Diphereline (Triptorelin) powder

The composition and form of issue:

Lyophilisate for preparation of solution for subcutaneous injection. 1 vial contains:

triptorelin acetate (in terms of triptorelin) 0.1 mg

auxiliary substances: mannitol — 10,0 mg 

the composition of the solvent (1 ampoule): sodium chloride water for injection 

in vials (with solvent) in packing contour cell 7 sets in a cardboard pack 1 pack.

Lyophilisate for preparation of suspension for intramuscular introduction of the prolonged action. 1 vial contains:

triptorelin acetate (in terms of triptorelin) 3.75 in* mg

auxiliary substances: copolymer of DL-lactic and glycolic acid mannitol carmellose sodium Polysorbate-80 

the composition of the solvent (ampoule 1): mannitol water for injection 

*taking into account characteristics of the dosage form laid in the preparation of an excess of the active component to ensure the introduction of effective dose 

in vials (complete with a solvent in ampoules, a syringe and two needles) in the paper cartons 1 set.

Lyophilisate for preparation of suspension for intramuscular introduction of the prolonged action. 1 vial contains:

triptorelin pamoate (in terms of triptorelin) 11,25* mg

auxiliary substances: copolymer of DL-lactic and glycolic acid mannitol carmellose sodium Polysorbate-80 

the composition of the solvent (ampoule 1): mannitol water for injection 

*taking into account characteristics of the dosage form laid in the preparation of an excess of the active component to ensure the introduction of effective dose 

in vials (complete with a solvent in ampoules, a syringe and two needles) in the paper cartons 1 set.

Description pharmaceutical form:

Diphereline 0.1 mg: lyophilisate almost white, dispersed in the supplied solvent with the formation of a clear solution, practically free from particles.

Diphereline 3.75 mg: powder white or white with kremovatam white color, dispersed in the supplied solvent to form a suspension of white or white with kremovatam white color.

Diferelin of 11.25 mg: powder in white or slightly yellowish, dispersed in the supplied solvent to form a suspension of white or slightly yellowish color.

The attached solvent — transparent, colorless solution.

Pharmacokinetics:

Diphereline 0.1 mg

After p/to the injection to healthy adult volunteers in a dose of 0.1 mg triptorelin is rapidly absorbed (time to reach Cmax — (0,63±0,26) h with a peak plasma concentration, components (1,85±0,23) ng/ml).

T1/2 is (7,6±1,6) h, 3-4 h after ending phase of distribution.

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

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

Diphereline 3.75 mg

After intramuscular injection of long-acting forms of the drug occurs the initial stage of fast liberation of medicinal substance with the subsequent phase of constant release of triptorelin. Cmax is (0,32±0,12) ng/ml.

The average number constantly triptorelin is released (46,6±7,1) µg/day.

Drug bioavailability is about 53% for 1 month.

Diphereline 11,25 mg

Intramuscular injection of Diphereline at a dose of 11.25 mg triptorelin Cmax in plasma (men and women) is determined approximately 3 h after injection. After a phase of decrease in concentration continued in the first month, 90-day 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).

Description pharmacological action:

Triptorelin is a synthetic Decapeptide analogue of natural gonadotropin-releasing hormone, gonadotropin releasing.

Diphereline 0.1 mg

Animal studies and clinical studies showed that after an initial period of stimulation prolonged use of Diphereline 0.1 mg inhibits the secretion of gonadotropins followed by suppression of ovarian function.

The constant use of Diphereline 0.1 mg inhibits the secretion of gonadotropins (FSH and LH). The intermediate suppression of endogenous LH peaks allows to improve the quality of folliculogenesis by increasing the number of maturing follicles and, consequently, increase the probability of pregnancy per cycle.

Diphereline 3.75 mg

After a short initial period of stimulation of the gonadotropic function of the pituitary gland triptorelin inhibits the secretion of gonadotropins and, consequently, the function of the testes and ovaries. The constant use of the drug inhibits the secretion of estrogen by the ovaries before menopause and decreases the secretion of testosterone, the concentration of which can achieve the performance that is observed after surgical castration.

Diphereline 11,25 mg

In the initial period of application Diphereline 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 reduction of indicators of testosterone (to levels corresponding to the state after testiculate) and estradiol (to levels corresponding to the state of postovariectomy) to approximately the 20 th day after the first injection and remain constant throughout the period of drug administration.

Long-term treatment with triptorelin inhibits the secretion of estradiol in females and, thus, prevents the development of endometrial ectopia.

Indications:

Diphereline 0.1 mg

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

Diphereline 3.75 mg

prostate cancer

precocious puberty

genital and extragenital endometriosis

fibroids of the uterus (before surgery)

female infertility (in vitro fertilization).

Diphereline 11,25 mg

prostate cancer with metastasis

genital and extragenital endometriosis (I–IV stages).

Contraindications:

Common dosages:

hypersensitivity

pregnancy

breast-feeding.

Diphereline 11,25 mg (optional):

gormononezawisimaya prostate cancer

state after prior surgery testiculate.

Diphereline 3,75 11,25 mg (optional):

Be wary, with osteoporosis.

Diphereline 11,25 mg (optional):

With caution in women with polycystic ovary syndrome.

Application of pregnancy and breast-feeding:

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

Pregnancy is a contraindication to the use of the drug. However, experience has shown that after ovulation, stimulated in the previous cycle, some women get pregnant without stimulation and continued to advance the course of ovulation stimulation.

Summary data: animal studies have shown that the drug has no teratogenic effect.

Thus, it is not expected the development of congenital anomalies in humans when using this drug, since 2 high-quality animal studies have not revealed any teratogenic effect.

The results of clinical studies involving a small number of pregnant women with the use of gonadotrophin-releasing hormone showed no fetal malformations or fetotoksicnosti.

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

Since there are no data on the penetration of the drug into breast milk and its possible effects on breastfeeding of the child, should be treated in the lactation period.

Side effects:

Common dosages

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

During treatment. The most frequent side effects such as sudden hot flashes, vaginal dryness, decreased libido and dyspareunia associated with pituitary-ovarian blockade.

Prolonged use of analogues of gonadotropin-releasing hormone can lead to demineralization of the bones and risk of osteoporosis (the above side effects was observed in short-term use of Diphereline 0.1 mg).

Allergic reactions: hives, rash, itching, rarely — angioedema.

In rare cases — nausea, vomiting, weight gain, increased blood pressure, emotional lability, impaired vision, pain at the site of injection.

Rarely — headache, joint and muscle pain.

Diphereline 3.75 mg additionally

In men — reduced potency. In the early treatment of patients with prostate cancer may experience temporary increased pain in the bones affected by metastases (symptomatic treatment). In some cases, there are obstructions in the ureters and the symptoms associated with metastatic compression of the spinal cord (pass through 1-2 weeks). Also during this period there may be a temporary increase in the activity of acid phosphatase in the blood plasma.

In the treatment of precocious puberty in girls may experience bleeding from the vagina.

Prolonged use of the drug can cause hypogonadotropic amenorrhea.

After cessation of treatment, ovarian function is restored and ovulation occurs on average 58 days after the last injection. The first menstruation comes on the 70th day after the last injection of Diphereline. This should be considered in the planning of contraception.

Diphereline 11,25 mg additionally

Men

At the beginning of treatment. Dysuric disorders (difficulty urinating, incomplete bladder emptying, pain), bone pain associated with metastases and metastatic compression of the spinal cord, which may worsen due to the temporary increase in the levels of testosterone in plasma at the beginning of treatment. These symptoms pass in 1-2 weeks. Also in this period may experience a temporary increase in liver enzymes in the blood plasma.

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

Women

At the beginning of treatment. Symptoms associated with endometriosis (pelvic pain, dysmenorrhoea), which can be heightened in connection with an initial transient increase in the concentration of estradiol in plasma and disappear after 1-2 weeks.

A month after the first injection can occur metrorrhagia.

Men and women:

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

Drug interactions:

Not described.

Method of application and dose:

Diphereline 0.1 mg P/K.

The short Protocol. Starting from the 2nd day of the cycle (at the same time starting the stimulation), and finished treatment 1 day prior to the scheduled administration of human chorionic gonadotropin. The course of treatment is 10-12 days.

Long Protocol. Daily subcutaneous injection of Diphereline® 0.1 mg starting from the 2nd day of the cycle. When pituitary desensitization (E2 <50 15-=”” 0=”” 1=”” p=””>

Rules of preparation of the solution. Immediately before injection to transfer the solvent into the vial of lyophilisate. Shake until complete dissolution. Used needles should be placed in special sharps container.

Diphereline 3,75 mg/m.

Cancer of the prostate. Diferelin 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 to children with body weight less than 20 kg 1,875 mg every 28 days.

The endometriosis. The drug should be administered during the first 5 days of the menstrual cycle at a dose of 3.75 mg every 4 weeks. Duration of therapy — not more than 6 months.

Female infertility. Diferelin must be entered 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 estrogen in blood plasma of less than 50 PCG/ml is normally determined 15 days after injection of Diphereline).

Fibroids of the uterus. The drug should be administered during the first 5 days of the menstrual cycle. Introduction Diphereline should be done every 4 weeks at a dose of 3.75 mg. the Duration of treatment — 3 months (for patients preparing for surgery).

Rules of preparing a suspension of

Dissolution of the lyophilizate in the attached solvent should be performed immediately before administration. Stir the contents of the vial, care should be taken to obtain a homogeneous suspension.

The cases of incomplete implementation of the injection, leading to loss of more slurry than usual remains in the syringe for injection, you must inform your doctor.

The introduction should be in strict accordance with the instructions.

1. To treat the injection site with a tissue with alcohol. Remove the needle cap with the pink nozzle and attach it to the syringe. To dial into the syringe all the solvent from the ampoule.

2. Remove the plastic cap from the vial of lyophilisate. Insert the needle through the cork from chlorobutyrate and transfer the solvent into the vial.

3. Pull the needle so that it remains in the bottle, but never touched suspension.

4. Gently stir the contents to obtain a homogeneous suspension, without turning the bottle.

5. Not inverting the bottle to dial into the syringe the entire suspension.

6. Pink to remove the needle from the syringe. Attach to syringe green needle (to tie tightly), starting just for the color tip.

7. To remove air from the syringe.

8. Immediately make an injection. Injection to enter only intramuscularly.

9. Immediately after the injection to close the needle using a protective device by one of the following ways:

– press in the protective device toward the tip of the needle. Close the needle and to latch the device

– turn the syringe. Using a flat surface apply pressure to the device and close the needle.

10. The needle is closed, if needle tip is covered by the device. Inspect closed device.

11. To detach the needle to use coloured head. Dispose of needles in containers designed for sharps.

Diferelin of 11.25 mg./m

Cancer of the prostate. Diferelin administered at a dose of 11.25 mg every 3 months.

The endometriosis. Diferelin administered at a dose of 11.25 mg every 3 months. Treatment should start in the first five days of the menstrual cycle. The duration of treatment depends on the severity of endometriosis and the observed clinical picture (the functional and anatomical changes) in the background therapy. As a rule, the treatment is carried out for 3-6 months. Not recommended for repeated treatment triptoreline or gonadotropin-releasing hormone.

Rules of preparing a suspension of

Dissolution of the lyophilizate in the attached solvent should be performed immediately before administration. Stir the contents of the vial, care should be taken to obtain a homogeneous suspension.

The cases of incomplete implementation of the injection, leading to loss of more slurry than usual remains in the syringe for injection, you must inform your doctor.

The introduction should be in strict accordance with the instructions.

1. To treat the injection site with a tissue with alcohol. Remove the needle cap with a pink tip and attach it to the syringe. To dial into the syringe all the solvent from the ampoule.

2. Remove the plastic cap from the vial of lyophilisate. Insert the needle through the cork from chlorobutyrate and transfer the solvent into the vial.

3. Pull the needle so that it remains in the bottle, but never touched suspension.

4. Not inverting the vial, gently stir the contents to obtain a homogeneous suspension.

5. Not inverting the bottle to dial into the syringe the entire suspension.

6. To remove the needle with pink tip from the syringe. To attach needle to syringe with a green tip (or needle with a green tip and a protective device), tightly screwed, picking up just for the color tip.

7. To remove air from the syringe.

8. Immediately make an injection.

If you are using a needle with a green tip and a protective device, then:

9. Immediately after the injection to close the needle using a protective device by one of the following ways:

9.1. To put pressure on the protector toward the needle tip. Close the needle and to latch the device.

Or:

9.2. Flip the syringe using a flat surface apply pressure to the device and close the needle.

10. The needle is closed, if needle tip is covered by the device. Inspect closed device.

11. To detach the needle, use a colored tip.

12. Dispose of needles in containers designed for sharps.

Overdose:

Cases of overdose are unknown.

Special instructions:

Diphereline 0.1 mg

Warning. The response of the ovaries to the introduction of Diphereline 0.1 mg, in combination with gonadotropins may significantly increase this in predisposed patients and particularly in cases of polycystic disease of the ovaries.

The response of the ovaries to the introduction of the drug in combination with gonadotropins may vary in patients, it can also be different from the same patients at different cycles.

Preventive measures. Stimulation of ovulation must be performed under medical supervision and with regular biological and clinical methods of analysis: an increase in the levels of estrogen in the plasma and ultrasound echocardiography. If the response of the ovaries excessive, it is recommended to interrupt the stimulation cycle and to stop the injection of gonadotropin.

Diphereline 3.75 mg

At the beginning of treatment may be exacerbation of the clinical symptoms, and therefore should be used with caution in Diferelin patients with prostate cancer, risk of obstruction of the ureters or compression of the spinal cord. Careful monitoring of these patients during the first month of therapy.

Before therapy with Diferelin need to confirm the absence of pregnancy.

To apply caution in patients with polycystic ovary syndrome when carrying out schemes for ovulation stimulation. This is due to the fact that a small number of patients may increase the number of induced follicles.

It is necessary to carefully monitor the level of stimulation cycle with in vitro fertilization to identify patients with risk of developing ovarian hyperstimulation syndrome, as the severity and frequency of the 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

The treatment of endometriosis. Before treatment should be deleted pregnancy.

During the first month of therapy should be to use a non-hormonal method of contraception.

Intramuscular injection of the drug leads to permanent hypogonadotropic amenorrhea.

Treatment should not be recommended for a period of more than 6 months. Not recommended for repeated therapy with triptorelin or other analogue of gonadotropin-releasing hormone.

The occurrence of metrorrhagia in the course of treatment, not counting the first month is not the norm, it was necessary to determine the concentration of estradiol in plasma. At lower concentration of estradiol to levels less than 50 PG/ml the presence of other organic lesions.

Ovarian function is restored after completion of therapy. The first menstruation occurs on average 134 days after the last injection. For this reason, begin to use birth control should be within 15 days after discontinuation of treatment, ie after 3.5 months after the last injection.

In the treatment of prostate cancer. The most pronounced beneficial effect observed in patients in the absence of other previously conducted hormonal therapy.

At the beginning of treatment may experience the emergence and exacerbation of the clinical symptoms (particularly bone pain, dysuric disorders), which bears a transitory character.

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

Treatment Diphereline should be carried out in strict accordance with the instructions for use. Any change in the volume of injected a/m suspension should be recorded.