Prostate Cancer: 3 Month 11.25 mg is indicated in the palliative treatment of advanced prostatic cancer. It offers an alternative treatment of prostatic cancer when orchiectomy or estrogen administration are either not indicated or unacceptable to the patient.

Endometriosis: 3 Month 11.25 mg is indicated in the treatment of endometriosis for a period of six months. It can be used as sole therapy or as an adjunct to surgery.

Uterine Fibroids: 3 Month 11.25 mg is also indicated in the treatment of leiomyoma uteri (uterine fibroids) for a period up to six months. Therapy may be preoperative prior to myomectomy or hysterectomy, or it may provide symptomatic relief for the perimenopausal woman who does not desire surgery.

Breast Cancer: 3 Month 11.25 mg is also indicated for the treatment of breast cancer in pre- and perimenopausal women in whom hormone therapy is specified.

Leuprorelin acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given on a continuous basis and in therapeutic doses. Animal and human studies indicate that following an initial stimulation, chronic administration of leuprorelin acetate results in suppression. Administration of leuprorelin acetate has resulted in inhibition of the growth of certain hormone-dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats), as well as atrophy of the reproductive organs.

In humans, administration of leuprorelin acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprorelin acetate results in decreased levels of LH and FSH and sex steroids. In males, testosterone is reduced to castrate or prepubertal levels. In premenopausal females, estrogens are reduced to postmenopausal levels. These hormonal changes occur within a month of initiating drug therapy at recommended doses.

General

• 3 Month 11.25 mg must be administered under the supervision of a physician.
• Upon reconstitution, the suspension should be discarded if not used immediately. the suspension should be discarded if not used immediately. As with other drugs administered by injection, the injection sites should be varied periodically.
• Reconstitute the microspheres immediately prior to administration: 3 Month 11.25 mg mg, administered as a single subcutaneous or intramuscular injection every three months.

Use in treatment of endometriosis: It is recommended that the therapy begin with the first day of the menstrual cycle after pregnancy has been ruled out. Development of amenorrhea is usually evidence of a clinical response, although spotting or bleeding from the atrophic endometrium can still occur.

Use in treatment of uterine fibroids: Recommended duration of therapy is up to 6 months.

No pharmacokinetic-based drug-drug interaction studies have been conducted with Leuprorelin Acetate Depot Suspension. However, because leuprorelin acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur.

Drug/Laboratory Test Interactions: Administration of leuprorelin acetate depot in women results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after leuprorelin acetate depot treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and for up to three months after discontinuation of leuprorelin acetate depot may be misleading.

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 with leuprorelin acetate and similar analogs have shown full reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks.

3 Month 11.25 mg is contraindicated in patients with known hypersensitivity to leuprorelin acetate, similar nonapeptides, or any of the excipients.

Isolated cases of anaphylaxis have been reported with the monthly formulation of Leuprorelin Acetate for Depot Suspension.

3 Month 11.25 mg is not suitable for the treatment of patients following an orchiectomy.

Undiagnosed abnormal vaginal bleeding.

3 Month 11.25 mg is contraindicated in women who are or may become pregnant while receiving the drug. 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 in rats. The effects on fetal mortality are logical consequences of the alterations in hormonal levels brought about by this drug. Therefore, the possibility exists that fetal abnormalities and spontaneous abortion may occur if the drug is administered during pregnancy.

The following adverse events are commonly associated with the pharmacological actions of leuprorelin acetate on steroidogenesis:

Men:

• Neoplasm benign, malignant and unspecified (including cysts and polyps): prostate tumor flare, aggravation of prostate cancer
• Metabolism and nutrition disorders: weight gain, weight loss
• Psychiatric disorders: loss or decreased libido, increased libido
• Nervous system disorders: headache, muscular weakness
• Vascular disorders: vasodilatation, hot flushes, hypotension, orthostatic hypotension
• Skin and subcutaneous tissue disorders: dry skin, hyperhidrosis, rash, urticaria, abnormal hair growth, hair disorder, night sweats, hypotrichosis, pigmentation disorder, cold sweat, hirsutism
• Reproductive system and breast disorders: gynecomastia, breast tenderness, erectile dysfunction, testicular pain, breast enlargement, breast pain, prostate pain, penile swelling, penis disorder, testicular atrophy
• General disorders and administration site conditions: mucosal dryness
• Investigations: PSA increased, bone density decreased
• Long exposure (6 to 12 months): diabetes mellitus, impaired glucose tolerance, total cholesterol increased, LDL increased, triglycerides increased, osteoporosis

Women:

• Metabolism and nutrition disorders: weight gain, weight loss
• Psychiatric disorders: loss or decreased libido, increased libido, affective lability
• Nervous system disorders: headache
• Vascular disorders: hot flushes, vasodilatation, hypotension
• Skin and subcutaneous tissue disorders: acne, seborrhea, dry skin, urticaria, abnormal skin odor, hyperhidrosis, abnormal hair growth, hirsutism, hair disorder, eczema, nail disorder, night sweats
• Reproductive system and breast disorders: vaginal hemorrhage, dysmenorrhea, menstrual disorder, breast enlargement, breast engorgement, breast atrophy, genital discharge, vaginal discharge, galactorrhea, breast pain, metrorrhagia, menopausal symptoms, dyspareunia, uterine disorder, vaginitis, menorrhagia
• General disorders and administration site conditions: feeling hot, irritability
• Investigations: bone density decreased
• Long exposure (6 to 12 months): diabetes mellitus, impaired glucose tolerance, total cholesterol increased, LDL increased, triglycerides increased, osteoporosis

It is not known whether leuprorelin acetate is excreted in human milk. Therefore, it should not be used by nursing mothers.

All Populations: As the effect of Leuprorelin Acetate for Depot Suspension – 3 Month 11.25 mg is present throughout the course of therapy, the drug should only be used in patients who require hormonal suspension for at least three months.

During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed. Worsening of pre-existing signs and symptoms during the first weeks of treatment may occur. Worsening of symptoms may contribute to paralysis with or without fatal complications.

Bone Mineral Density: Bone mineral density changes can occur during any hypoestrogenic state in women and in long-term use in prostate cancer in men. There are no data in men regarding reversibility after withdrawal of leuprorelin acetate. In women, bone mineral density loss may be reversible after withdrawal of leuprorelin acetate.

Convulsions: Postmarketing reports of convulsions have been observed in patients on leuprorelin acetate therapy. These included patients in the female and pediatric populations, patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above.

Special Populations: The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined.

Drugs acting on the Uterus, Drugs affecting (inhibiting) gonadotrophin

The shelf life for this product is 36 months unopened. Do not store above 25°C. Once reconstituted with the sterile diluent, the suspension should be administered immediately. Protect from freezing.