Endmet Special Precautions

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.