The drug diferelin application. Diferelin - instructions for use. Menstruation and pregnancy after Diferelin

Composition and form of release

Lyophilisate for solution for subcutaneous administration - 1 vial:

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

In vials (complete with solvent); in a blister pack 7 sets; in a pack of cardboard 1 pack.

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

Lyophilizate 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 drug contains an excess of the active ingredient to ensure the administration of an effective dose.

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

Description of the dosage form

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

Diphereline® 3.75 mg: white or off-white to off-white lyophilisate, dispersible in the supplied solvent to form a white or off-white to off-white suspension.

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

The supplied solvent is a clear, colorless solution.

pharmachologic effect

Antigonadotropic.

Pharmacokinetics

Diphereline® 0.1 mg

After subcutaneous injection in healthy adult volunteers at a dose of 0.1 mg, triptorelin is rapidly absorbed (time to reach Cmax - (0.63 ± 0.26) hours 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 the prolonged form of the drug, an initial stage of rapid release of the drug substance occurs, followed by a phase of continuous release of triptorelin. Cmax is (0.32±0.12) ng/ml.

The average amount of constantly released triptorelin is (46.6 ± 7.1) mcg / day.

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

Diphereline® 11.25 mg

With intramuscular injection of Diferelin at a dose of 11.25 mg Cmax triptorelin in blood plasma (in men and women) is determined approximately 3 hours after injection. After a phase of decreasing concentration, which lasts for the first month, until the 90th day, the concentration of circulating triptorelin remains constant (approximately 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 analog of natural gonadotropin-releasing hormone that releases gonadotropin.

Diphereline® 0.1 mg

Animal studies and clinical studies have shown that after an initial period of stimulation, long-term use of Diphereline® 0.1 mg inhibits the secretion of gonadotropins with subsequent suppression of ovarian function.

Continuous use of Diferelin® 0.1 mg inhibits the secretion of gonadotropins (FSH and LH). Suppression of intermediate endogenous LH peaks improves the quality of folliculogenesis by increasing the number of maturing follicles, and, as a result, increases 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 to the state of menopause, and also reduces the secretion of testosterone, the concentration of which can reach the levels observed after surgical castration.

iferelin® 11.25 mg

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

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

Instruction

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

1. Treat the injection site with an alcohol wipe. 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 inverting the vial.
3. Without turning the vial, draw the entire suspension into the syringe.
4. Remove the pink needle from the syringe. Attach a green needle to the syringe (screw tightly), taking only the colored tip.
5. Remove air from the syringe.
6. Inject immediately. The injection should be given intramuscularly only.

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

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

Diphereline® 11.25 mg. V / m Rules for the preparation of a suspension

The dissolution of the lyophilizate in the supplied solvent should be carried out immediately before administration. Stir the contents of the vial with care 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 an alcohol wipe. 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 stopper of chlorobutyl rubber and transfer the solvent to the vial.
3. Pull the needle so that it remains in the vial but does not touch the suspension.
4. Without turning the bottle upside down, gently shake the contents until a homogeneous suspension is obtained.
5. Without turning the vial, 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 protective device) to the syringe, screw tightly, taking only the colored tip.
7. Remove air from the syringe.
8. Inject immediately.
9. If a green-tipped needle with a safety device is used, then:
10. Immediately after the injection, close the needle with a protective device in one of the following ways:

• Push the guard towards the tip of the needle. Close the needle and lock the device.
• Invert the syringe using a flat surface, press down on the device and close the needle.

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

Use the colored tip to detach the needle.

Dispose of needles in sharps containers.

Indications for use

Diphereline® 0.1 mg

female infertility. Conducting ovarian stimulation in conjunction with gonadotropins (human menopause, human chorionic), FSH in programs of in vitro fertilization and embryo transfer, as well as other assisted reproductive technologies.

Diphereline® 3.75 mg

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

Diphereline® 11.25 mg

• prostate cancer with metastases;
• genital and extragenital endometriosis (I-IV stages).

Contraindications for use

Common for all dosages:

• hypersensitivity;
• pregnancy;
• lactation.

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

Diferelin® 3.75; 11.25 mg (optional):

• With caution - with osteoporosis.

Diphereline® 11.25 mg (optional):

• With caution - in women with polycystic ovary syndrome.

Use in pregnancy and children

Currently, gonadotropin-releasing hormone analogs 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 studies have shown that the drug does not have a teratogenic effect.

Therefore, congenital anomalies are not expected to develop in humans when using this drug, because. 2 high-quality animal studies did not reveal its teratogenic effect.

The results of clinical studies in a small number of pregnant women using a gonadotropin-releasing hormone analog showed no fetal malformations or fetotoxicity.

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

Since there are no data on the penetration of the drug into breast milk and its possible effects on a breast-fed child, 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 hot flashes, vaginal dryness, decreased libido and dyspareunia associated with pituitary-ovarian blockade.

Long-term use of gonadotropin-releasing hormone analogues can lead to bone demineralization, the risk of developing osteoporosis (the above side effect was not observed with short-term use of Diferelin® 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.

Very rarely - headache, joint and muscle pain.

Diphereline® 3.75 mg extra

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 (treatment is symptomatic). In some cases, obstruction of the ureters and symptoms associated with compression by spinal cord metastases are noted (they 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.

When treating precocious puberty, girls may experience spotting from the vagina.

Prolonged 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 Diferelin®. This must be taken into account in contraceptive planning.

Diphereline 11.25 mg extra

At the beginning of treatment. Dysuric disorders (difficulty urinating, incomplete emptying of the bladder, pain), bone pain associated with metastases and compression of spinal cord metastases, which may be aggravated by a temporary increase in plasma testosterone 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, decreased libido, gynecomastia, impotence, which is associated with a decrease in testosterone in the blood plasma.

At the beginning of treatment. Symptoms associated with endometriosis (pelvic pain, dysmenorrhea), which may increase due to the 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.

For men and women:

Mood disturbance, irritability, depression, feeling tired, sleep disturbance, weight gain, profuse sweat, paresthesia, blurred vision, fever.

drug interaction

Not described.

Dosage

Diferelin® 0.1 mg. PC.

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

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

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

Diphereline® 3.75 mg. V/m.

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

Precocious puberty. Children weighing over 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. Duration of therapy - no more than 6 months.

female infertility. Diferelin® should be administered on the second day of the cycle at a dose of 3.75 mg. Communication with gonadotropins should be monitored after desensitization of the pituitary gland (the concentration of estrogens in blood plasma less than 50 pg / ml is usually determined 15 days after the injection of Diferelin®).

Fibromyoma of the uterus. The drug must be administered in the first 5 days of the menstrual cycle. The introduction of Diphereline® 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).

Diphereline® 11.25 mg. V/m

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

Endometriosis. Diphereline® is administered at a dose of 11.25 mg every 3 months. Treatment must begin 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. It is not recommended to repeat the course of treatment with triptorelin or gonadotropin-releasing hormone.

Overdose

Cases of drug overdose are unknown.

Precautionary measures

Diphereline® 0.1 mg

Warning. The ovarian response to the administration of Diphereline® 0.1 mg in combination with gonadotropins may increase markedly in predisposed patients and, in particular, in cases of polycystic ovarian disease.

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

Preventive action. Ovulation stimulation should be carried out under the supervision of a physician and with regular biological and clinical methods of analysis: an increase in the content of estrogen in the plasma and ultrasound echocardiography. If the response of the ovaries is excessive, then it is recommended to interrupt the stimulation cycle and stop the injection of gonadotropin.

Diphereline® 3.75 mg

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

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

Use with caution in patients with polycystic ovary syndrome when conducting 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 stimulation of the cycle 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 dosing regimen of gonadotropin. If necessary, the introduction of human chorionic gonadotropin should be discontinued.

Diphereline® 11.25 mg

Treatment of endometriosis. Before starting treatment, pregnancy must be excluded.

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, except for 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 a level of less than 50 pg / ml, other organic lesions may be present.

Ovarian function is restored after completion of therapy. The first menstruation occurs on average 134 days after the last injection. For this reason, the use of contraception should be started 15 days after the withdrawal of 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 previously conducted hormonal therapy.

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

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

Treatment with Diferelin® must be carried out in strict accordance with the instructions for use. Any change in the volume of the intramuscular suspension administered must be recorded.

A drug Diphereline 11.25- antitumor agent, gonadotropin - releasing hormone analogue.
Triptorelin is a synthetic decapeptide analogue of 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 testicular and ovarian function.
In the initial period of use Diferelin 11.25 mg temporarily increases the concentration of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the blood, respectively, increases the concentration of testosterone in men and estradiol in women. Long-term treatment reduces the concentration of LH and FSH, which leads to a decrease in testosterone levels (to levels corresponding to post-testiculectomy) and a decrease in estradiol levels (to levels corresponding to post-ovariectomy) - 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 intramuscular injection of Diferelin at a dose of 11.25 mg, the maximum concentration of triptorelin in blood plasma (in men and women) is determined approximately 3 hours after injection. After a declining phase lasting for the first month, the circulating triptorelin concentration remains constant until day 90 (approximately 0.04 to 0.05 ng/mL in the treatment of endometriosis and approximately 0.1 ng/mL in the treatment of prostate cancer).

Indications for use

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

Mode of application

prostate cancer: Diphereline 11.25 administered intramuscularly at a dose of 11.25 mg every 3 months.
endometriosis: Diphereline is administered intramuscularly at a dose of 11.25 mg every 3 months.
Treatment must begin 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. It is not recommended to repeat the course of treatment with triptorelin or GnRH.
Suspension preparation rules:
The dissolution of the lyophilizate in the supplied solvent should be carried out immediately before administration. Stir the contents of the vial with care 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 the buttocks.
1. Break the neck of the ampoule (dot on the front side from above).
2. Draw up all the solvent into the syringe with a needle.
3. Remove the protective plastic cap from the top of the vial.
4. Transfer solvent to lyophilisate vial
5. Pull the needle so that it remains in the vial but does not touch the suspension.
6. Without inverting 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 agglomerates are present, shake until completely homogeneous).
8. Without turning the vial, draw the entire suspension into the syringe.
9. Remove the needle used to prepare the suspension and firmly attach the other needle to the tip of the syringe. Hold only the colored tip.
10. Remove air from the syringe.
11. Inject immediately into the gluteal muscle.
12. Dispose of needles in sharps containers.

Side effects

In men at the beginning of treatment - Dysuric disorders (difficulty urinating, incomplete emptying of the bladder, pain), bone pain associated with metastases and compression of spinal cord metastases, which may be aggravated due to a temporary increase in plasma testosterone at the beginning of treatment. These symptoms go away after 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 the content of testosterone in the blood plasma.
In women at the beginning of treatment. Symptoms associated with endometriosis (pelvic pain, dysmenorrhea), which may increase due to the initial transient increase in the concentration of estradiol in the blood plasma and disappear after 1 to 2 weeks.
One month after the first injection, metrorrhagia may occur.
During treatment.
Vaginal dryness, "hot" flushes, decreased libido, breast enlargement, dyspareunia, which is associated with pituitary-ovarian blockade.
Rarely - headache, arthralgia, myalgia.
In men and in women. Allergic reactions such as urticaria, rash, itching and very rarely Quincke's edema; mood disturbance, irritability, depression, fatigue, sleep disturbances, nausea, vomiting, weight gain, profuse sweating, hypertension, paresthesia, 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 Diferelina, its components or other analogues of gonadotropin-releasing hormone.
In men, hormone-independent prostate cancer, a condition after 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 available data, no teratogenic effects have been 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 are no data on the penetration of the drug into breast milk and its possible effects on a breast-fed child, treatment should not be carried out during breastfeeding.

Interaction with other drugs

Not described.

Overdose

:
Cases of drug overdose Diphereline 11.25 not known.

Storage conditions

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

Release form

Diphereline 11.25 - lyophilizate for the preparation of a suspension for intramuscular administration of prolonged action 11.25 mg.
Triptorelin 11.25 mg in a slightly tinted 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 cap to control the first opening.
2 ml of solvent per ampoule.
One empty sterile disposable polypropylene syringe with a capacity of 3 ml, two disposable hypodermic needles measuring 0.90 x 40 mm with yellow tips in a blister pack made of PVC and laminated paper.
One vial with the drug, one ampoule with a solvent, one blister pack with a syringe and two needles are placed in a cardboard box along with instructions for use.

Compound

:
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, carmellose sodium (sodium carboxymethylcellulose) 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 drug contains an excess of the active ingredient to ensure the administration of an effective dose.

Additionally

:
In the treatment of endometriosis:
Before starting treatment, pregnancy must be excluded.
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 periods longer than 6 months. It is not recommended to repeat the course of therapy with triptorelin or another GnRH analogue.
The occurrence of metrorrhagia during treatment, except for 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, other organic lesions may be present.
Ovarian function is restored after completion of therapy. The first menstruation occurs on average 134 days after the last injection. For this reason, contraception should be started 15 days after stopping treatment, that is, 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 previously conducted hormonal therapy.
At the beginning of treatment, there may be an appearance and intensification of clinical symptoms (in particular, bone pain, dysuric disorders), which are transient.
This implies careful monitoring of these patients during the first few weeks of therapy (plasma testosterone levels should not exceed 1 ng / ml).
Treatment with Diferelin must be carried out in strict accordance with the instructions for use. Any change in the volume of intramuscular suspension administered should be recorded.

Main settings

Name:	DIFERELIN 11.25
ATX code:	L02AE04 -

One of the most effective medicines designed to combat the most severe pathologies of the female and male reproductive system is Diferelin. Instructions, the price of this drug are often discussed by patients on specialized forums. As usual, this drug has its adherents and opponents. In this article, we will consider the mechanism of action of this drug and its pharmacological features.

Pharmacological group

The drug "Diferelin" is a drug with antigonadotropic action. In fact, it is an antihormone, as it has the ability to suppress the production of luteinizing and follicle-stimulating hormones in females and testosterone in men. Therefore, the drug "Diferelin" is actively used to treat uterine fibroids, endometriosis, prostate cancer, premature maturation in adolescents and other diseases.

Composition and form of release

The drug "Difelerin" is currently available in only one dosage form - a lyophilisate for creating solutions. In this case, three types of products are produced, differing in the concentration of the active substance and having different purposes:

• "Diferelin" 11.25 mg and 3.75 mg - for intramuscular injection;
• "Diferelin" 0.1 mg - for subcutaneous injections.

In everyday life, doctors and patients briefly refer to the above-mentioned varieties of the drug, adding numbers to its name indicating the content of the main substance in it.

As an active ingredient in the drug "Diferelin", reviews of which are mostly positive, triptorelin pamoate acts. It is he who has a pronounced therapeutic and pharmacological effect on the patient's body.

Medication "Diferelin" is sold in cardboard packages, in which there are vials with lyophilisate and a syringe with two needles. In addition, ampoules with a solvent are placed in them. It may be different. If mannitol is mainly used for lyophilizers "Diferelin" 3.75 and 11.25, then for the drug at a concentration of 0.1 mg, it is most often used

Therapeutic effect of "Diferelin"

From a biochemical point of view, this drug is an analogue of the GnRH hormone synthesized by the hypothalamus. It affects the pituitary gland, which is responsible for the production of sex hormones and thereby regulates the work of the organs of the female and male reproductive system: the prostate, ovaries, uterus, testicles. It turns out that the drug "Diferelin" regulates the level of production of sex hormones.

Reviews of its use indicate that it has a pronounced antitumor and antigonadotropic effect and is effective in the treatment of certain pathologies. For example, in infertility, this medicine suppresses the production of luteinizing hormone, which negatively affects ovulation, thereby increasing the likelihood of pregnancy. And with prostate cancer, this medication reduces testosterone levels to zero, characteristic of castrates, and increases the patient's chances of getting rid of a malignant neoplasm.

Effective magic "Diferelin" and endometriosis. By its effect on the production of sex hormones, it gradually introduces a woman into an artificially created state of menopause and thereby provokes atrophy of endometrial foci.

Indications for use

Depending on the concentration, the drug "Diferelin" has a different effect on the body. The use of this drug in medicine depends on the content of the main active substance in it. For example, injections of "Diphereline 0.1 mg" are indicated for infertility, to activate the ovaries and stimulate ovulation during IVF.

The use of this medication at a concentration of 3.75 mg is advisable in the fight against prostate cancer, uterine fibroids, premature maturation, genital and extragenital endometriosis, IVF protocols.

In the most serious cases, with prostate cancer with metastases and chronic endometriosis, Diferelin 11.25 mg is prescribed. Its use can significantly increase the patient's chances of recovery.

Instructions for use

The drug "Diferelin 0.1 mg" is used in short and long IVF protocols under the strict supervision of a doctor. It begins to be administered daily, one ampoule, starting from the second day of menstruation. The duration of such therapy is determined by the individual characteristics of the female body.

But the drug "Diferelin 11.25 mg" is administered to patients every three months. Moreover, men can make this injection at any time, and women - only in the first five days of the menstrual cycle. The duration of treatment with this drug lasts from three to six months, since it is not recommended to use it for more than six months.

The drug "Diferelin 3.75" has the widest range of use. Patient reviews testify to the extreme effectiveness of this drug. In addition, it is very convenient to use, as it does not require daily administration over a long period of time. Injections of the drug "Diferelin 3.75 mg" are usually done once a month. This is sufficient to ensure that the active substance enters the bloodstream in therapeutic dosages. Let us consider in more detail the scheme of using this medication in relation to various diseases.

prostate cancer

For men, the drug "Diferelin" is prescribed for prostate cancer. The injections are given to the patient once every twenty-eight days in such a way that the interval between injections of the drug is four weeks. A single dose of the drug is one vial of 3.75 mg. The duration of taking the medicine is determined by the rate of healing of the patient.

endometriosis

Injections of the drug "Diferelin" for endometriosis are given to women in the first five days of the next menstruation. The subsequent medication is taken after four weeks, and the course of therapy lasts a total of 3 to 6 months. It should be remembered that this medicine cannot be combined with the use of oral contraceptives.

In the process of treating endometriosis, the drug "Diferelin" causes an artificial menopause (amenorrhea). Patient reviews, however, indicate that after stopping treatment, the menstrual cycle is restored within a few months, sometimes a whole year. Repeated therapy with this medicine for relapses of endometriosis, as a rule, is not prescribed - other, no less effective medicines are used for this.

precocious puberty

For children, when stopping, the drug "Diferelin" is prescribed once every 28 days. In this case, a single dose of its use is calculated taking into account the patient's body weight. For children weighing more than 20 kilograms, a whole vial (3.75 mg) is injected, and for children with lower rates - half an ampoule (1.875 mg). The duration of therapy is determined by the attending physician, depending on the rate of normalization of the patient's condition.

Fibromyoma of the uterus

In the treatment of this disease, the drug "Diferelin" is administered once a month, one vial. Moreover, it should be taken during the first five days of the patient's menstrual cycle. Subsequent injections of the drug occur every four weeks. The duration of therapy usually does not exceed three months.

Overdose

At present, not a single case of an overdose of Diferelin has been identified. Patient reviews also indicate its relative safety. In addition, this drug does not affect the ability to control moving mechanisms. Therefore, during the course of therapy with this medicine, you can safely drive a car.

Side effects

When using the drug "Diferelin" the following side effects may occur:

• symptoms of spinal cord compression;
• increased pain;
• angioedema, urticaria, itching;
• obstruction of the ureters;
• headache;
• bone demineralization;
• decrease in potency;
• dryness of the vagina;
• sweating;
• reduction of the testicles;
• change in breast size;
• hypogonadotropic amenorrhea;
• ovarian hypertrophy;
• menorrhagia;
• asthenia;
• nausea, vomiting;
• hypertension;
• hot flashes;
• emotional lability;
• hematuria;
• the appearance of excess weight;
• peripheral edema;
• fever;
• anorexia;
• depression;
• tachycardia;
• alopecia;
• dyspnea;
• hyperemia of the injection site;
• paresthesia.

Contraindications for use

The drug "Diferelin" has separate contraindications for use. They are associated with the patient's state of health, as well as with his individual physiological characteristics. For example, men should not take this drug for non-hormonal prostate cancer and after having their testicles removed, and it is not recommended for women during pregnancy, breastfeeding, or polycystic ovary syndrome. Everyone, without exception, should use Diferelin with caution in osteoporosis and hypersensitivity to its components. In case of any negative symptoms, the patient should immediately seek advice from the attending physician.

General condition after application

As mentioned above, the drug "Diferelin" suppresses the production of sex hormones in women and men, thereby introducing them into a state of artificial castration. Of course, immersion in such a state and exit from it is accompanied by various psychological, endocrine-metabolic and neurovegetative disorders.

After completing the course of therapy with this medicine, the hormonal background is restored, but during this process the patient may be disturbed by irritability, fatigue, headaches, sweating, hot flashes, depression, fever and other unpleasant symptoms. However, within one and a half months after the end of the drug, the physical condition of the patient is completely normalized. That is, usually after the last injection of Diferelin 11.25 mg, the balance of hormones is restored after 4.5 months, and the effect of the drug with a concentration of 3.75 mg ends after 2.5 months. During the indicated periods of time, reproductive and sexual functions are completely rehabilitated in women and men and libido returns to normal.

Application during pregnancy

When carrying a child, treatment with Diferelin is contraindicated. However, this medicine is actively used to activate ovulation. Many women were able to become pregnant after several injections of the drug, but, not knowing about it, continued to take Diferelin. The action of this medication, as it was found, does not harm the unborn child: it does not provoke the risk of miscarriage and does not contribute to the development of congenital deformities. However, the mechanism of action of this drug on the female reproductive system during pregnancy still requires close study.

Analogues of the drug "Diferelin"

On the modern pharmaceutical market, there is only one synonymous drug that has the same active substance in its composition - this is Decapeptyl. In addition, in pharmacies you can find drugs that have the same therapeutic effect as the drug "Diferelin". A similar effect on the body is exerted by: Buserelin spray, Buserelin Depot lyophilisate, Zoladex capsules, Eligardt and Lucrin Depot preparations.

Tradename: Diferelin ®

International non-proprietary name:

Triptorelin (Triptorelin)

Dosage form:

lyophilisate for preparation of solution for subcutaneous administration

Compound:

Lyophilisate (1 vial)
Active ingredient: Triptorelin acetate, in terms of triptorelin 0.1 mg
Auxiliary component: Mannitol 10.0 mg
Solvent (1 ampoule): Sodium chloride, water for injections.

Description: an almost white lyophilisate, dispersible in the supplied solvent to form a clear solution, practically free of particles.

Pharmacotherapeutic group:

gonadotrolin is a hormone-releasing analog, antitumor agent.

ATX code: L02AE04

Pharmacological properties
Pharmacodynamics:
Triptorelin is a synthetic decapeptide. analogue of natural gonadotrolin - releasing hormone (releasing gonadotropin).
Animal and clinical studies have shown that after an initial period of stimulation, long-term use of Diphereline ® 0.1 mg suppresses gonadotropin secretion, followed by suppression of ovarian function (follicle-stimulating hormone and luteinizing hormone). Suppression of intermediate endogenous peaks of luteinizing hormone improves the quality of folliculogenesis, increasing the number of maturing follicles, and as a result, increases the likelihood of pregnancy per cycle.
Pharmacokinetics:
In healthy adult volunteers.
After subcutaneous injection at a dose of 0.1 mg, triptorelin is rapidly absorbed (time to peak concentration 0.63 ± 0.26 hours) with a peak plasma concentration of 1.85 ± 0.23 ng / ml. The half-life is 7.6 ± 1.6 hours, after 3-4 hours the distribution phase ends.
Total plasma clearance: 161 ± 28 ml/min.
Distribution volume: 1562 ± 158 ml/kg.

Indications for use
female infertility. Conducting ovarian stimulation together with gonadotropins (hMG, hCG, FSH) in programs of in vitro fertilization and embryo transfer, as well as other assisted reproductive technologies.

Contraindications
Pregnancy. It is necessary to exclude pregnancy before starting therapy with the drug.
Hypersensitivity.

Dosage and administration
Short protocol: Diferelin ® 0.1 mg is administered subcutaneously starting from the 2nd day of the cycle (simultaneously starting ovarian stimulation), and the treatment is completed 1 day before the planned administration of human chorionic gonadotropin. The course of treatment is 10 - 12 days.
Long protocol: Daily subcutaneous injections of Diferelin ® 0.1 mg start on the 2nd day of the cycle. With desensitization of the pituitary gland (E 2 ® 0.1 mg suppresses the secretion of gonadotropin approximately 15 days after the start of treatment), stimulation with gonadotropins is started and injections of Dipherelin ® at a dose of 0.1 mg are continued, ending them the day before the planned administration of human chorionic gonadotropin. The duration of treatment is determined by the doctor individually.
Rules for the preparation of the solution.
Immediately before injection, transfer the solvent to a vial with lyophytizate. Shake until completely dissolved. Used needles should be placed in a designated sharps container.

Side effect
At the start 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 hot flashes, vaginal dryness, decreased libido and dyspareunia associated with pituitary-ovarian blockade.
Prolonged use of gonadotropin-releasing hormone analogues can lead to bone demineralization, the risk of osteoporosis.
The above side effect was not observed with short-term use of Diferelin ® 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.
Rarely: headache, joint and muscle pain.

Overdose
Cases of drug overdose are not known.

Interactions with other drugs
Not described.

Incompatibility
Not described.

special instructions
Warning.
The ovarian response to the administration of Diferelin ® 0.1 mg in combination with gonadotropins may increase markedly in susceptible patients and in particular in cases of polycystic ovarian disease.
The response of the ovaries to the administration of the drug in combination with gonadotropins may vary in patients, and the reaction may also be different in the same patients with different cycles.
Preventive action.
Ovulation stimulation should be carried out under the supervision of a physician and with regular biological and clinical analysis methods: an increase in the content of estrogen in the plasma and ultrasonic echography. If the response of the ovaries is excessive, then it is recommended to interrupt the stimulation cycle and stop the injection of gonadotropin.

Pregnancy and lactation period
Currently, gonadotropin-releasing hormone analogs 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, no congenital anomalies are expected to develop in humans with the use of this drug, since 2 well-conducted animal studies have not revealed its teratogenic effect.
The results of clinical studies in a small number of pregnant women using gonadotropin-releasing hormone analog showed no fetal malformations or fetotoxicity.
However, further study of the effects of the drug on pregnancy is needed.

Impact on driving and operating machinery
Does not affect the ability to drive vehicles and control mechanisms.

Release form

Dosage form:

lyophilisate for the preparation of a solution for subcutaneous administration of 0.1 mg (complete with a solvent - 0.9% sodium chloride solution).
0.1 mg of triptorelin in a vial of colorless hydrolytic glass type I (Eur.F.), sealed with a chlorobutyl rubber stopper under an aluminum rim with a needle hole in the center and closed with a protective plastic cap to control the first opening.
1 ml of solvent in an ampoule of colorless hydrolytic glass type I (Eur.Pharm.).
7 vials with triptorelin and 7 ampoules with a solvent are placed in a PVC blister pack and, together with instructions for use, are placed in a cardboard box.

Storage conditions
At a temperature not higher than 25 ° C, out of the reach of children.

Best before date
2 years.
Do not use after the expiration date indicated on the package.

Terms of dispensing from pharmacies
On prescription.

Manufacturer
Ipsen Pharma Biotek France, 83870, Xin
If necessary, send consumer claims to the address of the representative office in the Russian Federation: 109147, Moscow, Taganskaya st., 19

Dosage form

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

Compound

One vial 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, carmellose sodium

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 solvent - homogeneous milky suspension

Pharmacotherapeutic group

Anticancer drugs and immunomodulators. Anticancer hormonal drugs. Hormones and their derivatives. Gonadotropin-releasing hormone analogues. Triptorelin

ATX code L02AE04

Pharmacological properties

Pharmacokinetics

After intramuscular administration of the prolonged form of the drug, there is an initial phase of release of the active substance, followed by a phase of continuous release of triptorelin for 28 days.

Pharmacodynamics

Triptorelin is a synthetic decapeptide analogue of 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 testicular and ovarian function.

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 using triptorelin, there may be an initial increase in the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the blood, and, as a result, an increase in the initial level of testosterone (the "flare" effect). Continued treatment with triptorelin reduces 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.

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 mild bleeding from the genital tract, which is 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 endometrial tissue.

Fibromyoma 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). The treatment thus provides suppression of the spontaneous peak of endogenous LH and leads to an improvement in the quality of folliculogenesis and increases the follicular response.

Indications for use

prostate cancer

Breast cancer in premenopausal women

Precocious puberty (before 8 years in girls and before 10 years in boys)

Genital and extragenital endometriosis

Uterine fibromyoma (before surgery)

Female infertility (in the in vitro fertilization program)

Dosage and administration

The drug is administered only intramuscularly.

prostate cancer

Mammary cancer

Diferelin® 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.

precocious 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.

Children weighing 20 to 30 kg: two-thirds (2/3) of the dose intramuscularly every 4 weeks (28 days), i.e. two-thirds of the volume of the reconstituted suspension.

Children weighing more than 30 kg: one dose intramuscularly every 4 weeks (28 days), i.e. inject the entire volume of the reconstituted suspension.

endometriosis

Diphereline® 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 observed during treatment (functional and anatomical). The course of treatment should last at least 4 months, but not more than 6 months. It is not recommended to take a second course of treatment with triptorelin or another gonadotropin-releasing hormone analogue.

Uterine fibromyoma (before surgery)

Diphereline® 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

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

Instructions for the administration of the drug

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

Suspension of the powder in the supplied solvent should be prepared immediately before administration by gently mixing 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 is usually left in the syringe after injection.

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

1 - PREPARATION OF THE PATIENT

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

2 - INJECTION PREPARATION

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

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

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

Remove the green cap from the vial cap.

Transfer the diluent to the lyophilisate vial.

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

Mix without inverting the vial until a homogeneous mixture is obtained.

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

Draw the entire suspension into the syringe without inverting the vial.

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

Force the air out of the syringe.

3 - INTRAMUSCULAR INJECTION

Inject immediately into the gluteal muscle

4 - AFTER THE INJECTION

Place the needles in a specially designed container.

Side effects

In men

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

Often (³ 1/10); often (of³ 1/100 to< 1/10); infrequently (from³ 1/1000 to< 1/100); rarely (from³ 1/10 000 up to< 1/1 000). It was not possible to determine the frequency of side effects after the drug was placed on the market. Therefore, the frequency of such effects was noted as "unknown".

Classes of organ systems	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 Appetite increase
Mental disorders		Depression mood swings	Insomnia Irritability	Confusion Reduced activity
	Paresthesia of the lower extremities	Dizziness Headache	paresthesia	Memory disorders
				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
	Lower back pain	Musculoskeletal pain Pain in the limbs	Arthralgia muscle cramps muscle weakness	Joint stiffness Joint swelling Musculoskeletal stiffness Osteoarthritis	Pain in the bones
		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 Reaction at the injection site	Lethargy Drowsiness	Chest pain Dystasia flu-like syndrome pyrexia	Malaise
			Elevation of alanine aminotransferase Increased aspartate aminotransferase Increase in blood creatinine Increase in blood urea Weight gain	Increased blood alkaline phosphatase Increase in body temperature Weight loss	Increase in blood pressure

Triptorelin causes a transient increase in circulating testosterone 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 carefully 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 analogues, there was an increase in the content of lymphocytes. This secondary lymphocytosis is likely related to GnRH-induced castration and indicates that sex hormones are involved in thymic involution.

Among women

As a consequence of the decrease in estrogen levels, the most commonly reported side effects (with an expected incidence of 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 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 (of³ 1/100 to< 1/10); infrequently (from³ 1/1000 to< 1/100). It was not adequately possible to determine the frequency of side effects after the drug was placed on the market. Therefore, the frequency of such effects was noted as "unknown".

Classes of organ systems	Often	Often	Infrequently	Frequency unknown
Immune System Disorders				Hypersensitivity reactions
Mental disorders	Sleep disturbance mood swings	Depression*	Depression**	Anxiety Confusion
Disorders from the nervous system	Headache			Dizziness
Disorders of the organs of vision				Decreased visual acuity visual disturbances
Disorders of the hearing organs and labyrinth				Vertigo/dizziness
Vascular disorders	Hot flashes
Respiratory, thoracic and mediastinal disorders
Gastrointestinal Disorders		Abdominal pain Discomfort in the abdomen
Skin and subcutaneous tissue disorders	Hyperhidrosis			Angioedema Hives
Musculoskeletal and connective tissue disorders		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		Weight gain		Increase in blood pressure

*with prolonged use

**for short-term use

At the beginning of treatment, very often (³ 10%) symptoms of endometriosis, including pelvic pain and dysmenorrhea, may worsen, which is associated with a period of initial transient increase in plasma estradiol. These symptoms are temporary and usually disappear 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 (of³ 1/100 to< 1/10). It was not possible to determine the frequency of side effects after the drug was placed on the market. Consequently, the frequency of such effects was noted as "unknown".

Classes of organ systems	Often	Often	Frequency unknown
Immune System Disorders		Hypersensitivity reactions
Mental disorders		Depression mood swings	Emotional lability Nervousness
Disorders from the nervous system		Headache
Disorders of the organs of vision			Decreased visual acuity visual disturbances
Vascular disorders		Hot flashes
Respiratory, thoracic and mediastinal disorders			Nose bleed
Gastrointestinal Disorders			Abdominal pain Discomfort in the abdomen
Skin and subcutaneous tissue disorders			Angioedema Hives
Musculoskeletal and connective tissue disorders
Disorders of the reproductive system and mammary glands		genital bleeding vaginal bleeding
Disorders of a general nature 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			Increase in blood pressure Weight gain

Contraindications

Hypersensitivity to triptorelin or other gonadotropin-releasing hormone analogues

Pregnancy, lactation

Drug Interactions

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

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, such as 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 disturbances, and ophthalmoplegia.

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

Diphereline® 3.75 mg contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially a “sodium-free” preparation.

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

prostate cancer

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

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

As with other GnRH agonists, isolated cases of spinal cord compression or urethral obstruction have been observed. If spinal cord compression or kidney failure develops, standard treatment for these complications should be initiated and, in extreme cases, immediate orchiectomy (surgical castration) should be considered. Careful 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 GnRH analogues, is associated with an increased risk of BMD loss and may lead to osteoporosis and an increased risk of bone fractures.

In addition, it has been observed from epidemiological data that patients with androgen blockade may develop metabolic changes (eg, impaired glucose tolerance), or an increased risk of cardiovascular disease. However, prospective data have not supported an association between GnRH analog treatment and increased cardiovascular mortality. Patients with a 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 is usually restored upon discontinuation of treatment. Therefore, the results of diagnostic tests of the function of the pituitary - gonads system, performed during treatment and after cessation of treatment with GnRH analogues, can be misleading.

At the beginning of treatment, a transient increase in the level of acid phosphatase may be observed.

It may be useful to periodically check the level of testosterone in plasma by an accurate method, it should not exceed 1 ng / ml.

Among women

Before prescribing Diphereline® 3.75 mg, it must be confirmed 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.

The data currently available suggest that in the majority of women bone recovery occurs after cessation of therapy.

There are no specific data in patients with established osteoporosis or with risk factors for osteoporosis (eg, chronic alcohol abuse, smokers, long-term therapy with drugs that reduce BMD, such as anticonvulsants or corticosteroids, family history of osteoporosis, malnutrition, such as anorexia nervosa). Since a decrease in BMD is likely to be more severe in these patients, treatment with triptorelin should be considered on an individual basis after a careful benefit/risk assessment. 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 may be significantly increased in some predisposed patients, especially in cases of polycystic ovary disease. As 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 may 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 close medical supervision with accurate and regular biological and clinical monitoring: frequent plasma estrogen assessment and ultrasonography.

In patients with renal or hepatic insufficiency, triptorelin has a mean half-life of 7-8 hours compared to 3-5 hours in healthy subjects. Despite this long 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 Diphereline® 3.75 mg results in 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, possible organic damage must be ruled out.

Because menstruation must stop during treatment with triptorelin, the patient should be instructed to notify her physician if regular menstruation persists.

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 fibroids. There have been several reports of bleeding in patients with submucosal uterine fibroids following therapy with GnRH analogues. As a rule, bleeding occurred 6-10 weeks after the start of therapy.

precocious 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 a thorough 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 menstruation begins an average of one year after cessation of 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 for central precocious puberty. However, after discontinuation of treatment, there is subsequent recovery of bone mass gain, and treatment ultimately has no effect on peak bone mass in late adolescence.

Epiphysiolysis of the femoral head may be detected after GnRH treatment is stopped. A hypothetical theory for this phenomenon is that low estrogen concentrations during treatment with GnRH agonists may weaken the epiphyseal plate. An increase in growth rate after treatment is stopped subsequently leads to a decrease in the force required to displace the epiphysis.

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. Before treatment, potentially fertile women should be carefully examined to exclude pregnancy. Non-hormonal methods of contraception should be used during therapy and before the resumption of menstruation.

Pregnancy must be ruled out before Diferelin® 3.75 mg is prescribed, 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 during breastfeeding.

Features of the influence of the drug on the ability to drive a vehicle or potentially dangerous mechanisms

No studies have been conducted on the effect of Diferelin® 3.75 mg on the ability to drive a car and work with mechanisms. However, the ability to drive and operate machines may be reduced as a result of dizziness, drowsiness, and visual disturbances, which may be either unwanted effects of treatment or manifestations of an underlying disease.