Diphereline
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIPHERELINE® (DIPHERELINE®)
Composition:
Active substance: triptorelin;
1 vial contains 31 mg of triptorelin pamoate, equivalent to 22.5 mg of triptorelin;
Excipients: poly(dl-lactide-co-glycolide) 75/25, poly(dl-lactide-co-glycolide) 85/15, mannite (E 421), sodium carmellose, polysorbate 80;
Solvent: water for injections.
Pharmaceutical form.
Powder and solvent for prolonged-release injectable suspension.
Main physicochemical characteristics.
Powder – lyophilized mass of white to slightly yellow color in a vial made of brown glass with a dark green plastic flip-off cap^TM;
Solvent (water for injections) – clear, colorless solution practically free from visible particles.
Pharmacotherapeutic group.
Agents used in hormone therapy. Hormones and related substances. Gonadotropin-releasing hormone analogues.
ATC code L02A E04.
Pharmacological Properties
Pharmacodynamics
Mechanism of Action and Pharmacodynamic Effects
Triptorelin, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when administered continuously at therapeutic doses. Studies in humans and animals show that following administration of triptorelin, there is an initial and transient increase in circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone in males and estradiol in females.
However, prolonged and continuous administration of triptorelin leads to suppression of LH and FSH secretion and inhibition of testicular and ovarian steroidogenesis.
In Men with Prostate Cancer
Reduction of serum testosterone levels to the range typically observed in surgically castrated men occurs approximately 2–4 weeks after initiation of treatment with Diphereline® (22.5 mg), formulated for the sustained release of 22.5 mg triptorelin over a 6-month period. Once post-castration testosterone levels are achieved by the end of the first month of therapy, they are maintained in serum for as long as the patient receives injections every twenty-four weeks.
This leads to further atrophy of the genital organs. These effects are generally reversible upon discontinuation of the medicinal product. Monitoring of therapeutic efficacy can be performed by measuring serum testosterone and prostate-specific antigen (PSA) levels. During clinical trial programs, a 97% relative reduction in median PSA levels was observed at 6 months of Diphereline® (22.5 mg) therapy.
In experimental animal models, triptorelin administration has been shown to suppress the growth of certain hormone-sensitive prostate tumors.
Clinical Efficacy and Safety in Patients with Prostate Cancer
Administration of Diphereline® (22.5 mg) to patients with advanced prostate cancer as two intramuscular injections (total of 2 doses over 12 months) resulted in achieving post-castration testosterone levels in 97.5% of patients by week 4 and maintaining these levels in 93.0% of patients from months 2 to 12 of therapy.
In several randomized, long-term clinical trials involving patients with locally advanced prostate cancer, androgen deprivation therapy (ADT) combined with radiotherapy (RT) has demonstrated superiority over RT alone (RTOG 85-31, RTOG 86-10, EORTC 22863, D’Amico et al., JAMA, 2008).
In a phase III randomized trial (EORTC 22961) involving 970 patients with locally advanced prostate cancer (predominantly T2c–T4, and several with T1c–T2b and pathologically confirmed regional nodal involvement), 483 patients received short-term androgen suppression (6 months) combined with radiotherapy, and 487 received long-term therapy (3 years). Using non-inferiority analysis, short-term versus long-term adjuvant and neoadjuvant hormonal therapy with GnRH agonists—primarily triptorelin (62.2%) or goserelin (30.1%)—was compared.
Five-year overall mortality was 19.0% and 15.2% in the short-term and long-term hormonal therapy groups, respectively, with a relative risk of 1.42 (95% CI = 1.79; or 95.71% CI = [1.09; 1.85], p = 0.65 for non-inferiority and p = 0.0082 for post hoc difference between groups). Five-year prostate cancer-specific mortality was 4.78% and 3.2% in the short-term and long-term hormonal therapy groups, respectively, with a relative risk of 1.71 (95% CI [1.14 to 2.57], p = 0.002). Overall quality of life, assessed using the QLQ-C30 questionnaire, did not differ significantly between the two groups (p = 0.37).
The evidence base for using this medicinal product in the treatment of high-risk localized prostate cancer is derived from published studies of radiotherapy combined with GnRH analogs. Clinical data from five published trials (EORTC 22863, RTOG 85-31, RTOG 92-02, RTOG 86-10, and D’Amico et al., JAMA, 2008) were analyzed. All demonstrated the benefit of combining GnRH analog therapy with radiotherapy. Published studies do not allow clear differentiation of the studied populations regarding indications for locally advanced versus high-risk localized prostate cancer. In patients with metastatic castration-resistant prostate cancer, clinical trials have demonstrated benefit from adding abiraterone acetate—an androgen biosynthesis inhibitor—or enzalutamide—an androgen receptor function inhibitor—to GnRH analogs such as triptorelin.
Clinical Efficacy and Safety in Children with Central Precocious Puberty
In an uncontrolled clinical study, 44 children (39 girls and 5 boys) with central precocious puberty received two intramuscular injections of Diphereline® (22.5 mg) over 12 months (48 weeks). Suppression of stimulated LH concentrations to prepubertal levels was achieved in 95.5% of patients by month 3, and in 93.2% and 97.7% of patients by months 6 and 12, respectively.
Therapy resulted in regression or stabilization of secondary sexual characteristics and slowing of accelerated bone maturation and growth.
In girls, initial ovarian stimulation followed by estrogen withdrawal during the first month of treatment may lead to low- or moderate-intensity withdrawal vaginal bleeding.
Pharmacokinetics
Absorption
After a single intramuscular injection of Diphereline® in patients with prostate cancer, tmax (time to maximum concentration) was 3 (2–12) hours, and Cmax (maximum concentration) over days 0–169 was 40 (22.2–76.8) ng/mL. Triptorelin did not accumulate over 12 months of therapy.
Distribution
Pharmacokinetic studies in healthy volunteers indicate that after intravenous bolus administration, triptorelin distribution and elimination follow a three-compartment model. Elimination half-lives are approximately 6 minutes, 45 minutes, and 3 hours, respectively.
The volume of distribution at steady state after intravenous administration of 0.5 mg triptorelin acetate is approximately 30 L in healthy male volunteers. Since there is no evidence of plasma protein binding of triptorelin at clinically relevant concentrations, drug interactions, including displacement from binding sites, are unlikely.
Biotransformation
Metabolites of triptorelin have not been identified in humans. However, pharmacokinetic studies indicate that C-terminal fragments produced by tissue degradation are completely broken down within tissues and further rapidly degraded in plasma or eliminated by the kidneys.
Excretion
Triptorelin is eliminated via both hepatic and renal pathways. After intravenous administration of 0.5 mg triptorelin in healthy male volunteers, 42% of the dose was excreted in urine as intact triptorelin; this percentage increased to 62% in patients with impaired liver function. In healthy volunteers, creatinine clearance (Clcreat) was 150 mL/min, compared to 90 mL/min in patients with impaired liver function. This indicates that the liver is the primary site of triptorelin elimination. In healthy volunteers, the terminal elimination half-life was 2.8 hours, and total triptorelin clearance was 212 mL/min. The latter depends on the combined hepatic and renal elimination.
Special Patient Populations
After intravenous administration of 0.5 mg triptorelin, elimination half-life was 6.7 hours in patients with moderate renal impairment (Clcreat 40 mL/min), 7.81 hours in those with severe renal impairment (Clcreat 8.9 mL/min), and 7.65 hours in patients with impaired liver function (Clcreat 89.9 mL/min).
Systematic evaluation of the effects of age and race on pharmacokinetics has not been conducted. However, pharmacokinetic data from young healthy male volunteers aged 20–22 years with high creatinine clearance (approximately 150 mL/min) showed that triptorelin elimination was twice as fast in this younger population. This is consistent with the known correlation between triptorelin clearance and total creatinine clearance, which decreases with age.
Due to the wide safety margin of triptorelin and the sustained-release formulation of Diphereline®, dose adjustment is not recommended in patients with hepatic or renal impairment.
Pharmacokinetic/Pharmacodynamic Relationship
Assessment of the pharmacokinetic/pharmacodynamic relationship of triptorelin is complex due to its nonlinear, time-dependent nature. Thus, following immediate administration in previously untreated patients, triptorelin induces a dose-dependent increase in LH and FSH response.
When administering the sustained-release formulation, triptorelin stimulates LH and FSH secretion—and consequently testosterone secretion—during the first few days after injection. As demonstrated in various bioequivalence studies, peak testosterone levels are reached within 4 days, with a corresponding Cmax value independent of the triptorelin release rate. This initial response is not sustained despite continuous triptorelin exposure, followed by progressive and equivalent reduction in testosterone levels. In this context, the extent of triptorelin exposure may vary considerably without altering the overall effect on serum testosterone levels.
Clinical characteristics.
Indications.
Treatment of locally advanced or metastatic hormone-dependent prostate cancer.
Treatment of high-risk localized or locally advanced prostate cancer, in combination with radiotherapy (see section "Pharmacodynamics").
Treatment of central precocious puberty in children from 2 years of age (in girls under 8 years of age and in boys under 10 years of age).
Contraindications.
Hypersensitivity to GnRH (gonadotropin-releasing hormone), its analogs, or to any of the excipients listed in the section "Composition" (see section "Side effects").
Pregnancy and breastfeeding (see section "Use during pregnancy or breastfeeding").
Interaction with other medicinal products and other forms of interaction.
Caution is required when using triptorelin in combination with medicinal products that modify the secretion of pituitary gonadotropic hormones, and careful monitoring of the patient's hormonal levels is recommended.
Since androgen deprivation therapy may prolong the QT interval, concomitant use of triptorelin with medicinal products that prolong the QT interval or may induce torsades de pointes ventricular tachycardia, such as class IA (quinidine, disopyramide) or class III (amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmics, as well as methadone, cisapride, moxifloxacin, and antipsychotics, requires careful assessment (see section "Special precautions for use").
Children
Interaction studies have been conducted only in adults.
Special precautions for use.
Administration of GnRH agonists may cause a decrease in bone mineral density. Previous data suggest that in men, the use of bisphosphonates together with a GnRH agonist may reduce bone mineral density loss. Particular attention should be paid to patients with additional risk factors for osteoporosis (such as alcohol abuse, smoking, long-term treatment with drugs causing decreased bone mineral density, e.g., anticonvulsants or corticosteroids, hereditary predisposition to osteoporosis, or malnutrition).
In rare cases, therapy with GnRH agonists may reveal a previously undiagnosed pituitary gonadotroph adenoma. In such patients, pituitary apoplexy may occur, characterized by sudden headache, vomiting, visual disturbances, and ophthalmoplegia.
There is an increased risk of depression (which may be severe) in patients undergoing treatment with GnRH agonists, including triptorelin. Therefore, patients should be informed about this risk and provided with appropriate treatment should symptoms arise.
Patients with existing depression require careful monitoring during therapy.
Intramuscular injections should be administered with caution in patients receiving anticoagulant therapy due to the risk of hematoma at the injection site. The efficacy and safety of Diphereline® (22.5 mg) have been demonstrated only following intramuscular administration.
Subcutaneous administration of this medicinal product is not recommended.
This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is essentially sodium-free.
Prostate cancer
At the beginning of treatment, triptorelin, like other GnRH agonists, causes a transient increase in serum testosterone levels. As a result, during the first weeks of treatment, isolated cases of temporary worsening of symptoms of prostate cancer may occur. During the initial phase of treatment, consideration should be given to concomitant administration of an appropriate antiandrogen to counteract the initial rise in serum testosterone levels and prevent clinical symptom exacerbation.
A small number of patients may experience a temporary worsening of symptoms of prostate cancer and temporary intensification of cancer-related pain (pain due to metastatic involvement), which should be managed symptomatically.
As with other GnRH agonists, isolated cases of spinal cord compression or ureteral obstruction have been observed. In the event of spinal cord compression or renal dysfunction, standard treatments for these complications should be initiated, and in exceptional cases, immediate orchiectomy (surgical castration) should be considered. Close monitoring during the first weeks of treatment is recommended, especially in patients with vertebral metastases at risk of spinal cord compression and/or patients with urinary tract obstruction. After surgical castration, triptorelin does not induce any further reduction in serum testosterone levels. Once post-castration testosterone levels are achieved by the end of the first month of therapy, serum testosterone levels are maintained as long as the patient receives injections every 6 months (every 24 weeks).
Therapeutic efficacy can be monitored by measuring serum testosterone and prostate-specific antigen (PSA) levels.
Prolonged androgen deprivation due to bilateral orchiectomy or administration of GnRH analogs is associated with an increased risk of bone mass loss and may lead to osteoporosis and an increased risk of bone fractures.
Androgen deprivation therapy may prolong the QT interval.
In patients with a history of QT prolongation or existing risk factors for QT prolongation, as well as in patients receiving medicinal products that may prolong the QT interval (see section "Interaction with other medicinal products and other forms of interaction"), the benefit-risk ratio should be carefully assessed, including the potential risk of developing torsades de pointes ventricular tachycardia, before initiating Diphereline® (22.5 mg) therapy.
Furthermore, based on epidemiological data, metabolic changes (e.g., glucose intolerance, hepatic steatosis) or an increased risk of cardiovascular diseases may occur during antiandrogen therapy. However, prospective data do not confirm a link between GnRH analog therapy and increased cardiovascular mortality. Patients at high risk of metabolic or cardiovascular diseases should be thoroughly evaluated before starting therapy, and appropriate monitoring should be performed during antiandrogen therapy.
Administration of triptorelin at therapeutic doses leads to suppression of the hypothalamic-pituitary-gonadal system. After discontinuation of treatment, normal function of this system usually recovers. Therefore, results of diagnostic tests assessing the hypothalamic-pituitary-gonadal system performed during or after discontinuation of GnRH analog therapy may be misleading.
Central precocious puberty
Before initiating treatment in children with progressive brain tumors, the risks and benefits should be carefully evaluated on an individual basis.
Pseudoprecocious puberty (e.g., tumors of the gonads or adrenal glands, or hyperplasia) and gonadotropin-independent precocious puberty (e.g., testotoxicosis, inherited Leydig cell hyperplasia) should be ruled out prior to treatment.
In girls, during the first month of treatment, initial stimulation of the ovaries followed by estrogen withdrawal due to therapy may lead to vaginal bleeding of low or moderate intensity.
Treatment is long-term and individually adjusted. Diphereline® (22.5 mg) should be administered with strict adherence to the injection interval—every 6 months. In exceptional circumstances, a delay of several days (169 ± 3 days) does not affect treatment outcomes.
After completion of therapy, signs of pubertal development appear.
Data on future fertility are still limited, but GnRH treatment is unlikely to affect future reproductive function and fertility. In most girls, regular menstruation resumes on average one year after treatment ends.
During treatment of central precocious puberty with GnRH agonists, bone mineral density may decrease due to the expected effects of estrogen suppression. However, after discontinuation of treatment, further bone mass accumulation occurs, and peak bone mass in late puberty is not affected.
After discontinuation of GnRH agonist therapy, slipped capital femoral epiphysis may occur. There is a theory that low estrogen concentrations during GnRH agonist therapy weaken the epiphyseal plate. The growth spurt following treatment cessation reduces the shear force required to displace the epiphysis.
Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in pediatric patients receiving triptorelin. Patients should be informed about the signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, visual disturbances, and tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of triptorelin should be considered.
Use during pregnancy or breastfeeding
Pregnancy
Diphereline® (22.5 mg) is indicated for use in adult males and children. Data on the use of triptorelin in pregnant women are too limited. Diphereline® (22.5 mg) is not indicated for use in women.
Pregnancy should be excluded before initiating treatment with Diphereline® (22.5 mg) in women.
Triptorelin is contraindicated during pregnancy, as concomitant use of GnRH agonists is associated with a theoretical risk of abortion or fetal developmental abnormalities. Before initiating treatment, women of childbearing potential should undergo thorough evaluation to exclude pregnancy. Non-hormonal contraception methods should be used during treatment and until menstrual cycles resume.
Animal studies have demonstrated effects on reproductive parameters.
Breastfeeding
Diphereline® (22.5 mg) is contraindicated during breastfeeding.
Ability to influence reaction speed when driving or operating machinery
No studies on the effect on the ability to drive or operate machinery have been conducted. However, the ability to drive vehicles or operate machinery may be impaired due to dizziness, somnolence, and visual disturbances, which are possible adverse effects of therapy or consequences of the underlying disease.
Method of Administration and Dosage
Dosage
The recommended dose of Diferelin® (22.5 mg) is 22.5 mg of triptorelin (1 vial), administered every six months (every twenty-four weeks) as a single intramuscular injection.
For the treatment of high-risk localized or locally advanced hormone-dependent prostate cancer when the medicinal product is used as adjuvant therapy and following radiotherapy, clinical data have demonstrated that radiotherapy followed by 3 years of antiandrogen therapy is more favorable than radiotherapy followed by 6 months of antiandrogen therapy (see section "Pharmacodynamics"). The duration of antiandrogen therapy recommended by clinical guidelines for patients with high-risk localized or locally advanced prostate cancer undergoing radiotherapy is 2–3 years.
For patients with metastatic castration-resistant prostate cancer who have not undergone surgical castration and are receiving a GnRH agonist (gonadotropin-releasing hormone), such as triptorelin, and for whom treatment with abiraterone acetate as an androgen biosynthesis inhibitor or enzalutamide as an androgen receptor function inhibitor is appropriate, therapy with the GnRH agonist should be continued.
Patients with Renal or Hepatic Impairment
Dose adjustment is not required for patients with renal or hepatic impairment.
Children
Precocious puberty in children (in girls under 8 years of age and in boys under 10 years of age)
Treatment of children with Diferelin® (22.5 mg) should be conducted under close supervision by a pediatric endocrinologist, pediatrician, or endocrinologist experienced in managing central precocious puberty.
Treatment should be discontinued upon attainment of physiological sexual maturity in both boys and girls and is not recommended to be prolonged in girls over 12–13 years of age with advanced bone maturation. Data in boys are limited. Regarding optimal timing of treatment discontinuation based on bone age, it has been reported that treatment should be discontinued in boys when bone maturation corresponds to an age of 13–14 years.
Method of Administration
As with other injectable medicinal products, the injection site should be rotated periodically.
After reconstitution, the Diferelin® (22.5 mg) suspension should be administered intramuscularly relatively quickly and continuously to avoid any potential needle blockage.
Precautions for Handling and Administration
Diferelin® (22.5 mg) is intended exclusively for intramuscular use.
Since Diferelin® (22.5 mg) is a microgranule suspension, inadvertent intravascular injection must be strictly avoided.
Diferelin® (22.5 mg) should be administered under close medical supervision.
Instructions for reconstituting this medicinal product prior to administration are provided below.
The injectable suspension must be reconstituted under aseptic conditions using only the solvent ampoule provided for injection.
Only the solvent supplied with the powder must be used. The instructions below must be strictly followed.
The information below is intended for healthcare professionals only
Instructions for Use
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| Prepare the patient by disinfecting the gluteal muscle at the injection site. This procedure should be performed in advance, as the medicinal product must be administered immediately after reconstitution. |
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| The package contains two needles:
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| Needle 1 – 38 mm – 20 G (20 gauge) |
Needle 2 – 38 mm – 20 G (20 gauge) |
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| The presence of bubbles in the upper part of the lyophilisate is normal for this medicinal product. |
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| 2 a
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| 2 b
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| 2 c
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| 2 d
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Note: Always keep your finger behind the shield. There are two methods to activate the safety system:
In both cases, press firmly and quickly until a distinct click is heard. Visually confirm that the needle is fully retracted and locked.
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Method A
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Children.
Premature sexual maturation in children (in girls under 8 years of age and in boys under 10 years of age).
Overdose.
Due to the pharmaceutical properties of Diphereline® and its method of administration, overdose is unlikely. There is no data regarding overdose in humans. In case of overdose, symptomatic treatment is recommended.
Adverse Reactions
General Tolerability in Men
Since patients with locally advanced or metastatic hormone-dependent prostate cancer are typically elderly and often have comorbidities commonly seen in this age group, adverse events were observed in more than 90% of patients participating in clinical studies, making it frequently difficult to assess a causal relationship. Based on data from treatment with other GnRH agonists or following surgical castration, the most commonly observed adverse reactions associated with triptorelin therapy resulted from the expected pharmacological effect. These effects included hot flushes and decreased libido.
With the exception of immunologic and allergic reactions (rare) and injection site reactions (< 5%), all adverse events were known to be related to changes in testosterone levels.
The adverse reactions listed below have been reported and were considered at least possibly related to triptorelin therapy. The occurrence of most of these events is associated with biochemical or surgical castration.
The frequency of adverse reactions is classified as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); frequency not known (cannot be estimated from available data).
| System organ class |
Very common |
Common |
Uncommon |
Rare |
Additional adverse reactions reported during the post-marketing period (frequency unknown) |
| Infections and infestations |
Rhinopharyngitis |
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| Blood and lymphatic system disorders |
Thrombocytosis |
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| Immune system disorders |
Hypersensitivity |
Anaphylactic reaction |
Anaphylactic shock |
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| Metabolism and nutrition disorders |
Anorexia, diabetes mellitus, gout, hyperlipidemia, increased appetite |
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| Psychiatric disorders |
Decreased libido |
Loss of libido, depression*, mood alterations* |
Insomnia, irritability |
Confusion, decreased activity, euphoric mood |
Anxiety |
| Nervous system disorders |
Paraesthesia of lower limbs |
Memory impairment, headache |
Paraesthesia |
Memory disturbance |
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| Eye disorders |
Visual disturbance |
Ocular sensitivity disorders, visual disorders |
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| Ear and labyrinth disorders |
Tinnitus, vertigo |
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Endocrine disorders |
Pituitary apoplexy** |
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| Cardiac disorders |
Palpitations |
QT interval prolongation* (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interactions") |
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| Vascular disorders |
Hot flushes |
Arterial hypertension |
Arterial hypotension |
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| Respiratory, thoracic and mediastinal disorders |
Dyspnoea, epistaxis |
Orthopnoea |
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| Gastrointestinal disorders |
Dry mouth, nausea |
Abdominal pain, constipation, diarrhoea, vomiting |
Abdominal distension, dysgeusia, flatulence |
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| Skin and subcutaneous tissue disorders |
Hyperhidrosis |
Acne, alopecia, erythema, pruritus, rash, urticaria |
Bullae, purpura |
Angioneurotic oedema |
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| Musculoskeletal and connective tissue disorders |
Back pain |
Musculoskeletal pain, limb pain |
Arthralgia, bone pain, muscle spasms, muscle weakness, myalgia |
Joint stiffness, joint swelling, musculoskeletal stiffness, osteoarthritis |
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| Renal and urinary disorders |
Nocturia, urinary retention |
Urinary incontinence |
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| Reproductive system and breast disorders |
Erectile dysfunction (including ejaculation disorder, impaired ejaculation) |
Pelvic pain |
Gynaecomastia, breast pain, testicular atrophy, testicular pain |
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| General disorders and administration site conditions |
Asthenia |
Injection site reactions (including erythema, inflammation and pain), oedema |
Lethargy, peripheral oedema, pain, chills, somnolence |
Chest pain, malaise, influenza-like illness, pyrexia |
Feeling unwell |
| Investigations |
Weight increased |
Increased ALT, increased AST, increased blood creatinine, increased blood pressure, increased blood urea, increased gamma-glutamyl transferase, weight decreased |
Increased blood alkaline phosphatase activity |
*This frequency is based on the frequency of effects typical for all GnRH agonists.
**Pituitary apoplexy has been reported after initial administration of the drug to patients with pituitary adenoma.
Triptorelin causes a temporary increase in circulating testosterone levels during the first week after administration of the first dose of the prolonged-release formulation. During this initial rise in circulating testosterone levels, some patients (≤5%) may experience a worsening of symptoms of existing prostate cancer ("flare"), typically manifested by urinary tract symptoms (<2%) and pain due to metastatic disease (5%), which can be managed symptomatically. 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 reported. Therefore, patients with spinal metastases and/or obstruction of upper or lower urinary tracts should be closely monitored during the first few weeks of therapy (see section "Special precautions").
The use of GnRH agonists in the treatment of prostate cancer increases the risk of bone loss and may lead to osteoporosis, as well as an increased risk of bone fractures. It may also lead to incorrect diagnosis of bone metastases.
General tolerability in children (see section "Special precautions")
The frequency of adverse reactions is classified as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100).
| System organ class |
Undesirable effects that occurred during treatment very commonly |
Undesirable effects that occurred during treatment commonly |
Undesirable effects that occurred during treatment uncommonly |
Additional adverse reactions reported in the post-marketing period (frequency unknown) |
| Immune system disorders |
Hypersensitivity |
Anaphylactic shock |
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| Metabolism and nutrition disorders |
Obesity |
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| Psychiatric disorders |
Mood lability |
Affective lability, depression, nervousness |
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| Nervous system disorders |
Headache |
Idiopathic intracranial hypertension (pseudotumor cerebri) (see section "Special precautions") |
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| Eye disorders |
Visual disturbance |
Blurred vision |
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| Vascular disorders |
Flushing |
Hypertension |
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| Respiratory, thoracic and mediastinal disorders |
Nosebleed |
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| Gastrointestinal disorders |
Abdominal pain |
Vomiting, constipation, nausea |
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| Skin and subcutaneous tissue disorders |
Acne |
Itching, rash, urticaria |
Angioneurotic edema |
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| Musculoskeletal and connective tissue disorders |
Neck pain |
Myalgia |
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| Reproductive system and breast disorders |
Vaginal bleeding (including vaginal haemorrhage, withdrawal bleeding, uterine haemorrhage, vaginal discharge, vaginal bleeding, particularly spotting) |
Breast pain |
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| General disorders and administration site conditions |
Injection site reactions (including injection site pain, irritation at injection site, and injection site inflammation) |
Malaise |
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| Investigations |
Increased body weight |
Increased blood pressure, increased blood prolactin level |
General Information
An increase in the number of lymphocytes has been observed in patients undergoing treatment with GnRH analogues. This secondary lymphocytosis is likely related to GnRH-induced castration, suggesting that gonadal hormones are probably involved in thymic involution.
Reporting of Adverse Reactions
Reporting of adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through the national reporting system.
Shelf Life
4 years.
The reconstituted suspension should be used immediately after reconstitution.
Storage Conditions
Keep out of the reach of children. Store at a temperature not exceeding 25 °C.
Incompatibilities
Since compatibility studies have not been performed, this medicinal product must not be mixed with other medicinal products.
Packaging
1 vial of powder with a solvent (water for injection) in a 2 ml ampoule No. 1, 1 blister containing 1 injection syringe and 2 injection needles in a cardboard box.
Prescription Status
Prescription only.
Manufacturer
IPSEN PHARMA BIOTECH/IPSEN PHARMA BIOTECH.
Manufacturer's Address and Location of Operations
Parc d’activites du Plateau de Signes, chemin departemental No. 402, 83870 SIGNES, France / Parc d’activites du Plateau de Signes, chemin departemental No. 402, 83870 SIGNES, France.
Marketing Authorization Holder
IPSEN PHARMA/IPSEN PHARMA.
Address of the Marketing Authorization Holder
65, quai Georges Gorse - 92100 Boulogne Billancourt, France / 65, quai Georges Gorse - 92100 Boulogne Billancourt, France.