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General: Treatment with triptorelin should be considered on an individual basis and should only be commenced if the potential benefits of the treatment outweigh the risks after a very careful evaluation. During treatment with triptorelin, patients should be routinely monitored by appropriate physical examinations and laboratory tests.
Triptorelin, like other GnRH agonists, causes a transient increase in serum testosterone levels at the initial phase of triptorelin therapy. This increase may also occur if the interval between two injections exceed 1 month. In contrast with the decline in the testosterone level produced by orchiectomy, this initial increase in circulating testosterone may result in temporary worsening (flare) of signs and/or symptoms of prostate cancer and/or development of new symptoms during the first weeks of treatment in a small (<5%) percentage of patients. Cancer-related pain (metastatic pain), bone pain, neuropathy, urethral or bladder outlet obstruction, or hematuria, have been reported. These will subside with continued treatment and can be managed symptomatically.
Worsening of the clinical condition may occasionally require discontinuation of therapy. The administration of an appropriate anti-androgen should also be considered to counteract the initial rise in serum testosterone levels and the worsening of clinical symptoms.
Pregnancy must be ruled out before initiating treatment with triptorelin (see Use in Pregnancy & Lactation). Non-hormonal methods of contraception may be used during triptorelin therapy until menses resume.
Retreatment for endometriosis cannot be recommended since safety data beyond 6 months of triptorelin use are not available. The etiology of any vaginal bleeding should be established before administered triptorelin as treatment for endometriosis. After menopause, medical treatment of endometriosis is indicated only for rare exceptions (e.g., in the event of estrogen-producing tumors involving reactivation of the endometriosis and if surgical treatment is contraindicated).
The use of triptorelin in children with progressive brain tumors should be considered on an individual basis and should only be initiated after a careful appraisal of the potential risks and benefits of triptorelin to the patient.
Pseudo-precocious puberty (e.g., gonadal or adrenal tumor or hyperplasia) and gonadotropin-independent precocious puberty (e.g., testicular toxicosis, familial Leydig cell hyperplasia) should be ruled out before starting triptorelin therapy.
Chemotherapy can induce temporary amenorrhea or a permanent loss of ovarian function due to its cytotoxic damage of gonadal tissue. Women who are premenopausal at breast cancer diagnosis and who become amenorrheic following chemotherapy may or may not have continued estrogen production from the ovaries. In order to avoid chemotherapy-induced menopause, premenopausal status should be confirmed, irrespective of menstrual status, after chemotherapy and before starting triptorelin therapy by obtaining blood estradiol and FSH concentrations within the reference ranges for pre-menopausal women. Adequate ovarian suppression (gonadotropin analog-induced menopause) following initiation of triptorelin treatment should be confirmed in subset of women considered for therapy with an aromatase inhibitor (in accordance with current clinical practice recommendations). Accordingly, ovarian suppression is confirmed by low blood concentrations of FSH and estradiol prior to starting aromatase inhibitor treatment. Measurements should be repeated every 3 months during combination therapy with triptorelin and an aromatase inhibitor to avoid aromatase inhibitor-induced rebound increase in circulating estrogen, with consequential implications for the breast cancer. It should be noted that circulating FSH levels are decreased in response to gonadotropin analog-induced ovarian suppression (induced menopause), unlike in a natural menopause where FSH levels are elevated.
Fetal or Neonatal Morbidity and Mortality: See Use in Pregnancy & Lactation.
Endocrine/Metabolic Effects: Bone Mineral Density Loss: The long-term use of GnRH agonists may cause a reduction in bone mineral density, which may also lead to incorrect diagnosis of bone metastases. Some of the bone density loss over the course of triptorelin therapy may not be reversible. The risk of skeletal fracture increases with the duration of treatment with triptorelin.
Triptorelin is associated with a high risk of osteoporosis when used as adjuvant therapy in combination with tamoxifen or an aromatase inhibitor. Osteoporosis has been reported with a higher frequency when triptorelin is used in combination with an aromatase inhibitor than in combination with tamoxifen (39% vs 25%).
In men, preliminary data suggest that the use of a bisphosphonate during GnRH agonist therapy may reduce bone mineral loss. No specific data is available for patients with established osteoporosis or with risk factors for decreased bone mineral content and/or bone mass [e.g., chronic alcohol abuse, smokers, long-term therapy with drugs that reduce bone mineral density (e.g., anticonvulsants, corticoids), family history of osteoporosis, malnutrition (e.g., anorexia nervosa)]. Thus, particular caution is necessary since reduction in bone mineral density is likely to be more detrimental in these patients. Treatment with triptorelin should be considered on an individual basis and should only be initiated if the benefits of treatment outweigh the risk following very careful appraisal.
Bone mineral density may be assessed before initiating treatment with triptorelin and may be monitored during therapy, especially in patients with multiple risk factors for osteoporosis. Adequate dietary calcium and vitamin D intake should be maintained, and treatment or prophylaxis for osteoporosis should be initiated when appropriate. Lifestyle modification, including smoking cessation, moderation in alcohol consumption, and regular weight bearing exercise, may be recommended for the prevention of triptorelin-related bone loss.
In prostate cancer patients, an assessment of bone lesions may require the use of bone scans. In addition to digital rectal examination, prostatic lesions may be monitored using ultrasonography/or CT scan. The status of obstructive uropathy may be assessed and/or diagnosed using intravenous pyelography, ultrasonography, or CT scan.
For the treatment of endometriosis, repeated courses of therapy with GnRH analogs should not be administered to women with major risk factors for loss of bone mineral density beyond 6 months.
In the treatment of central precocious puberty, reduced bone mineral density is expected during GnRH agonist therapy due to the effects of estrogen suppression. However, after cessation of treatment, subsequent bone mass accrual is preserved, and the peak bone mass in late adolescence does not appear to be affected by triptorelin therapy.
Slipped capital femoral epiphysis may occur after withdrawal of treatment with GnRH agonist. The low concentrations of estrogen during GnRH therapy may weaken the epiphysis. However, the increase in growth velocity after treatment discontinuation consequently results in the decrease in the shearing force required for the displacement of the epiphysis.
Hyperglycemia and Diabetes: Hyperglycemia and an increased risk for development of diabetes mellitus have been reported in patients receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Physicians should evaluate patients at high risk for diabetes, and carefully weigh the benefits and risks before initiation of triptorelin therapy. Monitoring of blood glucose and/or glycosylated hemoglobin (HbA1c) must be performed in patients receiving GnRH agonist within appropriate intervals; diabetic patients or patients at high risk may require more frequent monitoring when receiving this drug (i.e., with intervals not exceeding 3 months). Moreover, patients should be managed with current practice for treatment of hyperglycemia or diabetes.
Hypogonadism: Long-term administration of triptorelin in therapeutic doses will result to the suppression of pituitary gonadotropins and gonadal hormone production with clinical manifestations of hypogonadism. Normal function is usually restored after treatment discontinuation. However, whether the clinical symptoms of triptorelin-induced hypogonadism will reverse in all patients has not yet been established.
Serum Testosterone Levels: Triptorelin does not induce any further reduction in serum testosterone levels after surgical castration.
Once the castration levels of testosterone have been attained by the end of the first month, serum testosterone levels are maintained for as long as the patients receive their injection as scheduled. The effectiveness of triptorelin therapy can be monitored by measuring serum levels of testosterone and prostate specific antigen regularly, or as indicated.
Vaginal Bleeding: Triptorelin causes constant hypogonadotropic amenorrhea. Since menses should stop during triptorelin treatment, the patient should notify her physician if regular menstruation persists. If vaginal hemorrhage occurs following the first month of therapy, plasma estradiol levels should be measured; plasma estradiol levels less than 50 pg/mL may indicate that possible associated organic lesions should be investigated. Patients missing successive doses of triptorelin may experience breakthrough bleeding.
In girls treated for precocious puberty, initial ovarian stimulation at treatment initiation followed by the treatment-induced estrogen withdrawal may lead to vaginal bleeding of mild or moderate intensity in the first month.
Ovarian Cysts: As with other drugs that stimulate the release of gonadotropin or that induce ovulation, ovarian cysts have been reported to occur, usually within the first 2 months of treatment. In most cases, these enlargements resolve spontaneously in 4 to 6 weeks. However, in some cases they may require discontinuation of drug and/or surgical intervention.
Hypersensitivity Reactions: Anaphylactic shock, hypersensitivity, and angioedema have been reported with the use of triptorelin. If any hypersensitivity reaction develops, treatment with triptorelin should be discontinued immediately and appropriate supportive and symptomatic care should be provided.
Paresthesia and severe migraine are rare. Treatment should be discontinued in serious or recurring cases.
Metastatic Vertebral Lesions and Urinary Tract Obstruction: Cases of spinal cord compression contributing to weakness or paralysis, with or without fatal complications, have been reported in some patients treated with GnRH agonists. If spinal cord compression or renal impairment due to urethral obstruction develops, standard treatment for these conditions should be provided. Immediate orchiectomy may be considered in extreme cases.
The risk of neurologic and/or genitourinary complications is increased during the first few weeks of triptorelin therapy in prostate cancer patients with metastatic vertebral lesions and/or upper or lower urinary tract obstruction. Thus, these patients should be closely observed during the initial phase of triptorelin therapy.
Cardiovascular Effects: Thromboembolic events, including pulmonary embolism, cerebrovascular accident, myocardial infarction, deep vein thrombosis, transient ischemic attack, and thrombophlebitis, have been reported in patients receiving triptorelin. GnRH agonists, including triptorelin, may increase the risk of certain cardiovascular diseases (e.g., myocardial infarction, sudden cardiac death and stroke) in prostate cancer patients. Moreover, androgen deprivation therapy in patients with prostate cancer has demonstrated an adverse impact on the cardiovascular risk factors, including serum lipoproteins and obesity. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with other cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients at high risk for cardiovascular diseases should be carefully assessed before initiating triptorelin therapy. In addition, patients should also be regularly monitored at appropriate intervals for symptoms and signs suggestive of development of cardiovascular disease (e.g., periodic assessment of cardiovascular risk factors, blood pressure) and be managed according to current clinical practice. Patients with hypertension, hyperlipidemia, or cardiovascular disorders should be monitored for increased cardiovascular risk while undergoing triptorelin therapy.
Effect on QT/QTc Interval: Androgen deprivation therapy has the potential to prolong QT/QTc interval on the electrocardiogram (ECG). QT prolongation, a physiologic consequence of hormonal therapies that induces androgen ablation in males with prostate cancer, should be considered in assessing the risk-benefit of treatment with hormonal therapy. Physicians should consider whether the benefits of androgen deprivation therapy outweigh the potential risk (including the potential for Torsades de pointes) in patients with history of or risk factors for QT prolongation (e.g., congenital long QT syndrome, frequent electrolyte abnormalities, or congestive heart failure) and in patients taking concomitant drugs that might prolong the QT interval (see Interactions). Electrolyte abnormalities should be corrected. ECG recordings and serum electrolyte levels (i.e., potassium, calcium, and magnesium) are recommended to be obtained at baseline and periodically during triptorelin therapy in patients at risk for electrolyte abnormality and QT prolongation.
Hematologic Effects: Anemia is a known physiologic consequence of testosterone suppression. Assessment of the risk of anemia and its management according to clinical practice and guidelines should be considered.
Increased lymphocyte count occurred in patients treated with GnRH agonists. This secondary lymphocytosis seems to be related to the GnRH-induced castration and may imply that gonadal hormones are involved in thymic involution.
Pituitary Apoplexy: Cases of pituitary apoplexy have been rarely reported during postmarketing experience in patients administered with GnRH agonists, including triptorelin. In most cases, a previously unknown gonadotroph cell pituitary adenoma was diagnosed in patients experiencing pituitary apoplexy. Pituitary apoplexy, a clinical syndrome resulting from infarction of the pituitary gland, usually occurs within 2 weeks following the first dose of triptorelin; however, some cases occurred within the first hour after triptorelin administration. In these cases, pituitary apoplexy was characterized by sudden headache, vomiting, visual changes or impairment, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention is required. LHRH agonists should not be administered to patients with known pituitary adenoma.
Convulsions: There have been postmarketing reports of convulsions in patients treated with GnRH agonists. Convulsions occur in patients with a history of seizures, epilepsy, cerebrovascular disorders, or central nervous system anomalies or tumors; and in patients taking concomitant medications that induce convulsions (e.g., bupropion, selective serotonin reuptake inhibitors). Convulsions have also been reported to occur in patients without any of the aforementioned conditions.
Mood Changes and Depression: Psychiatric events, including the increased risk of mood changes and incident depression (which may be severe), have been reported in patients treated with GnRH agonists, such as triptorelin. Symptoms of emotional lability include crying, irritability, impatience, anger, and aggression. Patients should be properly informed and if symptoms occur, be treated as appropriate. The development or worsening of psychiatric symptoms should be observed. Moreover, patients with known depression should be closely monitored during GnRH therapy.
Ovarian hyperstimulation: In medically-assisted procreation, the risk of ovarian hyperstimulation cannot be ruled out, even if the patient has undergone prior treatment with triptorelin. The clinical and paraclinical signs of hyperstimulation are hypovolemia, tachycardia, hypotension, oliguria, dehydration, ascites, pleural effusion. These symptoms are also observed even with moderate ovarian hyperstimulation. Renal dysfunction, and coagulation disorder may possibly necessitate hospitalization, depending on their severity. Extreme caution and clinical and ultrasound monitoring is indicated at the first signs of hyperstimulation, particularly if this has been induced by exogenous gonadotropins during or at the end of the luteal phase.
There is an increased risk of ectopic or twin pregnancy (in the context of medically-assisted procreation) in the event of stimulation induced by exogenous gonadotropins. Ultrasound monitoring of the pregnancy is required during the first 4 weeks.
Carcinogenicity, Mutagenicity, Impairment of Fertility: Triptorelin is not mutagenic in vitro or in vivo. In mice, no oncogenic effect has been shown with intramuscular triptorelin administered every 28 days at doses up to 6,000 mcg/kg for 18 months. A 23-month carcinogenicity study in rats has shown an almost 100% incidence of benign pituitary tumors at each dose level of triptorelin administered every 28 days (120, 600, and 3,000 mcg/kg), resulting to premature death. Increased incidences of both pituitary adenomas and carcinomas were also observed at these dose levels. The increased incidence in pituitary tumors in rats is commonly observed during GnRH agonist treatment. The clinical relevance of this outcome is not known.
In chronic toxicity studies, macro- and microscopic changes in the reproductive organs of rats, beagle dogs, and monkeys were induced by clinically relevant doses of triptorelin. These alterations were considered as a reaction to suppressed gonadal function caused by the pharmacological activity of the compound. Although these changes were expected to cause a profound impairment in fertility, these were partially or largely reversed in male and female animal subjects, respectively, after discontinuation of treatment. Changes in reproductive organs included decrease in weight, atrophic histological changes in the testes, epididymis, seminal vesicle, and prostate glands, and spermatogenic arrest in males; and decreased uterine weights, ovarian atrophy, suppression of ovarian function with arrest of follicular development and inhibition of estrus cycling in females. The subcutaneous administration of triptorelin 10 mcg/kg in rats on days 6 and 15 of gestation did not affect their reproductive performance nor elicit any embryotoxic, teratogenic or any other effects on the development of their offspring (F1 generation). At 100 mcg/kg, a reduction in maternal weight gain and an increased in uterine resorptions were observed.
Atrophy of genital organs and reduced fertility were observed in rats and monkeys administered with triptorelin doses of 2 to 2,100 mcg/kg for 6 months. However, these effects were largely reversed after a 2- or 4-month recovery period. Testicular changes have also been reported to occur after prolonged administration of triptorelin in prostate cancer patients. Triptorelin may impair fertility in males of reproductive potential.
Sodium Content: This medicinal product contains <1 mmol (23 mg) sodium per vial.
Renal or Hepatic Impairment: After a single IV bolus administration of triptorelin, subjects with renal or hepatic impairment had higher triptorelin exposure than young healthy males. However, since triptorelin is a sustained-release formulation and taking into account the large safety margin of triptorelin, this is considered of no clinical relevance and no dose adjustment is recommended in patients with renal or hepatic impairment.
Effects on Ability to Drive or Use Machines: No studies have been performed. However, some adverse effects of triptorelin (e.g., apathy, dizziness, epileptic seizures, fatigue, somnolence, and visual disturbances) or from underlying disease may impair reflexes and the ability of the patient to drive and use machine.
Use in Children: The safety and effectiveness of triptorelin have not been established in children less than two years old.
Use in the Elderly: The clearance of triptorelin is partly correlated to the total creatinine clearance, which is known to decrease with age. Caution should be exercised in dosing the elderly, particularly if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity.
