Decapeptyl depot

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DЕCAPЕPTYL DЕPO (DECAPEPTYLDEPO)

Composition:

Active substance: triptorelin acetate;

1 vial with powder contains triptorelin acetate 4.12 mg, equivalent to triptorelin 3.75 mg;

Excipients: poly(lactic-co-glycolic acid) (1:1), propylene glycol dicaprylate dicaprate;

1 syringe (1 ml) of solvent contains: dextran 70; polysorbate 80; sodium chloride; sodium dihydrogen phosphate dihydrate; 1 N sodium hydroxide solution; water for injections.

Pharmaceutical form. Powder for suspension for injection.

Main physicochemical properties:

1 vial with powder contains a powder in the form of microcapsules from white to pale yellow in color; 1 syringe with solvent contains a clear, colorless liquid.

Pharmacotherapeutic group. Agents used for hormonal therapy. Gonadotropin-releasing hormone analogues. ATC code L02A E04.

Pharmacological properties.

Pharmacodynamics.

Triptorelin is a synthetic decapeptide analogue of the natural gonadotropin-releasing hormone (GnRH). GnRH is a decapeptide synthesized in the hypothalamus that regulates the biosynthesis and secretion of gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) by the pituitary gland. Triptorelin provides a stronger stimulation of pituitary LH and FSH secretion than an equivalent dose of gondadorelin, and has a longer duration of action. The initial increase in LH and FSH levels leads to an increase in serum testosterone concentration in men or serum estrogen concentration in women. Prolonged administration of GnRH agonists leads to suppression of LH and FSH secretion. This suppression results in reduced biosynthesis of steroid hormones, causing serum estrogen levels in women and serum testosterone levels in men to fall to postmenopausal or post-castration levels, respectively—i.e., to a hypogonadotropic hypogonadal state.

In children with precocious puberty, estradiol or testosterone concentrations decrease to prepubertal levels. Plasma levels of DHEAS (dehydroepiandrosterone sulfate) remain unchanged. From a medical standpoint, this leads to shrinkage of testosterone-sensitive prostate tumors in men and reduction of endometriosis lesions and estrogen-dependent uterine fibroids in women. Regarding uterine fibroids, the maximum treatment effect is observed in women with anemia (hemoglobin level ≤ 8 g/dL). In children with precocious puberty (PP), triptorelin treatment leads to suppression of gonadotropin, estradiol, and testosterone secretion to prepubertal levels. This results in slowing or even regression of signs of pubertal development and allows prediction of adult height in patients with PP.

Decapeptyl Depot prevents the rise in LH levels and, consequently, prevents premature ovulation and/or follicular luteinization; it reduces cycle cancellation rates and increases pregnancy rates in assisted reproductive technology (ART) cycles.

Pharmacokinetics.

After intramuscular administration of Decapeptyl Depot, triptorelin plasma concentration is determined by the slow degradation of the poly-(d,l-lactide-co-glycolide) polymer. The inherent mechanism of action of this dosage form enables sustained release of triptorelin from the polymer.

Following intramuscular or subcutaneous administration of the triptorelin depot formulation (sustained-release microcapsules), a rapid increase in triptorelin plasma concentration occurs, reaching a peak within the first few hours after injection. Subsequently, triptorelin concentration markedly declines over 24 hours. On day 4, levels reach a second peak, then decline in a biexponential manner to undetectable levels within 44 days. After subcutaneous injection, the decline in triptorelin concentration lasts longer, reaching below the limit of detection within 65 days.

During a 6-month treatment course with administration every 28 days, there is no evidence of triptorelin accumulation with either route of administration. After intramuscular or subcutaneous injection, triptorelin plasma concentration decreases to approximately 100 pg/mL by the time of the next dose (median values). It is presumed that nonsystemically available amounts of triptorelin are metabolized at the injection site, for example, by macrophages.

Systemically available triptorelin is inactivated in the pituitary gland via N-terminal cleavage by pyroglutamyl-peptidase and neutral endopeptidase. In the liver and kidneys, triptorelin is degraded into biologically inactive peptides and amino acids. Within 40 minutes after administration of 100 mcg triptorelin (and over the following hour), 3–14% of the administered dose is already excreted by the kidneys.

For patients with renal impairment, dose adjustment or individualization of treatment with triptorelin depot formulation is considered unnecessary due to the minor role of renal excretion and the wide therapeutic index of triptorelin as the active component.

Biological availability

Men

Systemic bioavailability of the active component triptorelin from the intramuscular depot is 38.3% during the first 13 days. Subsequent release is linear, averaging 0.92% of the dose per day. Bioavailability after subcutaneous administration is 69% relative to intramuscular administration.

Women

By day 27 of the study, on average, 35.7% of the administered dose can be accounted for, of which 25.5% is released during the first 13 days, with subsequent linear release averaging 0.73% of the dose per day.

General data

Kinetic parameter calculations within the standard paradigm (t1/2, Kel, etc.) are not appropriate in cases involving very slow release of the active component.

Clinical characteristics.

Indications.

Men

• Treatment of hormone-dependent progressive or metastatic prostate cancer.

Women

• Preoperative reduction of fibroid size to control bleeding and pain in women with symptomatic uterine fibroids.
• Treatment of symptomatic endometriosis confirmed by laparoscopy, when suppression of ovarian hormone production or surgical intervention is not the primary treatment option.
• Prevention of premature elevation of luteinizing hormone (LH) levels in women undergoing controlled ovarian stimulation as part of assisted reproductive technologies (ART).

Children:

• Treatment of confirmed central precocious puberty (girls under 9 years, boys under 10 years).

Contraindications.

• Known hypersensitivity to triptorelin, polyglycolic-lactic acid polymer, dextran, or to any excipient;
• hypersensitivity to gonadotropin-releasing hormone (GnRH) or to any GnRH analogue;
• pregnancy or breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Caution should be exercised when triptorelin is administered concomitantly with medicinal products affecting pituitary gonadotropin secretion; hormonal status monitoring of the patient is also recommended.

Since androgen deprivation may lead to QT interval prolongation, concomitant use of Decapeptyl Depot with medicinal products known to prolong the QT interval or those that may induce torsades de pointes ventricular tachycardia—such as class IA antiarrhythmics (e.g., quinidine, disopyramide) or class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, antipsychotics, etc.—should be carefully evaluated.

No formal drug interaction studies have been conducted. The possibility of interactions with commonly used medicinal products, including histamine-releasing agents, cannot be excluded.

Theoretically, calcium antagonists might interfere with the mechanism of action underlying GnRH and GnRH analogues. However, results from previous trials assessing the ability of triptorelin depot formulation to achieve long-term suppression of serum testosterone during concomitant therapy with calcium antagonists provided no evidence of such interaction.

Special precautions for use.

General

Administration of GnRH agonists may lead to a decrease in bone mineral density.

Preliminary data indicate that the use of bisphosphonates in combination with a GnRH agonist effectively counteracts the reduction in bone mineral density in men.

Particular caution is required in patients with additional risk factors for osteoporosis (such as chronic alcoholism, smoking; long-term treatment with drugs that reduce bone mineral density, e.g., anticonvulsants or corticosteroids; genetic predisposition to osteoporosis; nutritional disorders).

In rare cases, treatment with GnRH agonists may reveal a previously undiagnosed gonadotroph pituitary adenoma. In such patients, pituitary apoplexy may occur, characterized by sudden headache, vomiting, visual disturbances, and ophthalmoplegia.

Patients undergoing treatment with GnRH agonists such as triptorelin have an increased risk of developing depression (which may be severe). Patients should be informed about this risk and treated appropriately if symptoms occur.

Mood changes have been reported. Patients with a known history of depression should be closely monitored during treatment.

Men

Initially, triptorelin, like other GnRH agonists, causes a transient increase in serum testosterone levels. As a consequence, rare cases of transient worsening of signs and symptoms of prostate cancer may develop during the first weeks of treatment. During the initial phase of treatment, the possibility of adding an appropriate antiandrogen should be considered to counteract the initial rise in serum testosterone levels and the worsening of clinical symptoms.

In a small number of patients, a temporary worsening of signs and symptoms of prostate cancer (transient worsening of tumor clinical manifestations) and a temporary increase in cancer-related pain (metastatic pain) may occur, requiring symptomatic treatment.

As with other GnRH agonists, isolated cases of spinal cord compression or urethral obstruction have been observed. In the event of spinal cord compression or renal failure, standard treatment for these complications should be initiated, and in extreme cases, immediate orchidectomy (surgical castration) is recommended. Close monitoring is recommended during the first weeks of treatment, especially in patients with metastatic vertebral lesions due to the risk of spinal cord compression, and in patients with urethral obstruction.

After surgical castration, triptorelin does not cause any further reduction in serum testosterone levels.

Long-term androgen deprivation due to bilateral orchidectomy or the use of GnRH analogs leads to accelerated bone loss, which may result in osteoporosis and an increased risk of bone fractures.

Androgen deprivation may prolong the QT interval.

In patients with a history of risk factors for QT interval prolongation or in those currently having such risk factors, as well as in patients receiving concomitant medications that may prolong the QT interval, the benefit-risk ratio should be evaluated, including the potential for torsades de pointes, before initiating treatment with Decapeptyl Depot.

Furthermore, according to epidemiological data, metabolic changes (e.g., impaired glucose tolerance) or an increased risk of cardiovascular diseases have been observed in patients during antiandrogen therapy. However, prospective data have not confirmed an association between treatment with GnRH analogs and increased cardiovascular mortality. Patients at high risk of metabolic or cardiovascular disorders should undergo thorough evaluation before starting treatment and require appropriate monitoring during antiandrogen therapy.

Therapeutic doses of triptorelin cause suppression of the hypothalamic-pituitary-gonadal system. Normal function usually recovers after treatment ends. Therefore, diagnostic tests of hypothalamic-pituitary-gonadal function during and after completion of treatment with GnRH analogs may be misleading.

Women

Decapeptyl Depot should be prescribed only after a precise diagnosis (e.g., laparoscopy).

Before administering triptorelin, it must be confirmed that the patient is not pregnant.

During treatment with Decapeptyl Depot, menstruation ceases. If regular menstruation persists, the patient should inform her physician.

Loss of bone mineral density.

Administration of GnRH agonists over a six-month treatment course may cause a decrease in bone mineral density by an average of 1% per month. A 10% reduction in bone mineral density doubles or triples the risk of fractures. Therefore, treatment duration without bone-protective therapy should not exceed 6 months. Recovery of bone mass occurs within 6–9 months after discontinuation of treatment.

Available data indicate that in most women, bone mass recovers after treatment is discontinued.

There are no specific data on patients with severe osteoporosis or those with high-risk factors for osteoporosis (e.g., chronic alcoholism, smoking; long-term treatment with drugs that reduce bone mineral density, such as anticonvulsants or corticosteroids; genetic predisposition to osteoporosis; nutritional disorders such as anorexia nervosa). Since bone mineral density reduction may be more harmful in such patients, the decision to treat with triptorelin should be made individually after careful evaluation and only if the benefits outweigh the risks. Additional measures to prevent bone mineral density loss are recommended.

Uterine fibroids and endometriosis

Further uterine bleeding should not occur during treatment (except during the first month); otherwise, plasma estrogen levels should be checked. If estrogen levels are below 50 pg/mL, possible organic lesions should be investigated. Ovarian function recovers after treatment discontinuation. For example, menstrual bleeding resumes 7–12 weeks after the last injection.

During the first month of treatment, non-hormonal contraceptives should be used, as the initial gonadotropin surge may stimulate ovulation. They should also be used from 4 weeks after the last injection until menstruation resumes or until another contraceptive method is initiated.

During treatment of uterine fibroids, the size of the uterus and fibroids should be monitored regularly, e.g., by ultrasound. Disproportionately rapid reduction in uterine size compared to fibroid tissue shrinkage has in some cases led to bleeding and sepsis.

Cases of bleeding have been reported in patients with submucosal fibroids after treatment with GnRH analogs. Bleeding typically begins 6–10 weeks after starting treatment.

Prevention of premature LH surge

Assisted reproductive technologies are associated with an increased risk of multiple pregnancies, fetal death, ectopic pregnancy, and congenital fetal malformations. These risks are also possible when using Decapeptyl Depot as an adjunctive therapy during controlled ovarian hyperstimulation. The use of Decapeptyl Depot for controlled ovarian hyperstimulation may increase the risk of ovarian hyperstimulation syndrome (OHSS) and ovarian cyst formation.

Follicular stimulation induced by GnRH analogs and gonadotropins may be significantly enhanced in a small number of susceptible patients, particularly those with polycystic ovary syndrome.

As with other GnRH analogs, cases of OHSS have been reported with the use of triptorelin in combination with gonadotropins.

Ovarian hyperstimulation syndrome (OHSS)

OHSS is a distinct medical condition, clearly different from uncomplicated ovarian enlargement. OHSS is characterized by varying degrees of severity, including marked ovarian enlargement, high serum levels of sex steroid hormones, and increased vascular permeability, which may lead to fluid accumulation in the peritoneal, pleural, and rarely pericardial cavities.

In severe cases, symptoms of OHSS may include abdominal pain, abdominal distension, marked ovarian enlargement, weight gain, dyspnea, oliguria, and gastrointestinal symptoms such as nausea, vomiting, and diarrhea. Clinical examination may reveal reduced circulating blood volume, hemoconcentration, electrolyte imbalance, ascites, hemoperitoneum, pleural effusion, hydrothorax, acute respiratory distress, and thromboembolic complications.

Excessive ovarian response to gonadotropin treatment rarely leads to OHSS if hCG is not used to trigger ovulation. Therefore, in cases of OHSS, hCG administration should be postponed, and patients should be advised to abstain from sexual intercourse or use barrier contraception for at least 4 days. OHSS may progress rapidly (within 24 hours to several days) and evolve into serious complications; therefore, patients should be monitored for at least two weeks after hCG administration.

OHSS may be more severe and prolonged if pregnancy occurs. OHSS most commonly develops after the end of endocrine therapy and reaches its peak severity 7–10 days after treatment ends. Typically, OHSS resolves spontaneously with the onset of menstruation.

In cases of severe OHSS, gonadotropin treatment should be discontinued, the patient should be hospitalized, and specific therapy initiated, including bed rest, intravenous infusions of electrolyte or colloid solutions, and heparin.

OHSS frequently occurs in patients with polycystic ovary syndrome. The risk of OHSS may be higher when GnRH agonists are used in combination with gonadotropins than with gonadotropins alone.

Ovarian cysts

Ovarian cysts may occur in the initial phase of treatment with GnRH agonists. They are usually asymptomatic and non-functional.

Children

The biological age at the start of treatment should be up to 9 years in girls and up to 10 years in boys.

In girls, initial stimulation of the ovaries and subsequent estrogen release during the first month of treatment may lead to low- or moderate-intensity vaginal bleeding.

After therapy completion, signs of sexual maturation develop.

Current data on future fertility are limited. In most girls, menstruation resumes on average one year after treatment ends and is usually regular.

During treatment of central precocious puberty, GnRH agonists may reduce bone mineral density. However, after treatment cessation, further bone mass accumulation occurs, and peak bone mass in late puberty is not affected.

After discontinuation of GnRH agonist treatment, slipped capital femoral epiphysis may develop.

There is a theory that low estrogen concentrations during GnRH agonist treatment weaken the epiphyseal plate. Accelerated growth after treatment cessation leads to reduced transverse strength required for epiphyseal displacement.

Before treating children with progressive brain tumors, a careful individual risk-benefit assessment should be performed.

Pseudoprecocious puberty (e.g., tumors of the gonads or adrenal glands, hyperplasia) and gonadotropin-independent precocious puberty (e.g., Leydig cell tumors, inherited Leydig cell hyperplasia) should be ruled out prior to treatment.

Allergic and anaphylactic reactions have been reported in adults and children, including both injection-site reactions and systemic manifestations. The pathogenesis has not been determined. Such reactions occur more frequently in children.

Decapeptyl Depot contains less than 1 mmol (23 mg) of sodium per dose.

Use during pregnancy or breastfeeding.

Pregnancy.

Women of reproductive age should undergo thorough examination before starting treatment to exclude the possibility of pregnancy, and effective non-hormonal contraception should be used during treatment until menstruation resumes.

Triptorelin should not be used during pregnancy, as concomitant use of GnRH agonists is associated with a theoretical risk of miscarriage or fetal malformations.

Very limited data on triptorelin use during pregnancy do not indicate an increased risk of congenital malformations, but the number of long-term prospective developmental studies is too limited. Animal studies do not indicate direct or indirect harmful effects on pregnancy or postnatal fetal development, but evidence of fetotoxicity and delayed delivery exists. Based on pharmacological action data, an adverse effect on pregnancy and the fetus cannot be excluded; therefore, Decapeptyl Depot should not be used during pregnancy.

There are no clinical data establishing a causal relationship between triptorelin use and any subsequent oocyte development abnormalities, pregnancy course, or outcomes when triptorelin is used for infertility treatment.

Breastfeeding period.

It is unknown whether triptorelin passes into breast milk. Due to the potential for adverse reactions in infants, breastfeeding should be discontinued before starting and during treatment with the drug.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect on the ability to drive or operate machinery have not been conducted. However, the ability to drive or operate machinery may be impaired if the patient experiences dizziness, somnolence, or visual disturbances, which are possible side effects of treatment or related to the underlying disease.

Method of Administration and Dosage

The medication must be administered exclusively under the supervision of a qualified specialist in a healthcare facility equipped with the necessary resources for regular monitoring of treatment efficacy.

Treatment of children with triptorelin should be conducted under the overall supervision of a pediatric endocrinologist or pediatrician (endocrinologist) experienced in managing central precocious puberty.

Prior to initiating therapy, administration of estrogen-containing medications (e.g., oral contraceptives) should be discontinued. During treatment of uterine fibroids and endometriosis, non-hormonal contraceptive methods must be used throughout the first month of treatment.

It is essential to administer the sustained-release formulation strictly according to the instructions.

The suspension must be administered immediately after reconstitution.

Dosage and Administration

The contents of one syringe, corresponding to 3.75 mg of triptorelin, should be administered subcutaneously (e.g., into the abdominal wall, buttocks, or thigh) or deep intramuscularly every 28 days. The injection site must be rotated with each administration.

Men

• Prostate cancer

One injection of a single syringe containing 3.75 mg of triptorelin should be administered once every four weeks. To achieve sustained suppression of testosterone levels, treatment must be continued on a four-weekly schedule.

Women

• Uterine fibroids and endometriosis

One injection of a single syringe containing 3.75 mg of triptorelin should be administered once every four weeks. Treatment should be initiated within the first 5 days of the menstrual cycle.

• Assisted reproductive technologies

One injection on day 2 or 3 of the cycle (follicular phase) or on day 22 of the cycle (luteal phase).

Children:

• Central precocious puberty (CPP)

Initial dosing is based on the patient's body weight (see table). One injection of triptorelin is administered on days 0, 14, and 28. Subsequently, one injection should be given every 4 weeks. If the response is inadequate, injections may be administered every 3 weeks.

Duration of use

Men

• Prostate cancer

Treatment with Decapeptyl Depot is usually long-term.

Women

• Uterine fibroids and endometriosis

The duration of treatment depends on the initial severity of endometriosis and the progression of its clinical manifestations (functional and anatomical), as well as on the increase in uterine fibroid volume determined by ultrasound scanning during treatment. Usually, the maximum effect is achieved after 3–4 injections.

Due to the potential effect on bone density, the duration of treatment with Decapeptyl Depot without add-back therapy should not exceed 6 months.

Children

• Central precocious puberty (CPP)

Treatment should be discontinued if skeletal maturation occurs in girls aged 12 years and older and in boys aged 13 years and older.

Special patient groups

There is no need to adjust the dose in elderly patients.

According to available data, dose reduction or prolongation of the dosing interval is not required in patients with renal impairment.

Children. Indicated in children for the treatment of confirmed central precocious puberty (girls under 9 years of age, boys under 10 years of age).

Overdose.

Insufficient data on triptorelin overdose are available to draw conclusions about possible adverse reactions. Given the packaging type and formulation, overdose is unlikely.

In case of overdose, symptomatic treatment should be administered.

Adverse Reactions

Below is information on adverse events observed in patients treated with triptorelin during clinical studies and from post-marketing surveillance.

Due to decreased testosterone or estrogen levels, most patients experience adverse reactions, the most common of which are hot flushes (30% in men and 75–100% in women). Additionally, impotence and decreased libido were observed in 30–40% of male patients, and in over 10% of women – bleeding/spotting, increased sweating, vulvovaginal dryness and/or dyspareunia, decreased libido, headache, and mood changes.

Because testosterone levels usually increase during the first week of treatment, worsening of symptoms and increased complaints may occur (e.g., urinary obstruction, metastatic bone pain, spinal cord compression, muscle weakness, and leg edema). In some cases, urinary obstruction may reduce renal function. Neurological compression with asthenia and paresthesia of the legs is possible.

Men

As seen with other GnRH agonists or surgical castration, the most common adverse events associated with triptorelin use are due to the expected pharmacological effect of the drug: initial increase in testosterone levels followed by near-complete suppression of testosterone. These events include hot flushes (50%), erectile dysfunction, and loss of libido.

Adverse reactions probably related to triptorelin treatment have been reported. Most of these are associated with biochemical or surgical castration.

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), frequency not known.

Infections and infestations: frequency not known – rhinopharyngitis.

Immune system disorders: common – hypersensitivity; uncommon – anaphylactic reaction.

Metabolism and nutrition disorders: uncommon – decreased appetite; frequency not known – increased appetite, gout, diabetes mellitus.

Psychiatric disorders: very common – decreased libido; common – mood changes, depressed mood, depression, sleep disturbances; frequency not known – insomnia, confusion, decreased activity, euphoric mood, anxiety, loss of libido.

Nervous system disorders: common – headache; frequency not known – dizziness, paresthesia, memory impairment, dysgeusia, somnolence, dystasia.

Eye disorders: frequency not known – abnormal eye sensitivity, visual disturbances, blurred vision.

Ear and labyrinth disorders: frequency not known – tinnitus, dizziness.

Vascular disorders: very common – hot flushes; uncommon – embolism, hypertension; frequency not known – hypotension.

Respiratory, thoracic and mediastinal disorders: uncommon – asthma exacerbation; frequency not known – dyspnea, orthopnea, epistaxis.

Gastrointestinal disorders: common – nausea; uncommon – upper abdominal pain, dry mouth; frequency not known – abdominal pain, constipation, diarrhea, vomiting, abdominal distension, flatulence, gastralgia.

Skin and subcutaneous tissue disorders: common – hyperhidrosis; uncommon – hypotrichosis, alopecia; frequency not known – acneiform rash, pruritus, rash, bullae, Quincke's edema, urticaria, hemorrhagic rash.

Musculoskeletal and connective tissue disorders: very common – bone pain; common – myalgia, arthralgia; frequency not known – back pain, musculoskeletal pain, acute pain, muscle spasms, muscle weakness, joint stiffness, joint swelling, musculoskeletal stiffness, osteoarthritis.

Renal and urinary disorders: very common – urinary disorders.

Reproductive system and breast disorders: very common – erectile dysfunction; common – gynecomastia; uncommon – testicular atrophy; frequency not known – breast pain, testicular pain, ejaculation disorder.

General disorders and administration site conditions: common – fatigue, injection site reaction, injection site pain, irritability; frequency not known – injection site erythema, injection site inflammation, swelling, pain, chills, chest pain, influenza-like illness, hyperthermia, malaise.

Investigations: uncommon – increased blood lactate dehydrogenase, increased gamma-glutamyltransferase, increased aspartate aminotransferase, increased alanine aminotransferase, weight gain, weight loss; frequency not known – increased blood creatinine, increased blood pressure, increased blood urea, increased blood alkaline phosphatase, elevated body temperature, QT interval prolongation.

Triptorelin causes a transient increase in circulating testosterone levels during the first week after the first injection of the sustained-release formulation. Along with this initial testosterone surge, a temporary worsening of signs and symptoms of prostate cancer (transient clinical exacerbation) may occur in a small percentage of patients (≤ 5%), typically manifesting as increased urinary symptoms (< 2%) and metastatic bone pain (5%), which require symptomatic treatment. These symptoms are transient and usually resolve within one to two weeks.

Isolated cases of disease symptom exacerbation – urethral obstruction or spinal cord compression due to metastasis – have been observed. Therefore, patients with metastatic vertebral lesions and/or upper or lower urinary tract obstruction require close monitoring during the first weeks of treatment.

The use of GnRH agonists in the treatment of prostate cancer may lead to decreased bone mineral density, potentially resulting in osteoporosis and an increased risk of bone fractures.

Women

Due to decreased estrogen levels, the most frequently observed reactions (in ≥ 10% of women) include headache, decreased libido, sleep disturbances, mood swings, dyspareunia, dysmenorrhea, genital bleeding, ovarian hyperstimulation syndrome, ovarian enlargement, pelvic pain, abdominal pain, vulvovaginal dryness, hyperhidrosis, hot flushes, and asthenia.

Adverse reactions probably related to triptorelin treatment have been reported. Most of these are associated with biochemical or surgical castration.

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), frequency not known.

Immune system disorders: common – hypersensitivity; uncommon – anaphylactic reaction.

Psychiatric disorders: very common – decreased libido, mood swings, sleep disturbances; common – depressed mood, depression; frequency not known – confusion, anxiety.

Nervous system disorders: very common – headache; uncommon – paresthesia; frequency not known – dizziness.

Eye disorders: uncommon – visual disturbances; frequency not known – blurred vision.

Ear and labyrinth disorders: frequency not known – dizziness.

Vascular disorders: very common – hot flushes.

Respiratory, thoracic and mediastinal disorders: frequency not known – dyspnea.

Gastrointestinal disorders: very common – abdominal pain; common – nausea; frequency not known – abdominal discomfort, diarrhea, vomiting.

Skin and subcutaneous tissue disorders: very common – hyperhidrosis; frequency not known – pruritus, rash, Quincke's edema, urticaria.

Musculoskeletal and connective tissue disorders: very common – bone pain; common – myalgia, arthralgia; uncommon – back pain; frequency not known – bone disorders*, muscle spasms, muscle weakness.

Reproductive system and breast disorders: very common – vaginal bleeding, vulvovaginal dryness, dyspareunia, dysmenorrhea, ovarian hyperstimulation syndrome, ovarian enlargement, pelvic pain; frequency not known – breast pain, menorrhagia, metrorrhagia, amenorrhea.

General disorders and administration site conditions: very common – asthenia; common – fatigue, injection site reaction, injection site pain, irritability; frequency not known – injection site erythema, injection site inflammation, hyperthermia, malaise.

Investigations: uncommon – increased blood lactate dehydrogenase, increased gamma-glutamyltransferase, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood cholesterol; frequency not known – increased blood pressure, weight gain, weight loss.

* A slight loss of trabecular bone may occur. Symptoms usually resolve within 6–9 months after discontinuation of treatment.

Due to subsequent administration of gonadotropins to counteract adverse reactions, symptoms do not last longer than a few days during assisted reproductive technologies.

Treatment of infertility with GnRH analogs may lead to ovarian hyperstimulation. Therefore, follicular growth and the luteal phase should be carefully monitored using ultrasound. Additionally, multiple pregnancies have been reported.

During treatment of uterine fibroids, the size of the uterus and fibroids should be regularly assessed, e.g., by ultrasound.

Disproportionately rapid reduction in uterine size compared to fibroid tissue shrinkage may in some cases lead to bleeding and sepsis.

At the beginning of treatment, exacerbation of endometriosis symptoms, including pelvic pain and dysmenorrhea, is very common (≥ 10%) due to the initial transient increase in plasma estradiol levels. These symptoms are temporary and usually resolve within one to two weeks.

Genital bleeding, including menorrhagia and metrorrhagia, may occur approximately one month after the first injection. Ovarian enlargement and pelvic and/or abdominal pain are possible.

Children

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), frequency not known.

Immune system disorders: uncommon – anaphylactic reaction; frequency not known – hypersensitivity reaction.

Psychiatric disorders: common – mood swings, depression; frequency not known – affective lability, nervousness.

Nervous system disorders: frequency not known – headache.

Eye disorders: frequency not known – blurred vision, visual disturbances.

Vascular disorders: frequency not known – hot flushes.

Respiratory, thoracic and mediastinal disorders: frequency not known – epistaxis.

Gastrointestinal disorders: uncommon – nausea, vomiting; frequency not known – abdominal discomfort, abdominal pain.

Skin and subcutaneous tissue disorders: frequency not known – rash, Quincke's edema, urticaria, alopecia, erythema.

Musculoskeletal and connective tissue disorders: frequency not known – epiphyseal slippage*, myalgia.

Reproductive system and breast disorders: uncommon – vaginal bleeding, vaginal discharge; frequency not known – genital bleeding.

General disorders and administration site conditions: frequency not known – injection site erythema, injection site inflammation, malaise, pain, injection site pain.

Investigations: frequency not known – increased blood pressure, increased body weight.

* Several cases of slipped capital femoral epiphysis have been reported during triptorelin treatment.

Cases of pre-existing pituitary adenoma enlargement during treatment with LH-RH agonists have been reported, although such cases have not yet been specifically linked to triptorelin treatment.

Shelf life. 3 years; for the prepared suspension – 3 minutes.

Storage conditions. Store in the original packaging, out of reach of children, at +2 to +8 °C.

Incompatibilities.

In the absence of compatibility studies, the drug should not be mixed with other medicinal products.

Packaging. 1 pre-filled syringe with powder, 1 pre-filled syringe with solvent, connecting device, injection needles, in a cardboard package.

Prescription status. Prescription only.

Manufacturer.

Ferring GmbH, Germany.

Manufacturer's address and location of operations.

Wittland 11, 24109 Kiel, Germany.