactions are not described.

Terms of sale

On prescription.

Storage conditions

At temperatures up to 25 ° C, out of the reach of children.

Shelf life

Diphereline and alcohol

When taking any drug, it is not advisable to use alcohol ... When combined, it is possible to reduce the effect of treatment. When it comes to female infertility , then in this case it is forbidden to combine the drug with alcohol.

A drug Diphereline 3.75- antineoplastic agent, gonadotropin - hormone-releasing analogue.
Triptorelin is a synthetic decapeptide analogous to the natural gonadotropin-releasing hormone (releasing gonadotropin). After a short initial period of stimulation of the gonadotropic function of the pituitary gland, triptorelin suppresses the secretion of gonadotropins and, accordingly, the function of the testicles and ovaries. Continuous use of the drug inhibits the secretion of estrogen by the ovaries until menopause, and also reduces the secretion of testosterone, the concentration of which can reach the levels that are observed after surgical castration.
Pharmacokinetics:
After intramuscular administration of a prolonged form of the drug, the initial stage of rapid release of the drug occurs, followed by a phase of constant release of triptorelin (the maximum concentration is 0.32 ± 0.12 ng / ml). The average amount of persistently released triptorelin is 46.6 ± 7.1 μg / day.
The bioavailability of the drug is about 53% in 1 month.

Indications for use

A drug Diphereline 3.75 used in the treatment of prostate cancer; premature puberty; genital and extragenital endometriosis; fibroids of the uterus (before surgery); female infertility (in the in vitro fertilization program).

Mode of application

A drug Diphereline 3.75 injected only intramuscularly.
Prostate cancer:
Diphereline is administered at a dose of 3.75 mg every 4 weeks for a long time.
Premature puberty:
3.75 mg every 28 days (children weighing more than 20 kg),
1.875 mg every 28 days (children weighing less than 20 kg).
Endometriosis:
The drug should be administered in the first 5 days of the menstrual cycle - at a dose of 3.75 mg every 4 weeks. The duration of therapy is no more than 6 months.
Female infertility:
Diphereline should be administered on the second day of the cycle at a dose of 3.75 mg. The connection with gonadotropins should be monitored after desensitization of the pituitary gland (the concentration of estrogen in the blood plasma less than 50 pg / ml is usually determined 15 days after the injection of Dipherelin).
Fibroids of the uterus:
The drug must be administered in the first 5 days of the menstrual cycle. The introduction of Dipherelin should be carried out every 4 weeks at a dose of 3.75 mg.
Duration of treatment: 3 months (for patients preparing for surgery).
Suspension preparation:
The dissolution of the lyophilisate in the supplied solvent should be carried out immediately prior to administration. Stir the contents of the vial with caution until a homogeneous suspension is obtained.
Cases of incomplete injection, leading to the loss of more suspension than usually remains in the injection syringe, must be reported to the attending physician.
The introduction should be carried out in strict accordance with the instructions. The patient should be in the supine position. Disinfect the skin of your buttocks.
1. Break the neck of the ampoule (dot on the front side at the top).
2. Draw all of the solvent into the syringe and needle.
3. Remove the protective plastic cap from the top of the bottle.
4. Transfer the solvent to the lyophilisate vial
5. Pull the needle so that it remains in the vial, but does not touch the suspension.
6. Without turning the bottle, gently shake the contents until a homogeneous suspension is obtained.
7. Check the absence of agglomerates before drawing the suspension into the syringe (if there are agglomerates, shake until completely homogeneous).
8. Without turning the bottle over, draw the entire suspension into the syringe.
9. Remove the suspension needle and firmly attach the other needle to the tip of the syringe. Only hold on to the colored tip.
10. Remove air from the syringe.
11. Immediately inject into the gluteus muscle.
12. Dispose of needles in sharps containers.

Side effects

Allergic reactions such as hives, rash, itching, and very rarely Quincke's edema.
Several cases of nausea, vomiting, weight gain, arterial hypertension, increased emotional lability, visual impairment, pain at the injection site and fever, sensations of “hot flashes” have been described.
Long-term use of gonadotropin-releasing hormone analogs can lead to bone demineralization and is a possible risk factor for osteoporosis.
In men, a decrease in potency. At the beginning of treatment, patients with prostate cancer may experience a temporary increase in pain in the bones affected by metastases (symptomatic treatment). There have been isolated cases of ureteral obstruction and symptoms associated with compression by metastases of the spinal cord (disappear after 1-2 weeks). Also during this period, there may be a temporary increase in the activity of acid phosphatase in the blood plasma.
In women, headache, depression, sweating and changes in libido, dryness of the vaginal mucosa, dyspareunia, and changes in the size of the mammary glands.
When using Dipherelin in combination with gonadotropins, cases of ovarian hyperstimulation syndrome have been reported.
When treating premature puberty, girls may experience bloody issues from the vagina.
Long-term use of the drug can cause hypogonadotropic amenorrhea. After stopping treatment, ovarian function is restored and ovulation occurs on average 58 days after the last injection of the drug. The first menstruation occurs 70 days after the last injection of Dipherelin. This must be taken into account when planning contraception.

Contraindications

:
Hypersensitivity to Diphereline or other analogs of gonadotropin - hormone releasing, pregnancy and lactation.
With caution: with osteoporosis.

Pregnancy

:
The drug is contraindicated. Diphereline 3.75 for use during pregnancy and during breastfeeding.

Interaction with other medicinal products

Not described.

Overdose

:
Drug overdose cases Diphereline 3.75 are not known.

Storage conditions

At a temperature not exceeding 25 ° C, out of the reach of children.

Release form

Diphereline 3.75 - lyophilisate for the preparation of a suspension for intramuscular administration of prolonged action 3.75 mg.
3.75 mg of triptorelin in a slightly darkened glass vial, sealed with a rubber stopper under an aluminum rim with a hole for a needle in the center and closed with a protective plastic cover for the first opening control.
2 ml of solvent in a colorless glass ampoule.
One empty sterile disposable polypropylene syringe with a capacity of 3 ml, two hypodermic disposable needles measuring 0.90 x 40 mm with yellow tips in a PVC and laminated paper blister pack.
One bottle with the drug, one ampoule with a solvent, one blister pack with a syringe and two needles is placed in a cardboard box along with instructions for use.

Composition

:
Diphereline 3.75(1 bottle) contains: active ingredient: triptorelin acetate, calculated as triptorelin 3.75 * mg.
Auxiliary components: copolymer of DL-lactic and glycolic acids about 160.0 mg **, mannitol 85.0 mg, carmellose sodium 30.0 mg, polysorbate-80 2.0 mg, solvent (1 ampoule), mannitol 16.0 mg , water for injection up to 2000.0 mg.
* Taking into account the characteristics of the dosage form, the preparation contains an excess of the active component to ensure the administration of an effective dose.
** The amount depends on the level of encapsulation.

Additionally

:
At the beginning of treatment, there may be an increase in clinical symptoms, and therefore Dipherelin should be prescribed with caution in patients with prostate cancer who are at risk of developing ureteral obstruction or spinal cord compression. Careful observation of these patients is necessary during the first month of therapy.
Before starting therapy with Dipherelin, it is necessary to confirm the absence of pregnancy.
Use with caution in patients with polycystic ovary syndrome when performing ovulation stimulation schemes. This is due to the fact that in a small number of patients, the number of induced follicles may increase.
It is necessary to carefully monitor the level of cycle stimulation during in vitro fertilization in order to identify patients at risk of developing ovarian hyperstimulation syndrome, since the severity and frequency of manifestations of the syndrome may depend on the gonadotropin dosage regimen. If necessary, the introduction of human chorionic gonadotropin should be discontinued.

main parameters

Name:	DIFERELIN 3.75
ATX code:	L02AE04 -

Composition and form of release

Lyophilisate for the preparation of a solution for subcutaneous administration - 1 vial:

• active substances: triptorelin acetate (in terms of triptorelin) - 0.1 mg;
• excipients: mannitol - 10.0 mg;
• solvent composition (1 ampoule): sodium chloride; water for injections.

In vials (complete with solvent); 7 sets in a contoured cell package; in a pack of cardboard 1 packing.

• active substances: triptorelin acetate (in terms of triptorelin) - 3.75 * mg;

Lyophilisate for the preparation of a suspension for intramuscular administration of prolonged action - 1 vial:

• active substances: triptorelin pamoate (in terms of triptorelin) - 11.25 * mg;
• excipients: copolymer of DL-lactic and glycolic acids; mannitol; carmellose sodium; polysorbate-80;
• solvent composition (1 ampoule): mannitol; water for injections.

* Taking into account the characteristics of the dosage form, the preparation contains an excess of the active component to ensure the administration of an effective dose.

In vials (complete with solvent in ampoules, syringe and two needles) in a cardboard box 1 set.

Description of the dosage form

Diphereline® 0.1 mg: an almost white lyophilisate dispersed in the supplied solvent to form a clear solution practically free of particles.

Dipherelin® 3.75 mg: lyophilisate of white or white with a creamy shade, dispersed in the supplied solvent to form a suspension of white or white with a creamy shade.

Diphereline® 11.25 mg: a white or slightly yellowish lyophilisate, which is dispersed in the supplied solvent to form a white or slightly yellowish suspension.

The supplied solvent is a clear, colorless solution.

pharmachologic effect

Antigonadotropic.

Pharmacokinetics

Dipherelin® 0.1 mg

After subcutaneous injection into healthy adult volunteers at a dose of 0.1 mg, triptorelin is rapidly absorbed (time to reach Cmax - (0.63 ± 0.26) h with a peak plasma concentration of (1.85 ± 0.23) ng / ml).

T1 / 2 is (7.6 ± 1.6) hours, after 3-4 hours the distribution phase ends.

The total plasma clearance is (161 ± 28) ml / min.

The volume of distribution is (1562 ± 158) ml / kg.

Diphereline® 3.75 mg

After intramuscular administration of a prolonged form of the drug, the initial stage of rapid release of the drug occurs, followed by a phase of constant release of triptorelin. Cmax is (0.32 ± 0.12) ng / ml.

The average amount of continuously released triptorelin is (46.6 ± 7.1) μg / day.

The bioavailability of the drug is about 53% in 1 month.

Dipherelin® 11.25 mg

With intramuscular injection of Dipherelin® at a dose of 11.25 mg, Cmax of triptorelin in blood plasma (in men and women) is determined approximately 3 hours after injection. After a phase of decrease in concentration, lasting during the first month, until the 90th day, the concentration of circulating triptorelin remains constant (about 0.04-0.05 ng / ml - in the treatment of endometriosis and about 0.1 ng / ml - in the treatment of prostate cancer ).

Pharmacodynamics

Triptorelin is a synthetic decapeptide analogous to the natural gonadotropin-releasing hormone that releases gonadotropin.

Dipherelin® 0.1 mg

Animal studies and clinical studies have shown that after the initial period of stimulation, prolonged use of Dipherelin® 0.1 mg suppresses the secretion of gonadotropins, followed by suppression of ovarian function.

Constant use of Dipherelin® 0.1 mg inhibits the secretion of gonadotropins (FSH and LH). Suppression of intermediate endogenous peaks of LH allows you to improve the quality of folliculogenesis, increasing the number of maturing follicles, and, as a consequence, increase the likelihood of pregnancy per cycle.

Diphereline® 3.75 mg

After a short initial period of stimulation of the gonadotropic function of the pituitary gland, triptorelin suppresses the secretion of gonadotropins and, accordingly, the function of the testicles and ovaries. Continuous use of the drug inhibits the secretion of estrogen by the ovaries until menopause, and also reduces the secretion of testosterone, the concentration of which can reach levels that are observed after surgical castration.

iferelin® 11.25 mg

In the initial period of application, Dipherelin® 11.25 mg temporarily increases the concentration of LH and FSH in the blood, respectively, the concentration of testosterone in men and estradiol in women increases. Long-term treatment reduces the concentration of LH and FSH, which leads to a decrease in testosterone (to levels corresponding to the state after testiculectomy) and estradiol (to levels corresponding to the state of postovariectomy) by about the 20th day after the first injection and then remain unchanged throughout the entire period drug administration.

Long-term treatment with triptorelin suppresses the secretion of estradiol in women and, thus, prevents the development of endometrioid ectopias.

Instructions

Dipherelin® 3.75 mg. V / m. Suspension preparation rules

1. Treat the injection site with a napkin with alcohol. Remove the cap from the pink tip needle and attach it to the syringe. Draw up all the solvent from the ampoule into the syringe.
2. Gently shake the contents until a homogeneous suspension is obtained, without turning the bottle over.
3. Without turning the bottle over, draw the entire suspension into the syringe.
4. Remove the pink needle from the syringe. Attach a green needle to the syringe (screw tight), taking only the colored tip.
5. Remove air from the syringe.
6. Inject immediately. The injection should be administered intramuscularly only.

• push the guard towards the tip of the needle. Close the needle and snap the device;
• turn the syringe over. Using a flat surface, press down on the device and close the needle.

Use the colored attachment to detach the needle. Dispose of needles in sharps containers.

Dipherelin® 11.25 mg. V / m Suspension preparation rules

The dissolution of the lyophilisate in the supplied solvent should be carried out immediately prior to administration. Stir the contents of the vial with caution until a homogeneous suspension is obtained.

Cases of incomplete injection, leading to the loss of more suspension than usually remains in the injection syringe, must be reported to the attending physician.

The introduction should be carried out in strict accordance with the instructions.

1. Treat the injection site with a napkin with alcohol. Remove the cap from the pink tipped needle and attach it to the syringe. Draw up all the solvent from the ampoule into the syringe.
2. Remove the plastic cap from the lyophilisate vial. Insert the needle through the chlorobutyl rubber stopper and transfer the solvent into the vial.
3. Pull the needle so that it remains in the vial, but does not touch the suspension.
4. Without turning the bottle over, gently shake the contents until a homogeneous suspension is obtained.
5. Without turning the bottle over, draw the entire suspension into the syringe.
6. Remove the pink tipped needle from the syringe. Attach a green-tipped needle (or a green-tipped needle with a safety device) to the syringe, screw tightly, taking only the colored tip.
7. Remove air from the syringe.
8. Inject immediately.
9. If you are using a green tipped needle with a safety device:
10. Immediately after injection, close the needle with a safety device in one of the following ways:

• Push the guard towards the tip of the needle. Close the needle and snap the device into place.
• Invert the syringe using a flat surface, push down on the device and close the needle.

The needle is closed when the needle tip is covered by the device. Check if the device is securely closed.

Use a colored tip to detach the needle.

Dispose of needles in sharps containers.

Indications for use

Dipherelin® 0.1 mg

Female infertility. Conducting ovarian stimulation together with gonadotropins (human menopausal, human chorionic), FSH in in vitro fertilization and embryo transfer programs, as well as other assisted reproductive technologies.

Diphereline® 3.75 mg

• prostate cancer;
• premature puberty;
• genital and extragenital endometriosis;
• fibroids of the uterus (before surgery);
• female infertility (in the in vitro fertilization program).

Dipherelin® 11.25 mg

• metastatic prostate cancer;
• genital and extragenital endometriosis (stages I – IV).

Contraindications for use

Common to all dosages:

• hypersensitivity;
• pregnancy;
• lactation.

• hormone-independent prostate cancer;
• condition after previous surgical testiculectomy.

Dipherelin® 3.75; 11.25 mg (optional):

• With caution - with osteoporosis.

Diphereline® 11.25 mg (optional):

• With caution - in women with polycystic ovary syndrome.

Use during pregnancy and children

Currently, analogs of gonadotropin-releasing hormone are used in combination with gonadotropins to stimulate ovulation and pregnancy.

Pregnancy is a contraindication for the use of the drug. However, practice has shown that after ovulation stimulated in the previous cycle, some women became pregnant without stimulation and continued a further course of ovulation stimulation.

Summary data: animal experiments have shown that the drug does not have a teratogenic effect.

Therefore, human congenital anomalies are not expected to develop with this drug. 2 qualitatively performed animal studies did not reveal its teratogenic effect.

The results of clinical studies with the participation of a small number of pregnant women using an analogue of gonadotropin-releasing hormone showed the absence of fetal malformations or fetotoxicity.

However, further research is needed on the effects of the drug on pregnancy.

Since there is no data on the penetration of the drug into breast milk and its possible effects on a breastfed baby, treatment should not be carried out during breastfeeding.

Side effects

Common to all dosages

At the beginning of treatment. In the treatment of infertility, the combination with gonadotropins can lead to ovarian hyperstimulation. In this case, there is an increase in the size of the ovaries, pain in the abdomen.

During treatment. The most common side effects are sudden flushes, vaginal dryness, decreased libido, and dyspareunia associated with pituitary-ovarian blockade.

Long-term use of analogs of gonadotropin-releasing hormone can lead to bone demineralization, the risk of osteoporosis (the above-described side effect was not observed with short-term use of Dipherelin® 0.1 mg).

Allergic reactions: urticaria, rash, itching, rarely - Quincke's edema.

In rare cases - nausea, vomiting, weight gain, increased blood pressure, emotional lability, visual impairment, pain at the injection site.

It is extremely rare - headache, joint and muscle pain.

Diphereline® 3.75 mg additionally

In men, a decrease in potency. At the beginning of treatment, patients with prostate cancer may experience a temporary increase in pain in the bones affected by metastases (symptomatic treatment). In some cases, obstruction of the ureters and symptoms associated with compression by metastases of the spinal cord (disappear after 1-2 weeks) are noted. Also during this period, there may be a temporary increase in the activity of acid phosphatase in the blood plasma.

When treating premature puberty, girls may experience bleeding from the vagina.

Long-term use of the drug can cause hypogonadotropic amenorrhea.

After stopping 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 of Dipherelin®. This must be taken into account when planning contraception.

Diphereline 11.25 mg additionally

At the beginning of treatment. Dysuric disorders (difficulty urinating, incomplete emptying of the bladder, soreness), bone pain associated with metastases and compression by metastases of the spinal cord, which can be aggravated by a temporary increase in testosterone levels in the blood plasma at the beginning of treatment. These symptoms disappear in 1–2 weeks. Also during this period, there may be a temporary increase in the activity of liver enzymes in the blood plasma.

During treatment: flushing of the face, decreased libido, gynecomastia, impotence, which is associated with a decrease in the content of testosterone in the blood plasma.

At the beginning of treatment. Symptoms associated with endometriosis (pelvic pain, dysmenorrhea), which may increase due to an initial transient increase in the concentration of estradiol in the blood plasma and disappear after 1–2 weeks.

One month after the first injection, metrorrhagia may occur.

In men and women:

Mood disorders, irritability, depression, fatigue, sleep disturbance, weight gain, profuse sweat, paresthesia, blurred vision, fever.

Drug interactions

Not described.

Dosage

Dipherelin® 0.1 mg. PC.

Short protocol. Starting from the 2nd day of the cycle (simultaneously starting stimulation of the ovaries), and ending the treatment 1 day before the scheduled administration of human chorionic gonadotropin. The course of treatment is 10-12 days.

Long protocol. Daily subcutaneous injections of Dipherelin® 0.1 mg begin on the 2nd day of the cycle. With desensitization of the pituitary gland (E2

Solution preparation rules. Immediately before injection, transfer the solvent to the vial with the lyophilisate. Shake until completely dissolved. Used needles should be placed in a designated sharps container.

Dipherelin® 3.75 mg. V / m.

Prostate cancer. Differelin® is administered at a dose of 3.75 mg every 4 weeks for a long time.

Premature puberty. Children weighing more than 20 kg - 3.75 mg every 28 days; children weighing less than 20 kg - 1.875 mg every 28 days.

Endometriosis The drug should be administered in the first 5 days of the menstrual cycle - at a dose of 3.75 mg every 4 weeks. The duration of therapy is no more than 6 months.

Female infertility. Diphereline® should be administered on the second day of the cycle at a dose of 3.75 mg. The connection with gonadotropins should be monitored after desensitization of the pituitary gland (the concentration of estrogen in the blood plasma is less than 50 pkg / ml is usually determined 15 days after the injection of Dipherelin®).

Fibroids of the uterus. The drug must be administered in the first 5 days of the menstrual cycle. The introduction of Dipherelin® should be carried out every 4 weeks at a dose of 3.75 mg. The duration of the course of treatment is 3 months (for patients preparing for surgery).

Dipherelin® 11.25 mg. V / m

Prostate cancer. Differelin® is administered at a dose of 11.25 mg every 3 months.

Endometriosis Differelin® is administered at a dose of 11.25 mg every 3 months. Treatment should be started in the first five days of the menstrual cycle. The duration of treatment depends on the severity of endometriosis and the observed clinical picture (functional and anatomical changes) during therapy. As a rule, treatment is carried out for 3–6 months. Repeated treatment with triptorelin or gonadotropin-releasing hormone is not recommended.

Overdose

Cases of drug overdose are unknown.

Precautionary measures

Dipherelin® 0.1 mg

A warning. The response of the ovaries to the introduction of Dipherelin® 0.1 mg in combination with gonadotropins can significantly increase in patients predisposed to this, and, in particular, in cases of polycystic ovarian diseases.

The response of the ovaries to the administration of the drug in combination with gonadotropins can differ in patients, and it can also be different in the same patients in different cycles.

Preventive action. Stimulation of ovulation should be carried out under the supervision of a physician and with regular biological and clinical analysis methods: increasing the content of estrogen in plasma and conducting ultrasound echocardiography. If the ovarian response is excessive, then it is recommended to interrupt the stimulation cycle and stop gonadotropin injections.

Diphereline® 3.75 mg

At the beginning of treatment, there may be an increase in clinical symptoms, and therefore, Dipherelin® should be prescribed with caution to patients with prostate cancer who are at risk of developing ureteral obstruction or spinal cord compression. Careful observation of these patients is necessary during the first month of therapy.

Before starting therapy with Dipherelin®, it is necessary to confirm the absence of pregnancy.

Use with caution in patients with polycystic ovary syndrome when performing ovulation stimulation schemes. This is due to the fact that in a small number of patients, the number of induced follicles may increase.

It is necessary to carefully monitor the level of cycle stimulation during in vitro fertilization in order to identify patients at risk of developing ovarian hyperstimulation syndrome, since the severity and frequency of manifestations of the syndrome may depend on the gonadotropin dosage regimen. If necessary, the introduction of human chorionic gonadotropin should be discontinued.

Dipherelin® 11.25 mg

Endometriosis treatment. Pregnancy must be ruled out before starting treatment.

During the first month of therapy, non-hormonal contraceptives should be used.

Intramuscular injection of the drug leads to persistent hypogonadotropic amenorrhea.

The occurrence of metrorrhagia during treatment, apart from the first month, is not the norm, and therefore it is necessary to determine the concentration of plasma estradiol. With a decrease in the concentration of estradiol to less than 50 pg / ml, the presence of other organic lesions is possible.

Ovarian function is restored after completion of therapy. The first period occurs on average 134 days after the last injection. For this reason, you should start using contraception 15 days after stopping treatment, i.e. 3.5 months after the last injection.

In the treatment of prostate cancer. The most pronounced beneficial effect is observed in patients in the absence of other previous hormone therapy.

At the beginning of treatment, there may be the appearance and intensification of clinical symptoms (in particular, bone pain, dysuric disorders), which are of a transient nature.

This implies careful observation of these patients during the first few weeks of therapy (the level of testosterone in the blood plasma should not exceed 1 ng / ml).

Treatment with Dipherelin® must be carried out in strict accordance with the instructions for use. Any change in the volume of the injected i / m suspension should be recorded.

Dosage form

Lyophilisate for the preparation of a suspension for intramuscular administration of prolonged action, complete with a solvent

Composition

One bottle contains:

active substance: triptorelin acetate 4.2 mg, which corresponds to 3.75 mg triptorelin

Excipients: copolymer of DL-lactic and glycolic acids, mannitol, polysorbate 80, sodium carmellose

solvent composition: mannitol, water for injection

Description

The drug is an almost white sintered powder. The solvent is a clear, colorless liquid. Suspension diluted in a solvent is a homogeneous milky suspension

Pharmacotherapeutic group

Antineoplastic and immunomodulating agents. Antineoplastic hormonal drugs. Hormones and their derivatives. Gonadotropin-releasing hormone analogs. Triptorelin

ATX code L02AE04

Pharmacological properties

Pharmacokinetics

After intramuscular administration of the prolonged form of the drug, an initial phase of release of the active substance takes place, followed by a phase of constant release of triptorelin for 28 days.

Pharmacodynamics

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

After a short initial period of stimulation of the gonadotropic function of the pituitary gland ("flash" effect), triptorelin has an inhibitory effect on the secretion of gonadotropins, followed by suppression of the function of the testicles and ovaries.

In addition, animal studies have demonstrated a different mechanism of action: a direct effect on the gonads by reducing the sensitivity of peripheral receptors to GnRH.

Prostate cancer

When triptorelin is used, there may be an initial increase in blood luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and, as a consequence, an increase in baseline testosterone levels ("flash" effect). Continued treatment with triptorelin lowers LH and FSH levels to concentrations leading to castration steroid levels within 2-3 weeks after the first injection and throughout the duration of the drug use.

Suppression of pituitary gonadotropic hyperactivity in both sexes manifests itself in the form of suppression of estradiol or testosterone secretion, a decrease in the LH peak and an improvement in the ratio of growth to bone age.

Initial stimulation of the gonads can cause minor bleeding from the genital tract, prevented by the appointment of medroxyprogesterone or cyproterone acetate.

Endometriosis

Long-term treatment with triptorelin suppresses the secretion of estradiol and, thus, leads to the death of ectopic endometrioid tissue.

Fibroids of the uterus

Studies have shown a constant and pronounced decrease in the volume of confirmed uterine fibroids. This decrease is most pronounced during the third month of treatment.

Triptorelin treatment causes amenorrhea after the first month of treatment in most patients. This makes it possible to correct possible anemia caused by menorrhagia and / or metrorrhagia.

Female infertility

Long-term treatment with triptorelin suppresses gonadotropic secretion (FSH and LH). Treatment thus provides suppression of the spontaneous peak of endogenous LH and results in improved quality of folliculogenesis and increased follicular response.

Indications for use

Prostate cancer

Breast cancer in premenopausal women

Premature puberty (up to 8 years in girls and up to 10 years in boys)

Genital and extragenital endometriosis

Fibroids of the uterus (before surgery)

Female infertility (in the in vitro fertilization program)

Method of administration and dosage

The drug is administered only intramuscularly.

Prostate cancer

Mammary cancer

Differelin® is administered at a dose of 3.75 mg every 4 weeks for a long time. The duration of treatment is determined by the attending physician individually for each patient.

Premature puberty

Children weighing less than 20 kg: half (1/2) dose intramuscularly, every 4 weeks (28 days), that is, inject half the volume of the reconstituted suspension.

For children weighing from 20 to 30 kg: two thirds (2/3) of the dose intramuscularly, every 4 weeks (28 days), that is, inject two thirds of the volume of the reconstituted suspension.

For children weighing more than 30 kg: one dose intramuscularly, every 4 weeks (28 days), that is, inject the entire volume of the reconstituted suspension.

Endometriosis

Differelin® is administered at a dose of 3.75 mg every 4 weeks. Treatment should be started in the first five days of the menstrual cycle. The duration of treatment depends on the severity of endometriosis and the clinical changes (functional and anatomical) observed during treatment. The course of treatment should last at least 4 months, but not more than 6 months. It is not recommended to undertake a second course of treatment with triptorelin or another analogue of gonadotropin-releasing hormone.

Fibroids of the uterus (before surgery)

Differelin® is administered at a dose of 3.75 mg every 4 weeks. Treatment should be started in the first five days of the menstrual cycle. The duration of the course of treatment should not exceed 3 months.

Female infertility

Typically, Dipherelin® is administered on the second day of the cycle at a dose of 3.75 mg. The combination with gonadotropins is performed after desensitization of the pituitary gland (the concentration of estrogen in the blood plasma is less than 50 pg / ml), usually on the 15th day after the injection of Dipherelin® 3.75 mg.

Instructions for administering the drug

One package of the drug contains one dose for intramuscular administration and is intended for a single injection to one patient.

A suspension of the powder in the supplied solvent should be prepared immediately prior to administration by gently stirring the contents of the vial until a homogeneous mixture is obtained.

It is necessary to report cases of incomplete injection, which leads to the loss of more suspension than usually remains in the syringe after injection.

The introduction should be carried out in strict accordance with the instructions.

1 - PATIENT PREPARATION

The patient should lie on his stomach and the skin of the buttocks should be disinfected.

2 - PREPARATION OF THE INJECTION

The presence of bubbles on the surface of the lyophilisate is the normal appearance of the drug.

Break the isthmus of the ampulla (point in front).

Draw all of the solvent into a syringe with a needle.

Remove the green cap on the bottle cap.

Transfer the solvent to the lyophilisate vial.

Keep the needle above the liquid level. Do not remove the needle from the vial.

Stir without inverting the bottle until a homogeneous mixture is obtained.

Make sure that there are no lumps before drawing the suspension (in case of lumps, continue stirring until complete homogenization).

Draw all the suspension into the syringe without turning the bottle over.

Remove the needle used to prepare the drug. Attach another needle to the syringe (screw tight). To attach the needle, touch only the colored cannula.

Displace the air from the syringe.

3 - INTRAMUSCULAR INJECTION

Inject the drug into the gluteus muscle immediately

4 - AFTER THE INJECTION

Place the needles in a specially designed container.

Side effects

In men

As with therapy with other GnRH agonists, or after surgical castration, the most frequently observed side effects associated with triptorelin treatment were those related to its expected pharmacological action: an initial increase in testosterone levels followed by its almost complete suppression. These effects included hot flashes (50%), erectile dysfunction (4%), and decreased libido (3%).

Often (³ 1/10); often (from³ 1/100 to< 1/10); infrequently (from³ 1/1000 to< 1/100); rarely (from³ 1 / 10,000 to< 1/1 000). There was no proper way to determine the frequency side effects after the start of supply of the drug to the market. Consequently, the frequency of such effects was noted as “unknown”.

Organ system classes	Often	Often	Infrequently	Rarely	Frequency unknown
Infections and infestations				Nasopharyngitis
Disorders of the blood and lymphatic system
				Anaphylactic reaction Hypersensitivity
Endocrine Disorders				Diabetes
Metabolic and Nutritional Disorders			Anorexia Increased appetite
Mental disorders		Depression Mood swings	Insomnia Irritability	Confusion of consciousness Decreased activity
	Lower limb paresthesia	Dizziness Headache	Paresthesia	Memory impairment
				Abnormal sensation in the eyes Visual disturbances	Decreased visual acuity
			Noise in ears	Vertigo / dizziness
Vascular disorders	Hot flashes		Hypertension	Nose bleed Hypotension
				Orthopnea
			Abdominal pain	Bloating Dry mouth Dysgeusia (taste disorder) Flatulence
	Hyperhidrosis		Alopecia		Angioedema Hives
	Back pain	Musculoskeletal pain Limb pain	Arthralgia Muscle cramps Muscle weakness	Joint stiffness Swelling of the joints Musculoskeletal stiffness Osteoarthritis	Bone pain
		erectile disfunction Decrease / loss of libido	Gynecomastia Pain in the area of ​​the mammary glands Testicular atrophy Pain in the testicles	Ejaculation disorder
General disorders and condition at the injection site		Fatigue Erythema at the injection site Inflammation at the injection site Pain at the injection site Injection site reaction	Lethargy Drowsiness	Chest pain Dystasia Flu-like syndrome Pyrexia	Malaise
			Increased alanine aminotransferase Increased aspartate aminotransferase Increased blood creatinine Increased blood urea Increase in body weight	Increased blood alkaline phosphatase Increased body temperature Weight loss	Increased blood pressure

Triptorelin causes a temporary increase in testosterone levels in the bloodstream during the first week after the first injection of the sustained-release drug. As a result, in a small number of patients (< 5%) может наблюдаться временное ухудшение симптомов и признаков рака предстательной железы (эффект «вспышки»), что обычно проявляется в усилении мочевых симптомов (< 2%) и метастатической боли (5%). Эти состояния следует лечить симптоматически. Эти симптомы являются временными и обычно исчезают через одну-две недели.

There were isolated cases of exacerbation of the symptoms of the disease - either the development of urethral obstruction, or compression of the bone marrow by metastases. Therefore, during the first few weeks of therapy, it is necessary to closely monitor patients with metastatic lesions of the spine and / or obstruction of the upper or lower urinary tract.

The use of GnRH agonists for the treatment of prostate cancer can lead to a decrease in bone mass, which can lead to osteoporosis and an increased risk of bone fractures.

In patients treated with GnRH analogs, an increase in the lymphocyte count was noted. This secondary lymphocytosis is likely associated with GnRH-induced castration and indicates that sex hormones are involved in thymic involution.

Among women

As a consequence of the decrease in estrogen, the most common side effects (with an expected frequency in 10% of women or higher) were headache, decreased libido, sleep disturbance, mood changes, dyspareunia, dysmenorrhea, genital bleeding, ovarian hyperstimulation syndrome, ovarian hypertrophy, pelvic pain, abdominal pain, vulvovaginal dryness, hyperhidrosis, hot flashes.

The following side effects have been reported and were considered likely to be related to triptorelin treatment. Most of these effects are known to be associated with biochemical or surgical castration.

The incidence of side effects is classified as follows: Often (³ 1/10); often (from³ 1/100 to< 1/10); infrequently (from³ 1/1000 to< 1/100). There was no adequate ability to quantify the frequency of side effects once the drug was placed on the market. Consequently, the frequency of such effects was noted as “unknown”.

Organ system classes	Often	Often	Infrequently	Frequency unknown
Immune system disorders				Hypersensitivity reactions
Mental disorders	Sleep disturbance Mood swings	Depression*	Depression**	Anxiety Confusion of consciousness
Side disorders nervous system	Headache			Dizziness
Disorders of the organs of vision				Decreased visual acuity Visual disturbances
Hearing and labyrinth disorders				Vertigo / dizziness
Vascular disorders	Hot flashes
Side disorders respiratory system, chest and mediastinum
Gastrointestinal Disorders		Abdominal pain Discomfort in the abdomen
Disorders of the skin and subcutaneous tissue	Hyperhidrosis			Angioedema Hives
Disorders of the musculoskeletal system and connective tissue		Arthralgia Muscle cramps		Muscle weakness
Disorders of the reproductive system and mammary glands	Dyspareunia Dysmenorrhea Genital bleeding (menorrhagia, metrorrhagia) Decreased libido Ovarian hyperstimulation syndrome Ovarian hypertrophy Pelvic pain Vulvovaginal dryness	Pain in the area of ​​the mammary glands		Amenorrhea
		Erythema at the injection site Inflammation at the injection site Pain at the injection site		Pyrexia Malaise
Laboratory analyzes and research		Increase in body weight		Increased blood pressure

* with long-term use

** for short-term use

At the beginning of treatment, very often (³ 10%) may exacerbate symptoms of endometriosis, including pelvic pain and dysmenorrhea, which is associated with a period of initial transient increase in plasma estradiol. These symptoms are temporary and usually go away after one or two weeks.

Within one month after the first injection, genital bleeding may develop, including menorrhagia, metrorrhagia.

When using the drug in the treatment of infertility, its combination with gonadotropins can lead to ovarian hyperstimulation syndrome. Ovarian hypertrophy, pelvic pain, and / or abdominal pain may occur.

Long-term use of GnRH analogues can lead to a decrease in bone mass, which is a risk factor for osteoporosis.

In children

The incidence of side effects is classified as follows: Often (³ 1/10); often (from³ 1/100 to< 1/10). There was no adequate ability to quantify the frequency of side effects once the drug was placed on the market. Consequently, the frequency of such effects was noted as “unknown”.

Organ system classes	Often	Often	Frequency unknown
Immune system disorders		Hypersensitivity reactions
Mental disorders		Depression Mood swings	Emotional lability Nervousness
Nervous system disorders		Headache
Disorders of the organs of vision			Decreased visual acuity Visual disturbances
Vascular disorders		Hot flashes
Respiratory, Chest, and Mediastinal Disorders			Nose bleed
Gastrointestinal Disorders			Abdominal pain Discomfort in the abdomen
Disorders of the skin and subcutaneous tissue			Angioedema Hives
Disorders of the musculoskeletal system and connective tissue
Disorders of the reproductive system and mammary glands		Genital bleeding Vaginal bleeding
General disorders and conditions at the injection site		Erythema at the injection site Inflammation at the injection site Pain at the injection site	Malaise
Laboratory analyzes and research			Increased blood pressure Increase in body weight

Contraindications

Hypersensitivity to triptorelin or other analogs of gonadotropin-releasing hormone

Pregnancy, lactation period

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Drug interactions

When using triptorelin in combination with other drugs that alter the secretion of gonadotropins by the pituitary gland, special precautions must be taken, it is recommended to carefully monitor hormone levels.

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special instructions

The use of GnRH agonists can lead to a decrease in bone mineral density (BMD). Preliminary evidence suggests that in men, the use of bisphosphonates in combination with GnRH agonists may reduce bone mineral density loss. Particular caution is needed in patients with additional risk factors for osteoporosis (eg, chronic alcohol abuse, smokers, long-term therapy with drugs that reduce BMD, eg, anticonvulsants or corticosteroids, family history of osteoporosis, malnutrition).

In rare cases, treatment with GnRH agonists may reveal the presence of a previously unknown gonadotrophic pituitary adenoma. These patients may present with pituitary apoplexy, characterized by sudden headache, vomiting, visual impairment, and ophthalmoplegia.

Mood changes, including depression, have been reported. Patients with depression should be closely monitored during treatment.

Dipherelin® 3.75 mg contains less than 1 mmol sodium (23 mg) per dose, which is essentially a "sodium-free" preparation.

Attention should be paid to patients receiving anticoagulants, as hematomas can potentially appear at the injection site.

Prostate cancer

Initially, triptorelin, like other GnRH agonists, causes a transient increase in serum testosterone levels. As a consequence, sporadic worsening of signs and symptoms of prostate cancer can sometimes develop during the first weeks of treatment. At the initial stage of treatment, consideration should be given to the need for additional administration of a suitable antiandrogenic drug to counteract the initial rise in testosterone levels and worsening of clinical symptoms.

A small number of patients may experience a temporary worsening of signs and symptoms of prostate cancer and a temporary increase in metastatic pain, which can be treated symptomatically.

As with other GnRH agonists, spinal cord compression or urethral obstruction has been reported. If spinal cord compression or renal failure develops, standard treatment for these complications should be initiated, and in extreme cases, immediate orchiectomy (surgical castration) should be considered. Close monitoring is indicated during the first week of treatment, especially in patients with spinal metastases, at risk of spinal cord compression, and in patients with urinary tract obstruction. For the same reason, patients with suspected symptoms of spinal cord compression should be under special supervision at the beginning of treatment.

After surgical castration, triptorelin does not cause a further decrease in serum testosterone levels.

Long-term androgen deprivation, either after bilateral orchiectomy or after the use of GnRH analogues, is associated with an increased risk of BMD loss and can lead to osteoporosis and an increased risk of bone fractures.

In addition, according to epidemiological data, it has been observed that with androgen blockade, patients may develop metabolic changes (for example, impaired glucose tolerance), or an increased risk of cardiovascular disease. However, prospective data did not support an association between treatment with GnRH analogues and increased cardiovascular mortality. Patients at high risk of developing metabolic and cardiovascular diseases should be carefully evaluated before starting treatment and adequately monitored during androgen blockade therapy.

The use of triptorelin in therapeutic doses leads to the suppression of the "pituitary - gonads" system. Normal function usually recovers after stopping treatment. Therefore, the results of diagnostic tests of the function of the "pituitary - gonads" system carried out during treatment and after the termination of treatment with GnRH analogues can be misleading.

At the beginning of treatment, there may be a transient increase in acid phosphatase levels.

Periodic testing of plasma testosterone levels may be helpful accurate method, it should not exceed 1 ng / ml.

Among women

Before the appointment of Dipherelin® 3.75 mg, it is necessary to confirm that the patient is not pregnant.

The use of GnRH agonists can cause a decrease in BMD by an average of 1% per month over a six-month treatment period. Every 10% decrease in BMD leads to a two- or three-fold increase in the risk of fractures.

Currently available data suggest that in most women, bone recovery occurs after discontinuation of therapy.

There are no specific data on patients with established osteoporosis or risk factors for osteoporosis (eg, chronic alcohol abuse, smokers, long-term therapy with drugs that reduce BMD, eg, anticonvulsants or corticosteroids, family history of osteoporosis, malnutrition, eg, anorexia nervosa). Since the decrease in BMD is likely to be more dangerous in these patients, the possibility of treatment with triptorelin should be considered individually after careful assessment of the benefit / risk ratio. Consideration should be given to additional measures to counter the loss of BMD.

Female infertility

Follicular maturation induced by injection of triptorelin in combination with gonadotropins can be significantly increased in some predisposed patients, especially in cases of polycystic ovarian disease. As with treatment with other GnRH analogues, there have been reports of ovarian hyperstimulation syndrome associated with the use of triptorelin in combination with gonadotropins.

The ovarian response to the triptorelin-gonadotropin association can be different at the same dose in different patients and, in certain cases, from one cycle to another in the same patient.

Induced ovulation should be monitored under strict medical supervision with precise and regular biological and clinical monitoring: frequent assessment of plasma estrogen and ultrasonography.

In patients with renal or hepatic impairment, triptorelin has an average elimination half-life of 7-8 hours compared to 3-5 hours in healthy people... Despite this long-term exposure, triptorelin will not be present in the blood at the time of embryo transfer.

Endometriosis and treatment of uterine fibroids before surgery

Regular use, every four weeks, of one vial of Dipherelin® 3.75 mg leads to permanent hypogonadotropic amenorrhea.

If genital bleeding occurs after the first month of therapy, plasma estradiol levels should be measured. If this level is below 50 pg / ml, it is necessary to exclude possible organic damage.

Because menstruation must stop during triptorelin treatment, the patient should be instructed to notify her doctor if regular menses persist.

It is necessary to use non-hormonal methods of contraception during the entire period of treatment, including one month after the last injection.

Ovarian function resumes after the end of treatment, and ovulation occurs approximately 2 months after the last injection.

It is recommended during the treatment of uterine fibroids to regularly determine the size of the fibroid. There have been several reports of bleeding in patients with submucous uterine myoma following therapy with GnRH analogues. Typically, bleeding occurred 6-10 weeks after initiation of therapy.

Premature puberty

Treatment of children with triptorelin should be under the general supervision of a pediatric endocrinologist or pediatrician or endocrinologist experienced in the treatment of central precocious puberty.

Treatment of children with advanced brain tumors should be carried out after careful individual assessment of the benefit / risk ratio.

In girls, initial gonadal stimulation may result in mild to moderate vaginal bleeding during the first month of treatment.

After stopping treatment, the development of signs of puberty resumes.

Information regarding fertility in patients treated with GnRH analogues in childhood is limited. In most girls, regular periods begin on average one year after stopping therapy.

False precocious puberty (tumor or hyperplasia of the gonads or adrenal glands) and gonadotropin-independent precocious puberty (testotoxicosis, familial Leydig cell hyperplasia) should be excluded.

BMD may decrease during GnRH therapy in central precocious puberty. However, after stopping treatment, there is a subsequent restoration of bone mass and treatment ultimately has no effect on maximum bone mass in late adolescence.

Epiphysis of the femoral head can be detected after discontinuation of GnRH treatment. A hypothesized theory for this phenomenon is that low estrogen concentrations during treatment with GnRH agonists can weaken the epiphysial lamina. An increase in the growth rate after stopping treatment subsequently leads to a decrease in the force required to displace the pineal gland.

Pregnancy and lactation

Pregnancy

Triptorelin should not be used during pregnancy, as the use of GnRH agonists during pregnancy is associated with a theoretical risk of abortion or fetal abnormalities. Potentially fertile women should be carefully screened before starting treatment to rule out pregnancy. Non-hormonal methods of contraception should be used during therapy and before menstruation resumes.

Pregnancy should be excluded before the appointment of Dipherelin® 3.75 mg, including before use for the treatment of infertility.

When triptorelin is used in this situation, there is no clinical evidence of a causal relationship between triptorelin and any subsequent abnormalities in egg maturation or pregnancy or pregnancy outcome.

Lactation

Triptorelin should not be used while breastfeeding.

Features of influence medicinal product on the ability to manage vehicle or potentially dangerous mechanisms

No studies of the effect of Dipherelin® 3.75 mg on the ability to drive and operate machinery have been conducted. However, the ability to drive and operate machinery can be impaired as a result of dizziness, drowsiness and visual disturbances, which can be either unwanted effects of treatment or manifestations of an underlying medical condition.