Lupron (Leuprolide Acetate) - Warnings and Precautions

WARNINGS

Initially, LUPRON, like other LH-RH agonists, causes increases in serum levels of testosterone. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate cancer, may occasionally develop during the first few weeks of LUPRON treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other LH-RH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications.

Safe use of leuprolide acetate in pregnancy has not been established clinically. Before starting treatment with LUPRON, pregnancy must be excluded (see CONTRAINDICATIONS section).

Periodic monitoring of serum testosterone and prostate-specific antigen (PSA) levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.

PRECAUTIONS

Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy (see WARNINGS and ADVERSE REACTIONS sections).

Patients with known allergies to benzyl alcohol, an ingredient of the drug's vehicle, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site.

Information for Patients

See INFORMATION FOR PATIENTS which appears after the REFERENCE section.

Laboratory Tests

Response to leuprolide acetate should be monitored by measuring serum levels of testosterone and prostate-specific antigen (PSA). In the majority of patients, testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. Castrate levels were reached within two to four weeks and once attained were maintained for as long as drug administration continued.

Drug Interactions

See CLINICAL PHARMACOLOGY, Pharmacokinetics section.

Drug/Laboratory Test Interactions

Administration of leuprolide acetate in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within 4 to 12 weeks after treatment is discontinued.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were 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 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 full reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks. However, no clinical studies have been conducted with leuprolide acetate to assess the reversibility of fertility suppression.

Pregnancy

Teratogenic Effects

Pregnancy Category X

(see CONTRAINDICATIONS and WARNINGS sections)

When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/600 to 1/6 the human dose) to rabbits, LUPRON produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in major fetal malformations throughout gestation. There was increased fetal mortality and decreased fetal weights with the two higher doses of LUPRON in rabbits and with the highest dose in rats. The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug.

Nursing Mothers

It is not known whether leuprolide acetate is excreted in human milk. LUPRON should not be used by nursing mothers.

Pediatric Use

See labeling for LUPRON INJECTION for Pediatric Use for the safety and effectiveness in children with central precocious puberty.

Geriatric Use

In the clinical trials for LUPRON INJECTION, the majority (69%) of subjects studied were at least 65 years of age. Therefore, the labeling reflects the pharmacokinetics, efficacy and safety of LUPRON in this population.

WARNINGS

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 (see CLINICAL PHARMACOLOGY section).

Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the pubertal process. The consequences of poor control include the return of pubertal signs such as menses, breast development, and testicular growth. The long-term consequences of inadequate control of gonadal steroid secretion are unknown, but may include a further compromise of adult stature.

PRECAUTIONS

Patients with known allergies to benzyl alcohol, an ingredient of the vehicle of LUPRON INJECTION, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site.

Information for Parents

Prior to starting therapy with LUPRON INJECTION, the parent or guardian must be aware of the importance of continuous therapy. Adherence to daily drug administration schedules must be accepted if therapy is to be successful. Irregular dosing could restart the maturation process.

• During the first 2 months of therapy, a female may experience menses or spotting. If bleeding continues beyond the second month, notify the physician.
• Any irritation at the injection site should be reported to the physician immediately. If the child has experienced an allergic reaction to other drugs like LUPRON, this drug should not be used.
• Report any unusual signs or symptoms to the physician, like continued pubertal changes, substantial mood swings or behavioral changes.