Triptorelin-long (Diphereline), lyophilizate 3.75mg

In women

1. Preoperative treatment of uterine fibroids:

Patients with anemia (hemoglobin < 80 g/l);

To reduce the size of the fibroid in order to facilitate surgical intervention (reduced blood loss and length of surgery) or change surgical tactics (laparoscopic or transvaginal access).

2. Genital and extragenital endometriosis (stages I-IV).

3. treatment of female infertility: ovulation induction in combination with gonadotropins (FSH, hMG (human menopausal gonadotropin), hCG (human chorionic gonadotropin)) in assisted reproductive technology (ART) programs.

In men

1. Prostate cancer:

– treatment of locally advanced prostate cancer as monotherapy, as part of combination therapy or adjuvant against the background of radiation therapy;

– treatment of metastatic prostate cancer.

Active ingredient

Composition

Composition per 1 vial (lyophilizate):

Active ingredient:

Triptorelin acetate

3.92 mg (4.12 mg*)

calculated to tryptorelin

3.75 mg (3.94 mg*)

Excipients:

DL – lactic and glycolic acid copolymer (1:1)

200 mg

D – mannitol

85 mg

Carmellose sodium

30 mg

2 mg

* Given the nature of the dosage form, there is a 5% excess of the active ingredient in the drug to ensure an effective dose is administered.

The solvent to prepare the suspension is mannitol, 0.8% solution.

The composition per 1 ml: D – mannitol – 8.0 mg, water for injection – up to 1.0 ml.

Interaction

Directions for use

The drug Triptorelin-Long is administered intramuscularly (i.m.). The site of administration should be changed.

Tryptorelin-Long should only be used under the supervision of a physician experienced in this indication.

Fibroid uterus and endometriosis

The drug Triptorelin-Long is administered at a dose of 3.75 mg (1 injection) in an infusion once every 28 days. Treatment should be started in the first 5 days of the menstrual cycle.

The duration of treatment depends on the severity of endometriosis and the observed clinical picture (functional and anatomical changes) and changes in the size of the uterine myoma, determined by ultrasound, during therapy. The duration of use of the drug in endometriosis is 4-6 months because of the possible effect on bone density.

The duration of therapy for preoperative treatment of uterine fibroids is not more than 3 months.

The repeated treatment with triptorelin or other GnRH agonists is not recommended.

VRT

Tryptorelin-lopg is administered once in a dose of 3.75 mg (1 injection) by injection/m on day 2 of the menstrual cycle.

Prostate cancer

Tryptorelin-lopg is administered at a dose of 3.75 mg (1 injection) once every 28 days, monthly.

In patients with locally advanced prostate cancer treated in combination with radiation therapy, long-term antiandrogen therapy (3 years) is preferable to short-term antiandrogen therapy (6 months).

Application in selected patient groups

Dose adjustment is not required in elderly patients and patients with renal dysfunction.

Regulations for suspension preparation and administration

The drug is administered intramuscularly only.

The suspension for intramuscular injection is prepared immediately prior to administration using the solvent provided.

The drug should only be prepared and administered by specially trained medical personnel.

The vial of Triptorelin-Long should be held strictly vertically. Gently tap the vial to ensure that all of the drug is at the bottom of the vial.

– Open the syringe and attach the included 0.8mm x 40mm needle to draw out the solvent.

– Open the solvent ampoule and draw the entire contents of the ampoule into the syringe, setting the syringe to the 2 ml level.

– Remove the plastic cap from the bottle containing the product. Disinfect the rubber stopper of the vial with an alcohol swab. Insert the needle into the vial of the product through the center of the rubber stopper, and gently push the solvent into the inside wall of the vial without touching the contents of the vial with the needle.

– Remove the syringe and needle from the vial.

The bottle should remain still until the solvent has completely saturated and the product is in suspension. Without inverting the vial, check for dry residue on the walls and bottom of the vial. If you find a dry residue of the drug, leave the vial until it is completely saturated (about 3-5 minutes).

– After ensuring that there is no residual dry product, gently circulate the vial for 30-60 seconds to form a homogenous suspension.

Do not invert or shake the bottle.

– Replace the needle on the syringe with a 1.2 mm x 50 mm needle (for the suspension). Insert the needle through the rubber stopper into the vial. Then put the needle down and, tilting the vial at a 45 degree angle, slowly draw the entire suspension into the syringe. Do not turn the vial upside down as you draw. A small amount of drug may remain on the walls and bottom of the vial. Consumption for residue on the walls and bottom of the bottle is included.

– Immediately after drawing the suspension into the syringe, remove the needle. Replace with a 1.1 mm x 40 mm needle, gently invert the syringe and remove any air from the syringe.

Introduce the drug suspension immediately after preparation.

– Use an alcohol swab to disinfect the injection site. Insert the needle deep into the gluteal muscle, then pull the syringe plunger back slightly to make sure there is no vessel damage. Inject the suspension slowly with constant pressure on the syringe plunger. If the needle becomes blocked, replace it with another needle of the same diameter.

– Dispose of needles in containers designated for sharp objects.

– For repeated injections, the left and right gluteal muscles should be alternated.

– If incomplete injections result in loss of a large amount of suspension, the treating physician should be notified.

Special Instructions

Caution should be exercised in patients taking anticoagulants, as hematoma may develop at the injection site.

Fibroid and endometriosis

Pregnancy should be excluded before starting treatment.

The drug Triptorelin-Long should be prescribed only after in-depth diagnosis of uterine myoma and endometriosis (laparoscopy and/or hysteroscopy).

For the duration of treatment, including 3 months from the last injection, non-hormonal contraceptives should be used. Because of the possible effect of the drug Triptorelin-Long on bone mineral density, treatment should not be recommended for more than 6 months. A repeated course of therapy with triptorelin or other GnRH analogues is not recommended.

The treatment of uterine myoma should be performed under ultrasound monitoring, as rapid reduction in uterine size may in some cases lead to uterine bleeding of varying duration and intensity.

In uterine myoma, a combination of therapy with Triptorelin-Long followed by surgical treatment is most appropriate. Appointment of tryptorelin leads to a significant reduction in the size of myomatous uterus, which facilitates the technique of surgery. It is especially advisable to carry out a course of therapy with triptorelin in young patients in order to preserve reproductive function when organ preserving surgery can be performed with the help of laparoscopic technique.

In the first month, bleeding/bloody vaginal discharge of varying intensity and duration may occur. If bleeding/bleeding continues after the first month, plasma estradiol concentrations should be determined. If estradiol concentrations fall below 50 pg/mL, other organic lesions may be present.

After discontinuation of triptorelin therapy, ovarian function is restored in 7-12 weeks. Given that menstruation must stop for the duration of tryptorelin therapy, the patient should be properly instructed to inform her physician if regular menstruation persists. Prostate cancer

In its early stages, Triptorelin-Long causes a temporary increase in plasma testosterone concentrations. As a result during the first weeks of therapy there may be occurrence and increase of clinical symptoms (in particular bone pain, dysuria) which are transient and for which symptomatic therapy should be carried out. As with other GnRH agonists, isolated cases of spinal cord compression or urinary tract obstruction may be identified. In cases of spinal cord compression or urinary tract obstruction, standard treatment for these complications should be prescribed and in urgent cases orchiectomy (surgical castration) is contemplated.

Patients should be closely monitored during the first few weeks of therapy (plasma testosterone concentrations should not exceed 1 ng/ml) especially in patients with metastatic spinal cord lesions, patients at risk of spinal cord compression or urinary tract obstruction. For the same reason, special attention should be given at the start of treatment to patients with signs of spinal cord compression detected at the preliminary examination. During the initial phase of therapy, additional anti-androgenic medications should be considered to prevent an initial increase in plasma testosterone concentrations and a worsening of clinical symptoms.

Epidemiologic data have shown that patients during androgen deprivation therapy may develop metabolic abnormalities (e.g., impaired glucose tolerance); increased risk of cardiovascular disease. However, prospective data have not confirmed an association between GnRH agonist treatment and increased cardiovascular mortality. Patients at high risk for metabolic and cardiovascular disease should be carefully evaluated before treatment is prescribed and closely monitored during androgen deprivation therapy.

A temporary increase in plasma acid phosphatase activity may be observed at the beginning of therapy.

Pituitary and gland function

The use of triptorelin in therapeutic doses leads to suppression of the “gland-pituitary” system. Normal functioning of the sex glands and pituitary gland is usually restored after discontinuation of therapy. The results of a diagnostic test of gonadotropic pituitary function performed during and after discontinuation of therapy may therefore be incorrect.

Osteoporosis

The use of GnRH agonists may cause decreased bone mineral density (BMD).

In men, long-term androgen deprivation with bilateral orchiectomy or with the use of GnRH analogues may be associated with an increased risk of bone mass loss and may lead to osteoporosis and increased risk of bone fracture.

Preliminary data suggest that the use of bisphosphonates in combination with GnRH may reduce BMD loss. Particular attention should be given to patients with risk factors for osteoporosis (for example: chronic alcohol dependence; smoking; long-term therapy with medications that reduce BMD, such as anticonvulsants or glucocorticosteroids; a history of hereditary osteoporosis; and nutritional deficiencies or disorders).

In women, the use of GnRH agonists may be responsible for an average decrease in BMCT of 1% per month over six months of treatment. Every 10% decrease in BMCT leads to an increase in the risk of bone fracture by about 2 to 3 times.

In most women, the BMCT recovers after therapy is discontinued.

There are no available data on the use of triptorelin in patients with established osteoporosis or with risk factors for osteoporosis (e.g: chronic alcohol dependence; smoking; long-term therapy with medications that reduce BMD, such as anticonvulsant medications or glucocorticosteroids; a history of hereditary osteoporosis; nutritional deficiencies or disorders, such as anorexia neurosis). Given that a decrease in BMD is more likely in these patients, triptorelin treatment should be prescribed on an individual basis and can only be initiated if the benefit obtained from treatment is greater than the risk. Additional evaluation should be considered to avoid loss of BMCT.

Pituitary Tumor

Rarely, the use of GnRH agonists may reveal the presence of a previously undiagnosed gonadotropic pituitary adenoma. Hemorrhage to the pituitary gland is characterized by sudden headache, visual disturbances and ophthalmoplegia.

Depression

Patients treated with triptorelin have an increased risk of developing depression (which may be severe). Patients should be informed about the possible development of depression and should receive appropriate therapy if depression develops. Patients with already known depression should be closely monitored during therapy.

QT interval prolongation

Long-term androgen deprivation may prolong the QT interval. A risk/benefit assessment should be performed before prescribing triptorelin in patients with congenital prolonged QT interval syndrome, electrolyte disturbances, or chronic heart failure; or in patients taking medications that may prolong the QT interval or medications that may cause bidirectional spindle ventricular tachycardia, such as Class IA antiarrhythmic drugs (e.g., quinidine, procainamide) or III (for example, amiodarone, sotalol).

Induction of ovulation in ART

Tryptorelin-Long should only be used for IVF infertility treatment under the supervision of a specialist with experience in this field.

In IVF, Triptorelin-Long is used to stabilize the concentration of endogenous sex hormones followed by the administration of gonadotropins to stimulate follicle growth. The use of triptorelin helps to avoid premature spontaneous ovulation of stimulated follicles, which increases the effectiveness of the IVF program as a whole.

Tryptorelin-long is recommended with caution during IVF in patients with polycystic ovary syndrome because of the possible stimulation of a large number of follicles.

Tryptorelin-Long may lead to ovarian hyperstimulation syndrome, regular clinical monitoring is required, including ultrasound of the ovaries.

Plasma estradiol concentration determination is required to monitor ovarian response during ART ovulation induction (interrupt the ovulation stimulation cycle when there is excessive ovarian response and discontinue gonadotropin injections) and clinical manifestations of ovarian hyperstimulation syndrome.

Dose adjustment

Dose adjustment of hypotensive drugs is necessary when combined with Triptorelin-Long.

There are currently no data on the possible effect of Triptorelin-Long on the ability to drive vehicles and mechanisms. Nevertheless, the use of the drug may lead to the development of such adverse reactions as headache, decreased vision, drowsiness which may adversely affect the ability to drive vehicles and perform potentially dangerous activities requiring increased concentration and rapid psychomotor reactions. In case of occurrence of the above symptoms one should refrain from driving vehicles and mechanisms.

Contraindications

– Hypersensitivity to tryptorelin, other GnRH analogues, components of the drug and solvent;

– Condition after previous surgical testiculectomy;

– Pregnancy, period of breastfeeding;

– Childhood under 18 years of age.

– In patients with prostate cancer at high risk of ureteral obstruction or spinal cord compression;

– In patients diagnosed with or at high risk of osteoporosis;

– in patients diagnosed with depression;

– in patients taking anticoagulants, because of the possible development of hematoma at the injection site;

– when performing long-term androgen deprivation in patients with congenital long QT syndrome, with electrolyte disturbances or chronic heart failure, or in patients taking Class IA or Class III antiarrhythmic drugs;

– In androgen deprivation in men at high risk for metabolic disorders and cardiovascular disease;

In the HRT program in patients with polycystic ovaries, especially when the number of follicles determined by ultrasound is greater than 10.

Side effects

Unwanted reactions in men

The unwanted reactions when using triptorelin are related to its expected pharmacological effects: an initial increase in testosterone concentration and then an almost complete suppression of testosterone synthesis.

The frequency of adverse reactions that may occur during therapy is given as the following gradation: Very common (> 1/10), common (> 1/100, < 1/10), infrequent (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000) and frequency unknown (frequency cannot be determined from available data).

Infectious and parasitic diseases: very rare – rhinopharyngitis.

Immune system disorders: very rare – anaphylactic reactions, hypersensitivity.

Metabolic and nutrition disorders: rare – anorexia, decreased appetite, increased appetite; very rare – diabetes; frequency is unknown – gout.

Psychiatric disorders: often – mood changes, depression, sleep disturbance, decreased libido; rarely – irritability, insomnia; very rare – confusion, decreased activity, a sense of euphoria; often unknown – anxiety, loss of libido.

Nervous system disorders: very often – paresthesias of the lower extremities; often – headache; rarely – paresthesias, taste disorders, somnolence, astasia (impaired ability to stand, associated with impaired coordination), lethargy; very rarely – memory impairment; often unknown – dizziness.

Visual disorders: very rare – discomfort in the eyes, blurred vision; frequency unknown – visual impairment.

Hearing and labyrinth disorders: rare – tinnitus; frequency unknown – vertigo.

Vascular disorders: very common – “hot flashes”; infrequent – increased blood pressure, thromboembolism; frequency unknown – decreased blood pressure.

Respiratory system, chest and mediastinum disorders: infrequent – bronchial asthma; rare – dyspnea; very rare – nasal bleeding, dyspnea arising in the prone position.

Gastrointestinal disorders: frequently – nausea; rarely – abdominal pain, constipation, diarrhea, vomiting, abdominal bloating, flatulence, dry mouth; frequency unknown – gastralgia.

Skin and subcutaneous tissue disorders: very common – hyperhidrosis; infrequent – hypotrichosis; rare – alopecia, acne, itching, rash; very rare – blisters; frequency unknown – Quincke’s edema, urticaria, purpura.

Muscular and connective tissue disorders: very often – back pain; often – pain in the extremities; rare – muscle spasm, muscle weakness, myalgia, arthralgia; very rare – joint swelling, stiffness of muscles and joints, osteoarthritis; frequency unknown – musculoskeletal pain, joint stiffness, bone pain.

Kidney and urinary tract disorders: very common – dysuria.

Gender and mammary gland disorders: often – erectile dysfunction; rarely – gynecomastia, testicular atrophy, pain in the testicles, breast engorgement; frequency unknown – pain in the breast, lack of ejaculation.

General disorders and disorders at the injection site: very often – asthenia; often – increased fatigue, reaction at the injection site, pain at the injection site, redness at the injection site, inflammation at the injection site, swelling, irritability; rarely – pain; very rarely – fever, flu-like syndrome; often unknown – feeling of discomfort, chest pain, malaise.

Laboratory and instrumental data: infrequent – increased activity of lactate dehydrogenase, gamma-glutamyltransferase, decreased body weight; rare – increased activity of alanine aminotransferase, aspartate aminotransferase, increased body weight, increased concentration of creatinine, urea in blood plasma; very rare – increased activity of alkaline phosphatase in blood plasma, hyperthermia; frequency unknown – increased blood pressure.

Tryptorelin causes a transient increase in the concentration of circulating testosterone during the first week after the first injection of the drug. As a result, there may be a temporary worsening of prostate cancer symptoms, usually manifested by urinary tract abnormalities and an increase in pain due to a metastatic lesion. These symptoms are transient and usually disappear after 1-2 weeks.

In isolated cases, urinary tract obstruction or metastatic compression of the spinal cord has been reported. As a consequence, patients with metastatic spinal cord lesions and/or upper or lower urinary tract obstruction should be monitored more closely during the first few weeks of therapy. The use of GnRH agonists to treat prostate cancer may be associated with an increased risk of bone mass loss, the development of osteoporosis, and an increased risk of bone fractures.

Patients receiving long-term therapy with GnRH analogues in combination with radiation therapy may experience a greater number of adverse reactions, particularly gastrointestinal, that are associated with undergoing radiation therapy.

Adverse reactions in women

As a consequence of decreased estrogen concentrations, the most common adverse reactions may be: Headache, decreased libido, sleep disturbance, mood changes, dyspareunia, dysmenorrhea, vaginal bleeding, ovarian hyperstimulation syndrome, ovarian enlargement, pelvic pain, abdominal pain, dry vaginal and vulvar mucosa, increased sweating, “hot flashes” and asthenia.

The frequency of adverse reactions that may occur during therapy is given as the following gradation: Very common (> 1/10), common (> 1/100, < 1/10), infrequent (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000) and frequency unknown (frequency cannot be determined from available data).

Immune system disorders: infrequent – anaphylactic reactions; frequency unknown – hypersensitivity.

Psychiatric disorders: very common – decreased libido, mood changes, sleep disturbances; common – depression, depressed mood; common unknown – anxiety, confusion.

Nervous system disorders: very common – headache; common unknown – dizziness, paresthesias.

Visual organ disorders: frequency unknown – blurred vision, visual impairment.

Hearing and labyrinth disorders: frequency unknown – vertigo.

Vascular disorders: very common – “hot flashes”.

Respiratory system, chest and mediastinum disorders: frequency unknown – dyspnea.

Gastrointestinal disorders: very common – abdominal pain; common – nausea, abdominal discomfort; common unknown – diarrhea, vomiting. Skin and subcutaneous tissue disorders: very common – hyperhidrosis; frequency unknown – angioedema, itching, rash, urticaria.

Muscular and connective tissue disorders: very often – bone pain; often – arthralgia, muscle spasm; infrequently – back pain; frequency unknown – myalgia, muscle weakness, bone resorption.

Gender and mammary gland disorders: very often – vaginal bleeding, vaginal mucosal dryness, dyspareunia, dysmenorrhea, ovarian hyperstimulation syndrome, increased ovarian size, pelvic pain, menorrhagia, metrorrhagia; often – pain in the breasts; frequency unknown – amenorrhea.

General disorders and disorders at the injection site: very often – asthenia; often – fatigue, irritability, reactions at the injection site, pain at the injection site, erythema and inflammation at the injection site; often unknown – fever, malaise.

Laboratory and instrumental data: frequently – increase in body weight; infrequently – increased activity of lactate dehydrogenase, gamma-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase, increased cholesterol concentration; frequently unknown – increased blood pressure, decreased body weight.

At the beginning of treatment, during a brief increase in plasma estradiol concentrations, symptoms of endometriosis, including pelvic pain and dysmenorrhea, may worsen. These symptoms are transient and usually disappear after 1-2 weeks. Uterine bleeding, including menorrhagia, metrorrhagia may occur within one month of the first injection. Increased ovarian size, pelvic pain, and/or abdominal pain may occur.

Overdose

Triptorelin overdose has not been described.

In case of overdose symptomatic therapy is indicated.

Pregnancy use