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Description: Triptorelin (D-Trp6-LHRH) is a synthetic decapeptide agonist analog of gonadotropin-releasing hormone (GnRH) also known as luteinizing hormone releasing hormone (LHRH). Triptorelin is more potent than native GnRH. Triptorelin (as De-capeptyl� SR) has been widely used in Europe since 1986 as part of in vitro fertilization protocols and for treatment of hirsutism, endometriosis, or precocious puberty. The FDA approved triptorelin pamoate for use as hormonal therapy for the palliative treatment of prostate cancer in June 2000. Mechanism of Action: Triptorelin is a potent inhibitor of gonadotropin secretion when given continuously. Triptorelin produces a medical castration by inhibiting the production of testosterone or estrogen through a negative feedback mechanism. Following initial administration there is a transient surge in circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol. After chronic and continuous administration, usually 2�4 weeks after starting therapy, a sustained decrease in LH and FSH secretion and marked reduction in testicular and ovarian steroidogenesis is observed. In men, a reduction of serum testosterone concentration to a level typically seen in surgically castrated men is obtained. These effects are reversible after cessation of therapy. When administered to healthy male volunteers, single doses of triptorelin resulted in peak testosterone levels on day 4 and decreased thereafter to low levels by week 4. Similar profiles are observed in men with prostate cancer. Pharmacokinetics: Triptorelin pamoate suspension is administered by intramuscular depot injection; however, other non-depot formulations available outside the US may be given as subcutaneous or intramuscular injections. Triptorelin is not active when given orally. Intramuscular injection of the depot formulation releases triptorelin over a 1-month period. The bioavailability by intramuscular injection is 83%. Triptorelin does not appear to bind to plasma proteins. Triptorelin is distributed and eliminated according to a 3-compartment model and corresponding half-lives are 6 minutes, 45 minutes, and 3 hours. The metabolism of triptorelin is unknown, but is unlikely to involve hepatic cytochrome P450 enzymes. No metabolites of triptorelin have been identified. Data suggest that C-terminal fragments produced by tissue degradation are either completely degraded in the tissues, or rapidly degraded in the plasma, or cleared by the kidney. Triptorelin is eliminated by the kidney and liver. �Special Populations: Patients with hepatic or renal impairment show a 2- to 4-fold higher exposure to triptorelin than young healthy males. The clinical consequences of this increase, as well as the potential need for dose adjustment, are unknown.
Indications...Dosage For the palliative treatment of advanced prostate cancer: Intramuscular dosage: Adult males: 3.75 mg IM once monthly. Castration levels of serum testosterone (<= 1.735 nmol/l) were achieved in 91.2% and 97.7 % of patients at day 29 and 57, respectively, of triptorelin treatment. Maintenance of castration levels of serum testosterone from day 57 through day 253 was found in 96.4% of patients treated with triptorelin. For the treatment of advanced breast cancer�: Intramuscular dosage: Adult females: In a pilot study of premenopausal women with metastatic breast cancer, triptorelin 3.75 mg IM once monthly was given until disease progression occurred. In 11 patients evaluable for response, 5 achieved a partial remission, disease stabilization occurred in 3, and 3 patients failed to respond.[3025] In another study, 27 premenopausal women with hormone-sensitive, previously untreated metastatic breast cancer had an overall response rate of 70% (complete response 18%; partial response 52%). The median time to progression was 12 months.[3026] For pituitary downregulation in women undergoing controlled ovarian hyperstimulation and subsequent in vitro fertilization (IVF) or other assisted reproductive technology (ART) for the treatment of infertility�: Intramuscular dosage: Adult females: A single 3.75 mg IM dose has been given 15 days prior to initiation of ovarian stimulation therapy.[3027] For the treatment of endometriosis� with associated dysmenorrhea� or uterine leiomyomata� (fibroids): Intramuscular dosage: Adult females: In Europe, doses of 3.75�4.2 mg IM once monthly are recommended. In one trial, the extent and area of endometrial lesions decreased 45�50% and pain symptoms were significantly improved in patients treated with triptorelin.[3028] For the treatment of precocious puberty�: Intramuscular dosage: Female and male children: Studies have used triptorelin doses of 3.75 mg IM once monthly effectively. For the treatment of hirsutism�: Intramuscular dosage: Adults: Studies have used triptorelin 3.75 mg IM once every 28 days in combination with a triphasic oral contraceptive[3029] or conjugated estrogens and medroxyprogesterone.[3030] Triptorelin showed no advantage over flutamide or cyproterone. Patients with hepatic impairment: Although 2- to 4-fold higher levels have been reported in patients with hepatic impairment, no recommendations for dosage adjustment are available. Patients with renal impairment: Although 2- to 4-fold higher levels have been reported in patients with renal impairment, no recommendations for dosage adjustment are available. �non-FDA approved indication
Administration Intramuscular Administration �For intramuscular use only; do not administer intravenously. �Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. �Store vials at room temperature 15�30 degrees C (59�86 degrees F). Reconstitution: �The product should be reconstituted with sterile water only; no other diluent should be used. �Using a syringe fitted with a 20-gauge needle, withdraw 2 ml sterile water for injection, USP, and inject into the vial. �Shake well to thoroughly disperse particles to obtain a uniform suspension. The suspension will appear milky. �Withdraw the entire contents of the vial into the syringe and use immediately. Intramuscular injection: �Aspirate prior to injection to avoid injection into a blood vessel. If a vessel is penetrated, withdraw the needle and use a new syringe and needle at a different injection site. �Injection sites should be alternated. Contraindications Triptorelin is contraindicated in patients with hypersensitivity to triptorelin or other GnRH analogs and during pregnancy (FDA pregnancy category X). Triptorelin may cause fetal harm if it is administered to a pregnant woman. If a woman becomes pregnant during triptorelin therapy, treatment should be stopped immediately. Because the consequences are not known, breast-feeding should be avoided during therapy with triptorelin. Due to transient increases in testosterone levels, triptorelin may cause the onset or worsening of prostate cancer symptoms (flare) such as bone pain, neuropathy, hematuria, or urethral or bladder outlet obstruction. Patients with urinary tract obstruction or metastatic vertebral lesions should be monitored carefully for signs of renal impairment or spinal cord compression, respectively, during initial triptorelin treatment. Patients with hepatic disease/dysfunction or renal impairment showed 2- to 4-fold higher exposure to triptorelin than young healthy males. The clinical consequences of this increase, as well as the potential need for dose adjustment, are unknown. Since triptorelin suppresses the pituitary-gonadal axis, diagnostic tests for pituitary insufficiency or other pituitary-gonadal function conducted during treatment and after cessation of therapy may be misleading. As with other GnRH analog treatments, triptorelin therapy will interrupt menstruation; women who continue to menstruate or who experience breakthrough bleeding while receiving triptorelin should notify their physician. The drug should not be administered to women with dysfunctional uterine bleeding or undiagnosed vaginal bleeding. Triptorelin is not FDA-approved for use in women. Triptorelin should be used with caution in patients with osteoporosis. GnRH analog therapy increases the risk of reduced bone mineral density. The addition of hormone replacement therapy (estrogens and/or progestins) to triptorelin therapy for endometriosis or uterine fibroids may be effective in reducing the bone mineral loss in women. Safe and effective use of triptorelin in children has not been established. However, in clinical trials triptorelin has been used for the treatment of precocious puberty. Interactions There have been no formal drug interaction studies performed with triptorelin. In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia (e.g., some antipsychotics, cimetidine, methyldopa, metoclopramide, and reserpine) should not be administered concomitantly with triptorelin since hyperprolactinemia downregulates the number of pituitary GnRH receptors. While no drug interactions have been reported with triptorelin, therapy with androgens or estrogens is relatively contraindicated during prostate or breast cancer treatment. However, in the treatment of endometriosis, the use of hormone replacement therapy has decreased the loss of bone density and vasomotor symptoms associated with GnRH treatment without loss of GnRH efficacy. Some herbal or alternative therapies may have effects on hypothalamic-pituitary function or hormone concentrations and thus may interfere with fertility therapies. For example, black cohosh, Cimicifuga racemosa, a phytomedicinal that may potentially suppress luteinizing hormone (LH), may antagonize fertility therapies that augment gonadotropin release. Due to a lack of data, herbal therapies touted for women's health are not recommended for use with prescribed fertility treatments. Prasterone, dehydroepiandrosterone, DHEA is a weak androgen that has complex hormonal effects. It is unclear what actions prasterone, dehydroepiandrosterone, DHEA would have on other exogenous hormonal regimens. It would seem prudent to not administer DHEA with triptorelin since DHEA may interfere with this therapy. Adverse Reactions In men, hot flashes (59%) and impotence (7%) occur as a result of triptorelin-induced testosterone suppression. Gynecomastia, a libido decrease, and testicular atrophy may also occur in men treated with triptorelin. No studies have been preformed to assess the effect of triptorelin on male fertility. The transient increases in testosterone levels in men at the initiation of triptorelin therapy may be associated with temporary worsening of prostate cancer symptoms including bone pain (12%), hematuria, urinary retention (1%), and bladder outlet obstruction. Isolated cases of spinal cord compression with weakness or muscle paralysis of the lower extremities have occurred. An injection site reaction (4%) associated with pain has been reported in a small number of patients. Anaphylactoid reactions, including anaphylactic shock and angioedema, have been reported with triptorelin therapy. Other adverse reactions occurring in > 1% of patients treated include anemia, diarrhea, dizziness, emotional lability, fatigue, headache, hypertension, insomnia, pruritus, urinary tract infection, and nausea/vomiting. Menopausal symptoms, including hot flashes and diaphoresis, are associated with triptorelin use in females due to decreases in estrogen levels. Premenopausal women will develop amenorrhea. Other adverse reactions to triptorelin therapy in women include fluid retention, alopecia, menorrhagia, vaginal irritation/dryness, and weight gain. A small loss of bone mineral density, specifically trabecular bone density occurs during triptorelin therapy. |
Triptorelin Trelstar� Depot | Trelstar� Depot 3025. Neskovic-Konstantinovic ZB, Vuletic LB, Nikolic-Stanojevic LI, et al. Therapeutic and endocrine effects of Decapeptyl, synthetic LH-RH agonistic analogue in premenopausal women with metastatic breast cancer. A pilot phase II study. Oncology 1994;51:95�101. 3026. Garcia-Giralt E, Beuzeboc P, Dieras V, et al. Phase II trial of decapeptyl (D-TRP-6), a potent luteinizing hormone releasing hormone analogue in untreated advanced breast cancer. Am J Clin Oncol 1996;19:455�8. 3027. Gianaroli L, Ferraretti AP, Feliciani E, et al. Prospective randomized study of D-Trp6-LHRH versus buserelin in long desensitization protocols for medically assisted conception cycles. Hum Reprod 1994;9:220�5. 3028. Bergqvist A, Bergh T, Hogstrom L, et al. Effects of triptorelin versus placebo on the symptoms of endometriosis. Fertil Steril 1998;69:702�8. 3030. Carmina E, Lobo RA. Gonadotrophin-releasing hormone agonist therapy for hirsutism is as effective as high dose cyproterone acetate but results in a longer remission. Hum Reprod 1997;12:663�6. 3029. Pazos F, Escobar-Morreale HF, Balsa J, et al. Prospective randomized study comparing long-acting gonadotropin-releasing hormone agonist triptorelin, flutamide, and cyproterone acetate, used in combination with an oral contraceptive, in the treatment of hirsutism. Fertil Steril 1999;71:122�8. |