Pamorelin

Triptorelin embonate.

Triptorelin is a sterile, lyophilized, biodegradable, and white to off-white powder contained in a single-dose vial. The reconstituted suspension is a homogeneous, milky, prolonged-release suspension.
Each vial contains: Triptorelin (as embonate) 3.75 mg, 11.25 mg, or 22.5 mg.
3.75 mg Lyophilized Powder for Injection: After reconstitution in 2 mL solvent, 1 mL of reconstituted suspension contains 1.875 mg of triptorelin.
11.25 mg Lyophilized Powder for Injection: After reconstitution in 2 mL solvent, 1 mL of reconstituted suspension contains 5.625 mg of triptorelin.
22.5 mg Lyophilized Powder for Injection: After reconstitution in 2 mL solvent, 1 mL of
reconstituted suspension contains 11.25 mg of triptorelin.

Pharmacology: Pharmacodynamics: Triptorelin is a synthetic decapeptide agonist analog of gonadotropin-releasing hormone (GnRH). After the initial administration, there is a transient increase in circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol. However, triptorelin is a potent inhibitor of gonadotropin secretion with chronic and continuous (usually 2 to 4 weeks after initiation of therapy) administration of therapeutic doses, resulting to sustained reduction in LH and FSH secretion and suppression of testicular and ovarian steroidogenesis. A reduction of serum testosterone concentration to a level typically seen in surgically castrated men is obtained. Consequently, tissues and functions that depend on these hormones for maintenance become quiescent. These effects are usually reversible after discontinuation of treatment.
In patients with metastatic castration-resistant prostate cancer, clinical studies have shown the benefit from the addition of abiraterone acetate, an androgen biosynthesis inhibitor, or of enzalutamide, an androgen receptor inhibitor, to GnRH analogues, such as triptorelin.
Pharmacokinetics: Triptorelin is inactive when given orally. Following a single intramuscular (IM) injection to patients with prostate cancer, mean peak triptorelin serum concentrations (C_max) of 28.4 ng/mL, 38.5 ng/mL and 44.1 ng/mL occurred in 1 to 3 hours after the 3.75 mg, 11.25 mg and 22.5 mg doses, respectively. Triptorelin did not accumulate over 9 months (3.75 mg and 11.25 mg) and 12 months (22.5 mg) of treatment.
After IM injection of prolonged-release triptorelin 3 mg in patients with endometriosis, the maximum blood level of triptorelin is obtained between 2 to 6 hours after injection and the peak value reached is 11 ng/mL. There was no evidence of accumulation of triptorelin following monthly injections over 6 months. The minimum blood level oscillates between 0.1 and 0.2 ng/mL. The bioavailability of the prolonged-release product is approximately 50%.
Results of pharmacokinetic investigations conducted in healthy men and women indicate that after intravenous (IV) bolus administration, triptorelin is distributed and eliminated according to a three-compartment model, and corresponding half-lives are approximately 6 minutes, 45 minutes and 3 hours in men, and 3 minutes, 47 minutes, and 5 hours in women.
The volume of distribution following a single IV bolus dose of 0.5 mg of triptorelin peptide was 30 to 33 L in healthy male volunteers and women with endometriosis. It is not known whether triptorelin is distributed into milk and there is no evidence that it binds to plasma proteins.
Triptorelin is degraded by peptidases in different tissues and plasma into inactive fragments, or is cleared by the kidneys and liver. It is unlikely that hepatic microsomal enzymes (cytochrome P450) are involved in the metabolism or clearance of triptorelin. The effect of triptorelin on the activity of other drug metabolizing enzymes is also unknown. In vitro studies demonstrated that triptorelin is not a significant CYP inhibitor/inducer, and P-glycoprotein substrate or inhibitor. No metabolites of triptorelin have been identified.
Triptorelin is eliminated by the kidneys and principally by the liver. Following IV administration of 0.5 mg triptorelin peptide to 6 healthy male volunteers with a creatinine clearance of 149.9 mL/min, 41.7% of the dose was excreted in urine as intact peptide with a total triptorelin clearance of 211.9 mL/min.
Following a 0.5 mg IV bolus dose in 19 women, the total clearance was estimated to be 110 mL/min. Twenty percent (20%) of the dose was eliminated in the urine.
Special Populations: Pediatric: In children 6 to 8 years old with central precocious puberty, triptorelin reached its C_max 4 hours after each injection. The geometric mean C_max after the first and second triptorelin injections are 39.9 ng/mL and 36.5 ng/mL, respectively. There was no significant accumulation detected following the second triptorelin injection, as shown by the mean geometric accumulation ratio of 0.91 for C_max.
Age and Race: The effects of age and race in the pharmacokinetics of triptorelin have not been studied systematically. However, in a pharmacokinetic study with healthy male volunteers aged 20 to 22 years with elevated creatinine clearance (approximately 150 mL/min), triptorelin was eliminated twice as fast in the young population compared with patients with moderate renal insufficiency. This is related to the fact that triptorelin clearance is partly correlated to total creatinine clearance, which is known to decrease with age.
Hepatic and Renal Impairment: Following the IV administration of 0.5 mg triptorelin peptide, the percentage of the dose excreted in urine as intact peptide was increased in patients with liver disease who have a creatinine clearance of 89.9 mL/min than in healthy volunteers with a creatinine clearance of 149.9 mL/min (62.3% versus 41.7%).
Renal and hepatic impairment did not affect the distribution half-life of 0.5 mg triptorelin administered as an IV bolus injection. However, renal insufficiency led to a decrease in total triptorelin clearance proportional to the decrease in creatinine clearance. Moreover, increases in volume of distribution and subsequent increase in elimination half-life were also observed. Subjects with hepatic insufficiency have a more pronounced decrease in triptorelin clearance than that observed in subjects with renal insufficiency. Since there were only minimal increases in the volume of distribution, the elimination half-life of subjects with hepatic insufficiency was similar to that of patients with renal insufficiency. In males with hepatic or moderate or severe renal impairment, the area under the plasma concentration-time curve (AUC) increased two- to four-fold compared with healthy males.

Palliative treatment of locally advanced, non-metastatic hormone-dependent prostate cancer, as an alternative to surgical castration
Treatment of metastatic hormone-dependent prostate cancer.
As adjuvant treatment to radiotherapy in patients with high-risk localized or locally advanced prostate cancer.
Additional Indication for Triptorelin 3.75 mg Lyophilized Powder for Injection (IM): As adjuvant treatment, in combination with tamoxifen or an aromatase inhibitor, of hormone receptor positive early stage breast cancer in women at high risk of recurrence who are confirmed as premenopausal after completion of chemotherapy.
For the pituitary down-regulation in the context of assisted reproduction technology.
Additional Indication for Triptorelin 3.75 mg Lyophilized Powder for Injection (IM/SC) and 11.25 mg Lyophilized Powder for Injection (IM): Treatment of endometriosis.
Additional Indication for Triptorelin 22.5 mg Lyophilized Powder for Injection (IM): Treatment of central precocious puberty (CPP) in children 2 years and older with an onset of CPP before 8 years in girls and 10 years in boys.

Triptorelin is administered as a single intramuscular (IM) injection. The 3.75 mg format may also be administered as a single subcutaneous (SC) injection.
As with other drugs administered by injection, the injection site should be varied periodically.
Since triptorelin is a suspension of microgranules, inadvertent intravascular injection must be strictly avoided.
Recommended Dosing for Triptorelin: Prostate Cancer: Triptorelin should be prescribed by and administered under the supervision of a qualified physician experienced in the use of hormonal therapy in prostate cancer. (See table.)

Click on icon to see table/diagram/image

Due to different release characteristics, the different dosage strengths of triptorelin are not additive and must be selected based on the desired dosing schedule. The treatment duration of androgen deprivation therapy recommended by medical guidances for T3 (locally extensive prostate cancer) to T4 (metastatic prostate cancer) patients receiving radiotherapy is 2 to 3 years.
In patients with metastatic castration-resistant prostate cancer not surgically castrated receiving a GnRH agonist, such as triptorelin, and eligible for treatment with abiraterone acetate, an inhibitor of androgen biosynthesis, or enzalutamide, an inhibitor of androgen receptor function, treatment with the GnRH agonist should be continued.
The efficacy of treatment can be monitored by measuring serum levels of testosterone and prostate specific antigen (PSA) and by subjective evaluation (symptomatic improvement, e.g. of urinary symptoms, cancer pain etc.). Testosterone levels can be measured immediately before or after injection.
Breast cancer (For 3.75 mg preparations only): The recommended dose is triptorelin 3.75 mg (1 vial) administered once a month (i.e., every 4 weeks) as an intramuscular injection in combination with tamoxifen or an aromatase inhibitor.
Triptorelin should be commenced after completion of chemotherapy, once premenopausal status has been confirmed.
Treatment with triptorelin must be initiated at least 6 to 8 weeks before starting aromatase inhibitor treatment. A minimum of 2 injections of triptorelin (with an interval of 4 weeks between injections) should be administered before commencement of aromatase inhibitor treatment.
During treatment with an aromatase inhibitor, triptorelin must not be interrupted to avoid rebound increases in circulating estrogens in premenopausal women.
Patients who have discontinued triptorelin treatment should also discontinue aromatase inhibitors within 1 month of the last triptorelin administration.
The recommended treatment duration for adjuvant treatment in combination with other hormonotherapy is up to 5 years.
Pituitary down-regulation in the context of assisted reproduction technology (For 3.75 mg preparations only): Various protocols are proposed for the use of triptorelin 3.75 mg: In the "long protocol", a single injection of triptorelin 3.75 mg causes complete pituitary suppression (down-regulation) prior to the induction of stimulation with exogenous gonadotropins. The extent of the pituitary suppression is measured by the level of circulating estrogens. Stimulation with exogenous gonadotropins is induced only when the E₂ levels is <50 pg/mL.
The "long protocol" is also employed outside medically assisted procreation. The dosage of gonadotropins administered to induce follicular maturation should be adjusted because the aim of treatment is maturation of a single follicle.
In the "short protocol", stimulation with exogenous gonadotropins is induced at the same time as, or very shortly after, the single injection of triptorelin 3.75 mg. In this case, the effect of the GnRH agonists during the first few days of stimulation potentiates the effects of the exogenous gonadotropins ("flare-up"). The "short protocol" should not be used outside medically-assisted procreation.
The extent of pituitary suppression (in the "long protocol") can be evaluated by measuring levels of E₂. Regular biological and endocrinological tests with control ultrasound scans are required during medically assisted procreation. In the event of excessive ovarian stimulation, reduce or discontinue gonadotropin administration.
Endometriosis (For 3.75 mg and 11.25 mg preparations only): Single IM or SC (for 3.75 mg preparation only) injection every 28 days, to be initiated in the first 5 days of the menstrual cycle. The maximum duration of treatment should be 6 months.
Treatment duration depends on the initial severity of the disease and the changes observed in the clinical features (functional and anatomical) during treatment.
Experience in women has been limited to women ≥18 years old treated for 6 months.
Maintaining estradiol suppression is important in the management and relief of chronic pain associated with endometriosis. Missing an appointment by a few days should not disrupt the benefits of treatment, but keeping a consistent schedule of triptorelin injections is an important part of treatment.
An improvement in symptoms (e.g., dysmenorrhea, dyspareunia, tenesmus, pelvic pain) can be expected during treatment. If necessary, therapeutic follow-up can be based on the usual biological parameters (E₂, progesterone).
Precocious puberty (For 22.5 mg preparations only): The treatment of children with triptorelin 22.5 mg should be under the overall supervision of a pediatric endocrinologist, a pediatrician, or an endocrinologist with expertise in the treatment of central precocious puberty.
Treatment should be discontinued around the physiological age of puberty in boys and girls and should not be continued in girls with a bone maturation of more than 12 to 13 years. There are limited data available in boys relating to the optimum time to stop treatment based on bone age; however it is advised that treatment be discontinued in boys with a bone maturation age of 13 to 14 years.
The therapy is a long-term treatment, and should be individually adjusted. Triptorelin 22.5 mg should be administered as precisely as possible in regular six-monthly (24 weekly) periods, respectively. An exceptional delay of the injection date for a few days (169 ± 3 days, respectively) does not influence the results of the therapy.
The development of puberty characteristics will occur after discontinuation of treatment. Information with regards to fertility is still limited, but future reproductive function and fertility appears to be unaffected by GnRH treatment. In most girls, regular menses will start on average one year after discontinuation of therapy.
Directions for Reconstitution: The powder should be reconstituted immediately before use. The lyophilized microgranules are to be reconstituted in 2 mL of Sterile Water for Injection only. No other diluents should be used.
Using a syringe fitted with a sterile 21-gauge needle, withdraw 2 mL of Sterile Water for Injection and inject into the vial.
Shake the vial gently and thoroughly to completely disperse the powder to obtain a homogeneous milky suspension.
The suspension should be administered immediately after reconstitution since the product does not contain any preservative. Once reconstituted, the suspension of triptorelin should be injected relatively rapidly and in an uninterrupted manner in order to avoid any potential blockage of the needle.
For single use only. Discard any unused suspension.
Special Populations: Renal and Hepatic Impairment: No dosage adjustment is necessary for patients with renal or hepatic impairment.

The pharmaceutical properties and the route of administration of triptorelin make accidental or intentional overdose unlikely. Moreover, there is no experience of overdosage in clinical trials. Aside from the effect of higher doses of triptorelin on sex hormone concentration and on the reproductive tract, animal data do not predict any other effects of triptorelin overdosage. If overdosage occurs, therapy should be discontinued immediately and the appropriate supportive and symptomatic treatment should be administered.

Hypersensitivity to triptorelin, GnRH, luteinizing hormone releasing hormone (LHRH), GnRH agonist analogs, or any component in the product.
Pregnant or breastfeeding women (see Use in Pregnancy & Lactation).
Women with undiagnosed abnormal vaginal bleeding.
Patients with spinal cord compression secondary to prostate cancer metastases.
In the pre-menopausal breast cancer setting: Initiation of aromatase inhibitor before adequate ovarian suppression with triptorelin has been achieved.

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.

Pregnancy: Pregnancy Category X. Triptorelin is contraindicated in women who are or may become pregnant during treatment with this drug. Expected hormonal changes that occur with triptorelin treatment increase the risk of pregnancy loss and fetal harm if the drug is administered to a pregnant woman. The patient should be informed of the potential hazard to the fetus if this drug is used during pregnancy, and the treatment should be discontinued if the patient becomes pregnant while receiving triptorelin.
Lactation: It is not known if triptorelin is distributed in the breast milk. However, since triptorelin slightly decreases prolactin levels, reduced lactation may be observed. Since there are no well-controlled studies on the effect of triptorelin in breastfeeding women and in breastfed infants, and many drugs are excreted in human milk, a decision should be made to either discontinue breastfeeding, or discontinue triptorelin therapy, considering the importance of the drug to the mother.

The majority of adverse effects related to triptorelin results from its pharmacological action, i.e., induced variation in serum testosterone levels, either an increase in testosterone at the initiation of treatment, or a decrease in testosterone once castration is achieved in men. These effects included hot flushes, erectile dysfunction, and decreased libido. Hot flushes, vaginal dryness, and amenorrhea occurred in female patients. Abnormalities in laboratory values (i.e., decreased hemoglobin and red blood cell counts; and increased glucose, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels) also occurred in patients treated with triptorelin.
Infections and infestations: Influenza, urinary tract infection.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Metastatic pain, pathological fracture, pituitary adenoma, (temporary) tumor flare (prostate cancer).
Blood and lymphatic system disorders: Anemia, lymphadenopathy, lymphocytosis, thrombocytosis.
Immune system disorders: Anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, angioedema, angioneurotic edema, hypersensitivity, immuno-allergic reactions, urticaria.
Endocrine disorders: Pituitary apoplexy.
Metabolism and nutrition disorders: Anorexia, decreased appetite, diabetes mellitus, edema, fluid retention, glucose intolerance, gout, hyperglycemia, hyperlipidemia, hyperuricemia, increased appetite, obesity, peripheral edema, weight gain.
Psychiatric disorders: Aggression, altered mental status, anger, anxiety, confusional state, crying, decreased activity, depression, depression aggravated, disorientation, disturbance in attention, emotional/affect lability, emotional distress, euphoric mood, impatience, insomnia, loss of libido, mood changes, mood disorder, nervousness, sleep disorder, somnolence, suicide attempts, suicide ideation.
Nervous system disorders: Amnesia, central nervous system hemorrhage, cerebral ischemia, cerebrovascular accident, convulsions, dizziness, dysstasia, headache, hypoesthesia, loss of consciousness, memory impairment, migraine, neuropathy, paresthesia (especially of lower extremities), paralysis of lower extremities, spinal cord compression, tremor, vertigo.
Eye disorders: Abnormal sensation in the eye, conjunctivitis, dry eye, eye pain, ophthalmoplegia, papilledema, visual blurred, visual changes, visual disturbances, visual impairment.
Ear and labyrinth disorders: Otitis externa, tinnitus.
Cardiac disorders: Chest pain, myocardial infarction, myocardial ischemia, palpitations.
Vascular disorders: Cardiovascular collapse, deep vein thrombosis, embolism, flushing, hypertension, hypotension, syncope, syncope vasovagal, transient ischemic attack, thromboembolic events, thrombophlebitis.
Respiratory, thoracic and mediastinal disorders: Bronchitis, coughing, dyspnea, epistaxis, interstitial lung disease, nasopharyngitis, orthopnea, pharyngitis, pulmonary embolism, rhinitis, sinusitis, upper respiratory tract infection.
Gastrointestinal disorders: Abdominal discomfort, abdominal distension, abdominal pain, anal pruritus, constipation, diarrhea, dry mouth, dysgeusia, dyspepsia, flatulence, gastroenteritis, gastroesophageal reflux, mouth ulceration, nausea, tenesmus, vomiting.
Hepatobiliary disorders: Abnormal hepatic function, cholestatic hepatitis.
Skin and subcutaneous tissue disorders: Acne, alopecia, blister, bullous eruption, bruising, dry skin, eczema, erythema, hirsutism, onychoclasis, photosensitivity reactions, purpura, pruritus, rash, seborrhea, skin disorder.
Musculoskeletal and connective tissue disorders: Arthralgia, back pain, bone fracture, bone loss, bone pain, joint stiffness, joint swelling, leg cramps, leg pain, muscle cramps, muscular weakness (especially of the lower extremities), musculoskeletal disorder, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, osteoarthritis, osteoporosis, pain in extremity.
Renal and urinary disorders: Bladder outlet obstruction, dysuria, hematuria, nocturia, pollakiuria, renal impairment, renal pain, urethral disorders, urethral obstruction, urinary incontinence, urinary retention.
Reproductive system and breast disorders: Breast disorder, breast pain, coital bleeding, cystocele, dysmenorrhea, dyspareunia, ejaculation disorder, ejaculation failure, genital hemorrhage, gynecomastia, impotence, mastitis, menorrhagia, menstrual disorder, metrorrhagia, orchitis (noninfective), ovarian cyst, ovarian hyperstimulation syndrome, ovarian hypertrophy pelvic pain, pelvic pain, perineal pain, prostate disorder, reduced size of genitalia, testicular atrophy, testicular disorder, testicular pain, uterine hemorrhage, vaginal bleeding, vaginal discharge, vaginal dryness, vulvovaginal dryness, withdrawal bleeding.
General disorders and administration site conditions: Aggravation of postoperative problems, asthenia, dependent edema, fatigue, hyperhidrosis, influenza-like syndrome, injection site bruising, injection site edema, injection site erythema, injection site extravasation (after subcutaneous injection), injection site induration, injection site inflammation, injection site pain, injection site pruritus, injection site reaction, injection site swelling, irritability, lethargy, malaise, pain, pyrexia, rigors.
Investigations: Altered serum testosterone levels, decreased estrogen levels, decreased hemoglobin, decreased red blood cells, decreased weight, increased alanine aminotransferase, increased alkaline phosphatase, increased aspartate aminotransferase, increased blood creatinine, increased blood pressure, increased blood prolactin, increased blood urea, increased blood urea nitrogen, increased blood urea nitrogen (not originating from proteins), increased body temperature, increased plasma estradiol levels, increased estrogen levels, increased fasting glucose, increased gamma-glutamyltransferase, increased glucose, increased lymphocyte count, increased mean testosterone levels, increased plasma estradiol levels, increased prostatic antigen, increased prothrombin time, increased weight, prolonged QT.
Injury, poisoning and procedural complications: Fractures.

Drugs affecting pituitary secretion of gonadotropins: Caution should be exercised when drugs that affect the pituitary secretion of gonadotropins are concomitantly used with triptorelin. Monitoring of the patient's hormonal status is also recommended.
Drugs that induce hyperprolactinemia [e.g., antipsychotic agents (chlorpromazine, haloperidol, molindone, olanzapine, prochlorperazine, risperidone), methyldopa, metoclopramide, reserpine]: Since the number of GnRH receptors is decreased in patients with hyperprolactinemia, drugs that induce hyperprolactinemia may reduce the efficacy of triptorelin. The concomitant use of these drugs with triptorelin is not recommended.
Drugs that prolong QTc interval and induce Torsades de pointes: Androgen deprivation treatment may prolong QTc interval. Thus, the concomitant use of triptorelin with drugs that prolong the QTc interval and induce Torsades de pointes should be carefully evaluated. Such drugs include but are not limited to the following examples: Class IA (e.g., quinidine, disopyramide), Class III (e.g. amiodarone, sotalol, dofetilide, ibutilide, dropedarone), or Class IC (e.g., flecainide, propafenone) antiarrhythmic drugs, antipsychotics (e.g., chlorpromazine), antibiotics and analogues (e.g., erythromycin, clarithromycin, azithromycin), quinolone antibiotics (e.g., moxifloxacin), antimalarials (e.g., quinine), azole antifungals, 5-hydroxytrypt amine (5-HT3) receptor antagonists (e.g., ondansetron), methadone, and beta-2 adrenoceptor agonists (e.g., salbutamol).
Anticoagulants: Since there is a potential risk of hematoma at the injection site, intramuscular triptorelin should be used in caution in patients treated with anticoagulants.
Antihypertensives: Adjustments of antihypertensive therapy may be required in patients receiving triptorelin.
Laboratory test alterations: Chronic or continuous administration of triptorelin in therapeutic doses results in suppression of pituitary-gonadal axis. Normal function of the pituitary-gonadal axis is usually restored within 4 to 12 weeks after treatment discontinuation. Thus, diagnostic tests of the pituitary-gonadal function conducted during treatment and within 4 to 12 weeks after cessation of therapy may be misleading.
Decreased hemoglobin and red blood cell count, and increased glucose, blood urea nitrogen (BUN), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase levels were reported. Majority of the changes were mild to moderate.

Incompatibilities: In the absence of compatibility studies, triptorelin should not be mixed with other medicinal products.
Handling Precautions: Wash hands with soap and water and put on gloves immediately prior to preparing the injection.
Used injection needles should be disposed of in a designated container.

Store at temperatures not exceeding 30°C.

Cancer Hormone Therapy / Trophic Hormones & Related Synthetic Drugs

L02AE04 - triptorelin ; Belongs to the class of gonadotropin releasing hormone analogues. Used in endocrine therapy.

Rx