Endmet

Leuprorelin acetate.

Each Lyophilized vial contains: Leuprorelin BP (as acetate) 3.75 mg, Excipients q.s.
Diluent Composition: Each ampoule contains Carboxymethyl cellulose, Sodium USNF 5.0 mg, D-Mannitol USP 50 mg, Polysorbate 80 USNF 1 mg, Glacial Acetic Acid USP (for pH adjustment) q.s., Water for Injection USP q.s. to 2 ml.
Leuprorelin acetate is a synthetic nonapeptide analogue of naturally occurring gonadotropin releasing hormone (GnRH or LhRH). It possesses greater potency than the natural hormone. Prolide is a formulation of leuprorelin acetate. Each lyophilized vial containing microspheres, when mixed with diluents becomes a suspension.
Leuprorelin acetate suspension is administered as an intramuscular or subcutaneous injection once in a month or every 3 months.

Pharmacology: Leuprorelin acetate is a long-acting GnrH analog. A single monthly injection of leuprorelin acetate results in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins.
Repeated dosing at monthly intervals results in decreased secretion of gonadal steroids; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. This effect is reversible on discontinuation of drug therapy.
Leuprorelin acetate is not active when given orally. Intramuscular injection of the depot formulation provides plasma concentrations of leuprorelin over a period of one month.
Pharmacokinetics: Absorption: A single dose of leuprorelin acetate was administered by intramuscular injection to healthy female volunteers. The absorption of leuprorelin was characterized by an initial increase in plasma concentration, with peak concentration ranging from 4.6 to 10.2 ng/ml at four hours post dosing. However, intact leuprorelin and an inactive metabolite could not be distinguished by the assay used in the study. Following the initial rise, leuprorelin concentrations started to plateau within two days after dosing and remained relatively stable for about four to five weeks with plasma concentrations of about 0.30 ng/ml.
Distribution: The mean steady-state volume of distribution of leuprorelin following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.
Metabolism: In healthy male volunteers, a 1 mg bolus of leuprorelin administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.
In rats and dogs, administration of 14C-labeled leuprorelin was shown to be metabolized to smaller inactive peptides, a pentapeptide (metabolite I), tripeptides (metabolites II and Ill) and a dipeptide (metabolite IV). These fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprorelin concentrations.
Excretion: Following administration of Prolide to 3 patients. less than 5% of the dose was recovered as parent and M-i metabolite in the urine.

Endometriosis: Leuprorelin acetate is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions. Leuprorelin acetate monthly with norethindrone acetate 5 mg daily is also indicated for initial management of endometriosis and for management of recurrence of symptoms. Duration of initial treatment or retreatment should be limited to 6 months.
Uterine leiomyomata (fibroids): Leuprorelin acetate concomitantly with iron therapy is indicated for the preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata. The clinician may wish to consider a one-month trial period on iron alone in as much as some of the patients will respond to iron alone. (see Table 1.) Leuprorelin acetate may be added if the response to iron alone is considered inadequate. Recommended duration of therapy with leuprorelin acetate is up to three months.
Experience with leuprorelin acetate in females has been limited to women 18 years of age and older. (See Table 1.)

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Leuprorelin acetate must be administered under the supervision of a physician.
Endometriosis: The recommended duration of treatment with leuprorelin acetate alone or in combination with norethindrone acetate is six months. The choice of leuprolide acetate alone or leuprorelin acetate plus norethindrone acetate therapy for initial management of the symptoms and signs of endometriosis should be made by the health care professional in consultation with the patient and should take into consideration the risks and benefits of the addition of norethindrone to leuprorelin acetate alone.
If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of leuprorelin acetate monthly and norethindrone acetate 5 mg daily may be considered. Retreatment beyond this one six-month course cannot be recommended. It is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits. Leuprorelin acetate alone is not recommended for retreatment. If norethindrone acetate is contraindicated for the individual patient, then retreatment is not recommended.
An assessment of cardiovascular risk and management of risk factors such as cigarette smoking is recommended before beginning treatment with leuprorelin acetate and norethindrone acetate.
Uterine leiomyomata (fibroids): Recommended duration of therapy with leuprorelin acetate is up to 3 months. The symptoms associated with uterine leiomyomata will recur following discontinuation of therapy. If additional treatment with leuprorelin acetate is contemplated, bone density should be assessed prior to initiation of therapy to ensure that values are within normal limits.
The recommended dose of leuprorelin acetate , incorporated in a depot formulation. The lyophilized microspheres are to be reconstituted and administered monthly as a single intramuscular injection.

In rats, subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence that there is a clinical counterpart of this phenomenon. In early clinical trials using daily subcutaneous Leuprorelin acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose.

Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in leuprorelin acetate.
Undiagnosed abnormal vaginal bleeding.
Leuprorelin acetate is contraindicated in women who are or may become pregnant while receiving the drug. Leuprorelin acetate may cause fetal harm when administered to a pregnant woman. Major fetal abnormalities were observed in rabbits but not in rats after administration of depot throughout gestation. There was increased fetal mortality and decreased fetal weights in rats and rabbits. The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by the drug. If this drug is used during pregnancy orif the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Use in women who are breast-feeding.

Safe use of leuprorelin acetate or norethindrone acetate in pregnancy has not been established clinically. Before starting treatment with leuprorelin acetate, pregnancy must be excluded.
When used monthly at the recommended dose, leuprorelin acetate usually inhibits ovulation and stops menstruation. Contraception is not insured, however, by taking leuprorelin acetate. Therefore, patients should use non-hormonal methods of contraception.
Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued and the patient must be apprised of the potential risk to the fetus.
During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiologic effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy.
Reference id: 2960300.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported post-marketing.
The following applies to co-treatment with leuprorelin acetate and norethindrone acetate: Norethindrone acetate treatment should be discontinued if there is a sudden partial or complete loss of vision or if there is sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn.
Because of the occasional occurrence of thrombophlebitis and pulmonary embolism in patients taking progestogens, the physician should be alert to the earliest manifestations of the disease in women taking norethindrone acetate.
Assessment and management of risk factors for cardiovascular disease is recommended prior to initiation of add-back therapy with norethindrone acetate. Norethindrone acetate should be used with caution in women with risk factors, including lipid abnormalities or cigarette smoking.

Information for patients: An information pamphlet for patients is included with the product. Patients should be aware of the following information: Since menstruation usually stops with effective doses of leuprorelin acetate, the patient should notify her physician if regular menstruation persists. Patients missing successive doses of leuprorelin acetate may experience breakthrough bleeding.
Patients should not use leuprorelin acetate if they are pregnant, breast feeding, have undiagnosed abnormal vaginal bleeding, or are allergic to any of the ingredients in prolide.
Safe use of the drug in pregnancy has not been established clinically. Therefore, a non-hormonal method of contraception should be used during treatment. Patients should be advised that if they miss successive doses of leuprorelin acetate, breakthrough bleeding or ovulation may occur with the potential for conception. If a patient becomes pregnant during treatment, she should discontinue treatment and consult her physician.
Adverse events occurring in clinical studies with leuprorelin acetate that are associated with hypoestrogenism include: hot flashes, headaches, emotional ability, decreased libido, acne, myalgia, reduction in breast size, and vaginal dryness. Estrogen levels returned to normal after treatment was discontinued.
Patients should be counselled on the possibility of the development or worsening of depression and the occurrence of memory disorders.
The induced hypoestrogenic state also results in a loss in bone density over the course of treatment, some of which may not be reversible. Clinical studies show that concurrent hormonal therapy with norethindrone acetate 5 mg dally Is effective In reducing loss of bone mineral density that occurs with leuprorelin acetate. (all patients received calcium supplementation with 1000 mg elemental calcium.).
If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of leuprorelin acetate and norethindrone acetate 5 mg daily may be considered. Retreatment beyond this one six month course cannot be recommended. It is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits. Retreatment with leuprorelin acetate alone is not recommended.
In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, leuprorelin acetate therapy may pose an additional risk. In these patients, the risks and benefits must be weighed carefully before therapy with leuprorelin acetate alone is instituted, and concomitant treatment with norethindrone acetate 5mg daily should be considered. Retreatment with gonadotropin-releasing hormone analogs, including leuprorelin acetate is not advisable in patients with major risk factors for loss of bone mineral content.
Norethindrone acetate may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunctions require careful observation during norethindrone acetate add-back therapy.
Patients who have a history of depression should be carefully observed during treatment with norethindrone acetate and norethindrone acetate should be discontinued if severe depression occurs.
Laboratory tests: See Adverse Reactions.
Carcinogenesis, mutagenesis, impairment of fertility: A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no Leuprorelin acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with Leuprorelin acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities.
Mutagenicity studies have been performed with Leuprorelin acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential.
Clinical and pharmacologic studies in adults (>18 years) with Leuprorelin acetate and similar analogs have shown reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks. Although no clinical studies have been completed in children to assess the full reversibility of fertility suppression, animal studies (prepubertal and adult rats and monkeys) with Leuprorelin acetate and other GnRH analogs have shown functional recovery.
Use in Children: Experience with Leuprorelin Acetate for treatment of endometriosis has been limited to women 18 years of age
and older.
Use in the Elderly: This product has not been studied in women over 65 years of age and is not indicated in this population.

Pregnancy: Teratogenic Effects: Pregnancy Category X (see Contraindications). When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024. and 0.024 mg/kg (1/300 to 1/3 of the human dose) to rabbits, Leuprorelin Acetate produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with the two higher doses of Leuprorelin Acetate in rabbits and with the highest dose (0.024 mg/kg) in rats.
Nursing Mothers: It is not known whether Leuprorelin Acetate is excreted in human milk. Many drugs are excreted in human milk, and because the effects of Leuprorelin Acetate on lactation and/or the breast-fed child have not been determined, Leuprorelin Acetate should not be used by nursing mothers.

Clinical Trials: Estradiol levels may increase during the first weeks following the initial injection of Leuprolide Acetate, but then decline to menopausal levels. This transient increase in estradiol can be associated with a temporary worsening of signs and symptoms (see Warnings).
As would be expected with a drug that lowers serum estradiol levels, the most frequently reported adverse reactions were those related to hypoestrogenism.
The monthly formulation of Leuprolide Acetate 3. 75 mg was utilized in controlled clinical trials that studied the drug in 166 endometriosis and 166 uterine fibroids patients. Adverse events reported in ≥5% of patients in either of these populations and thought to be potentially related to drug are noted in the following table. (See Table 2.)

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In one controlled clinical trial utilizing the monthly formulation of leuprorelin acetate, patients diagnosed with uterine fibroids received a higher dose (7.5 mg) of leuprorelin acetate. Events seen with this dose that were thought to be potentially related to drug and were not seen at the lower dose included glossitis, hypesthesia, lactation, pyelonephritis, and urinary disorders. Generally, a higher incidence of hypoestrogenic effects was observed at the higher dose.
Table 3 lists the potentially drug-related adverse events observed in at least 5% of patients in any treatment group during the first 6 months of treatment in the add-back clinical studies.
In the controlled clinical trial, 50 of 51 (98%) patients in the LD group and 48 of 55 (87%) patients in the LD/N group reported experiencing hot flashes on one or more occasions during treatment. During Month 6 of treatment, 32 of 37 (86%) patients in the LD group and 22 of 38 (58%) patients in the LD/N group reported having experienced hot flashes. The mean number of days on which hot flashes were reported during this month of treatment was 19 and 7 in the LO and LOIN treatment groups, respectively. The mean maximum number of hot flashes in a day during this month of treatment was 5.8 and 1.9 in the LD and LD/N treatment groups, respectively. (See Table 3.)

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Changes in Bone Density: In controlled clinical studies, patients with endometriosis (six months of therapy) or uterine fibroids (three months of therapy) were treated with leuprorelin acetate 3.75 mg. In endometriosis patients, vertebral bone density as measured by dual energy x-ray absorptiometry (DEXA) decreased by an average of 3.2% at six months compared with the pretreatment value. Clinical studies demonstrate that concurrent hormonal therapy (norethindrone acetate 5 mg daily) and calcium supplementation is effective in significantly reducing the loss of bone mineral density that occurs with leuprorelin acetate treatment, without compromising the efficacy of leuprorelin acetate in relieving symptoms of endometriosis.
Leuprorelin acetate plus norethindrone acetate 5 mg daily was evaluated in two clinical trials. The results from this regimen were similar in both studies. Prolide was used as a control group in one study. The bone mineral density data of the lumbar spine from these two studies are presented in Table 4. (See Table 4.)

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When leuprorelin acetate was administered for three months in uterine fibroid patients, vertebral trabecular bone mineral density as assessed by quantitative digital radiography (QDR) revealed a mean decrease of 2.7% compared with baseline. Six months after discontinuation of therapy, a trend toward recovery was observed. Use of Prolide for longer than three months (uterine fibroids) or six months (endometriosis) or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss and is not recommended.
Changes In Laboratory Values During Treatment: Plasma Enzymes: Endometriosis: During early clinical trials with leuprorelin acetate, regular laboratory monitoring revealed that AST levels were more than twice the upper limit of normal in only one patient. There was no clinical or other laboratory evidence of abnormal liver function.
In two other clinical trials, 6 of 191 patients receiving Leuprolide Acetate 3. 75 mg plus norethindrone acetate 5 mg daily for up to 12 months developed an elevated (at least twice the upper limit of normal) SGPT or GGT. Five of the 6 increases were observed beyond 6 months of treatment. None were associated with elevated bilirubin concentration.
Uterine Leiomyomata (Fibroids): In clinical trials with leuprorelin acetate, five (3%) patients had a post-treatment transaminase value that was at least twice the baseline value and above the upper limit of the nominal range. None of the laboratory increases were associated with clinical symptoms.
Lipids: Endometriosis: In earlier clinical studies, 4% of the leuprorelin acetate patients and 1% of the danazol patients had total cholesterol values above the normal range at enrollment. These patients also had cholesterol values above the normal range at the end of treatment.
Of those patients whose pretreatment cholesterol values were in the normal range, 7% of the leuprorelin acetate patients and 9% of the danazol patients had post-treatment values above the normal range.
The mean (±SEM) pretreatment values for total cholesterol from all patients were 178.8 (2.9) mg/dL in the leuprorelin acetate groups and 175.3 (3.0) mg/dL in the danazol group. At the end of treatment, the mean values for total cholesterol from all patients were 193.3 mg/dL in the leuprorelin acetate group and 194.4 mg/dL in the danazol group. These increases from the pretreatment values were statistically significant (p<0.03) in both groups.
Triglycerides were increased above the upper limit of normal in 12% of the patients who received leuprorelin acetate and in 6% of the patients who received danazol.
At the end of treatment, HDL cholesterol fractions decreased below the lower limit of the normal range in 2% of the leuprorelin acetate patients compared with 54% of those receiving danazol. LDL cholesterol fractions increased above the upper limit of the normal range in 6% of the patients receiving leuprorelin acetate compared with 23% of those receiving danazol. There was no increase in the LDL/HDL ratio in patients receiving leuprorelin acetate but there was approximately a two-fold increase in the LDL/HDL ratio in patients receiving danazol.
In two other clinical trials, leuprorelin acetate plus norethindrone acetate 5 mg daily was evaluated for 12 months of treatment. leuprorelin acetate was used as a control group in one study. Percent changes from baseline for serum lipids and percentages of patients with serum lipid values outside of the nominal range in the two studies are summarized in the tables as follows. (See Table 5.)

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Changes from baseline tended to be greater at Week 52. After treatment, mean serum lipid levels from patients with follow up data returned to pretreatment values. (See Table 6.)

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Low HDL-cholesterol (<40 mg/dL) and elevated LDL-cholesterol (>160 mg/dL) are recognized risk factors for cardiovascular disease. The long-term significance of the observed treatment-related changes in serum lipids in women with endometriosis is unknown. Therefore assessment of cardiovascular risk factors should be considered prior to initiation of concurrent treatment with leuprorelin acetate and norethindrone acetate.
Uterine Leiomyomata (Fibroids): In patients receiving Prolide , mean changes in cholesterol (+11 mg/dL to +29 mg/dL), LDL cholesterol (+8 mg/dL to +22 mg/dL), HDL cholesterol (0 to +6 mg/dL), and the LDL/HDL ratio (-0.1 to +0.5)were observed across studies. In the one study in which triglycerides were determined, the mean increase from baseline was 32 mg/dL.
Other Changes: Endometriosis: The following changes were seen in approximately 5% to 8% of patients. In the earlier comparative studies, leuprorelin acetate was associated with elevations of LOH and phosphorus, and decreases in WBC counts. Danazol therapy was associated with increases in hematocrit, platelet count, and LOH. In the hormonal add-back studies leuprorelin acetate in combination with norethindrone acetate was associated with elevations of GGT and SGPT.
Uterine Leiomyomata (Fibroids): Hematology: (see Clinical studies as previously mentioned section). In Leuprorelin Acetate treated patients, although there were statistically significant mean decreases in platelet counts from baseline to final visit, the last mean platelet counts were within the normal range. Decreases in total WBC count and neutrophils were observed, but were not clinically significant.
Chemistry: Slight to moderate mean increases were noted for glucose, uric acid, BUN, creatinine, total protein, albumin, bilirubin, alkaline phosphatase, LOH, calcium, and phosphorus. None of these increases were clinically significant.
Postmarketing: During postmarketing surveillance, the following adverse events were reported. Like other drugs in this class, mood swings, including depression, have been reported. There have been rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of depression or other psychiatric illness. Patients should be counseled on the possibility of development or worsening of depression during treatment with Leuprorelin Acetate.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported. Rash, urticaria, and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (eg: joint and muscle pain, headaches, sleep disorder, gastrointestinal distress, and shortness of breath) have been reported individually and collectively.
Other events reported are: Cardiovascular System- Hypotension;
Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack. Although a temporal relationship was reported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH analogs and these events.
Hemic And Lymphatic System- Decreased WBC;
Central/Peripheral Nervous System- Convulsion, Peripheral neuropathy, Spinal fracture/paralysis; Musculoskeletal System- Tenosynovitis-like symptoms;
Urogenital System - Prostate pain.
Pituitary apoplexy.
During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

Drug Interactions: See Pharmacology: Pharmacokinetics under Actions.
Drug/laboratory test interactions: Administration of leuprorelin acetate in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and for up to three months after discontinuation of leuprolide acetate may be misleading.

Direction for Reconstitution: The vial of Leuprorelin Acetate (Prolide) containing sterile lyophilized microspheres should be reconstituted immediately prior to administration.
Since the product does not contain a preservative the suspension should be discarded if not used immediately. Leuprorelin Acetate (Prolide) should be administered as a single subcutaneous or intramuscular injection in accordance with the following directions: 1. Detach the flip cap from the Prolide vial and ampoule containing 2 mL diluent.
2. Using a syringe 21 gauge needle, withdraw 2 mL of diluent from the ampoule and inj vial of Leuprorelin Acetate using aseptic technique. Remove the syringe and keep aseptic.
3. Shake the vial gently for 15 to 20 seconds to thoroughly dispense the particles and to obtain a uniform milky suspension.
4. Immediately withdraw the entire contents of the vial into the syringe, change the needle on syringe with a 21 gauge needle and apply sterile dressing to injection site if required.
5. The injection should be given as soon as possible after mixing. If any settling of suspension occurs in vial or syringe, resuspended by gentle shaking and administer immediately.
No other fluid should be given for the reconstitution Leuprorelin acetate (Prolide).
How to use: Due to different release characteristics a fractional dose of the 3-month depot formulation is not equivalent to the same dose of the monthly formulation and should not be given.
1. Ensure that the fluid is at the bottom section of the diluent ampoule (flick or tap lightly if needed).
Hold the ampoule & Snap open.
2. Inject diluent into the vial.
3. Shake well for thorough dispersion.
4. The suspension will appear milky.
5. Inject the entire contents intramuscularly/subcutaneously.

Store at temperatures not exceeding 25°C. Protect from light. Avoid heat and do not freeze.

Trophic Hormones & Related Synthetic Drugs

L02AE02 - leuprorelin ; Belongs to the class of gonadotropin releasing hormone analogues. Used in endocrine therapy.

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