Safe use of leuprolide acetate or norethindrone acetate in pregnancy has not been established clinically. Before starting treatment with LUPRON DEPOT, pregnancy must be excluded.
When used monthly at the recommended dose, LUPRON DEPOT usually inhibits ovulation and stops menstruation. Contraception is not insured, however, by taking LUPRON DEPOT. 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.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported post-marketing.
The following applies to co-treatment with LUPRON 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 If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn.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 LUPRON DEPOT, the patient should notify her physician if regular menstruation persists. Patients missing successive doses of LUPRON DEPOT may experience breakthrough bleeding.
- Patients should not use LUPRON DEPOT if they are pregnant, breast feeding, have undiagnosed abnormal vaginal bleeding, or are allergic to any of the ingredients in LUPRON DEPOT.
- 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 LUPRON DEPOT, 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 LUPRON DEPOT that are associated with hypoestrogenism include: hot flashes, headaches, emotional lability, decreased libido, acne, myalgia, reduction in breast size, and vaginal dryness. Estrogen levels returned to normal after treatment was discontinued.
- Patients should be counseled 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. For a period up to six months, this bone loss should not be clinically significant. Clinical studies show that concurrent hormonal therapy with norethindrone acetate 5 mg daily is effective in reducing loss of bone mineral density that occurs with LUPRON. (All patients received calcium supplementation with 1000 mg elemental calcium.) (See Changes in Bone Density section).
- If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of LUPRON DEPOT 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 LUPRON DEPOT 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, LUPRON DEPOT therapy may pose an additional risk. In these patients, the risks and benefits must be weighed carefully before therapy with LUPRON DEPOT alone is instituted, and concomitant treatment with norethindrone acetate 5 mg daily should be considered. Retreatment with gonadotropin-releasing hormone analogs, including LUPRON is not advisable in patients with major risk factors for loss of bone mineral content.
- Because 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.
See ADVERSE REACTIONS section.
See CLINICAL PHARMACOLOGY, Pharmacokinetics.
Drug/Laboratory Test Interactions
Administration of LUPRON DEPOT 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 LUPRON 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 leuprolide 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 leuprolide 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 leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential.
Clinical and pharmacologic studies in adults (>18 years) with leuprolide 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 leuprolide acetate and other GnRH analogs have shown functional recovery.
Pregnancy Category X (see CONTRAINDICATIONS section).
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, LUPRON DEPOT 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 LUPRON DEPOT in rabbits and with the highest dose (0.024 mg/kg) in rats.
It is not known whether LUPRON DEPOT is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of LUPRON DEPOT on lactation and/or the breast-fed child have not been determined, LUPRON DEPOT should not be used by nursing mothers.
Experience with LUPRON DEPOT 3.75 mg for treatment of endometriosis has been limited to women 18 years of age and older. See LUPRON DEPOT-PED® (leuprolide acetate for depot suspension) labeling for the safety and effectiveness in children with central precocious puberty.
This product has not been studied in women over 65 years of age and is not indicated in this population.