Included as part of the "PRECAUTIONS" Section
Initially, LUTRATE DEPOT, like other GnRH agonists, causes increases in serum levels of testosterone to approximately 50% above
baseline during the first weeks of treatment. Isolated cases of ureteral obstruction and spinal cord compression have been observed,
which may contribute to paralysis with or without fatal complications. Transient worsening of symptoms may develop. A small number
of patients may experience a temporary increase in bone pain, which can be managed symptomatically.
Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of
Hyperglycemia And Diabetes
Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may
represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or
glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of
hyperglycemia or diabetes.
Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH
agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular
risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for
symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.
Effect On QT/QTc Interval
Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation
therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte
abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider
periodic monitoring of electrocardiograms and electrolytes.
Postmarketing reports of convulsions have been observed in patients on leuprolide acetate therapy. These included patients with a history
of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and in 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. Patients receiving a GnRH agonist who experience convulsion should be managed according
to current clinical practice.
Monitor serum levels of testosterone following injection of LUTRATE DEPOT 22.5 mg for 3-month administration. In the majority of
patients, testosterone levels increased above baseline during the first week, and then declined thereafter to castrate levels (< 50 ng/dL)
within four weeks. [see Clinical Studies and ADVERSE REACTIONS].
Based on findings in animal studies, LUTRATE DEPOT may cause fetal harm when administered to a pregnant woman. In animal
developmental and reproductive toxicology studies, administration of the monthly formulation of leuprolide acetate on day 6 of
pregnancy (sustained exposure was expected throughout the period of organogenesis) caused adverse embryo-fetal toxicity in animals
at doses less than the human dose, based on body surface area, using an estimated daily dose. Advise pregnant patients and females of
reproductive potential of the potential risk to the fetus [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two-year carcinogenicity studies were conducted with leuprolide acetate 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. No carcinogenicity studies have been conducted with LUTRATE DEPOT.
Genotoxicity studies were conducted with leuprolide acetate using bacterial and mammalian systems. These studies provided no
evidence of mutagenic effects or chromosomal aberrations.
Leuprolide may reduce male and female fertility. Administration of leuprolide acetate to male and female rats at dose of 0.024, 0.24,
and 2.4 mg/kg as monthly depot formulation for up to 3 months (approximately as low as 1/30 of the human dose based on body surface
area using an estimated daily dose in animals and humans) caused atrophy of the reproductive organs, and suppression of reproductive
function. These changes were reversible upon cessation of treatment.
Use In Specific Populations
Based on findings in animal studies and mechanism of action, LUTRATE DEPOT may cause fetal harm when administered to a pregnant
woman [see CLINICAL PHARMACOLOGY]. There are no available data in pregnant women to inform the drug-associated risk. In animal
developmental and reproductive toxicology studies, administration of a monthly formulation of leuprolide acetate on day 6 of pregnancy
(sustained exposure was expected throughout the period of organogenesis) caused adverse embryo-fetal toxicity in animals at doses less
than the human dose based on body surface area using an estimated daily dose (see Data). Advise pregnant patients and females of
reproductive potential of the potential risk to the fetus.
Major fetal malformations were observed in developmental and reproductive toxicology studies in rabbits after a single administration
of the monthly formulation of leuprolide acetate on day 6 of pregnancy at doses of 0.00024, 0.0024, and 0.024 mg/kg (approximately
1/1600 to 1/16 the human dose based on body surface area using an estimated daily dose in animals and humans). Since a depot
formulation was utilized in the study, a sustained exposure to leuprolide was expected throughout the period of organogenesis and to
the end of gestation. Similar studies in rats did not demonstrate an increase in fetal malformations, however, there was increased fetal
mortality and decreased fetal weights with the two higher doses of the monthly formulation of leuprolide acetate in rabbits and with the
highest dose (0.024 mg/kg) in rats.
The safety and efficacy of LUTRATE DEPOT have not been established in females. There is no information regarding the presence of
LUTRATE DEPOTin human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted
in human milk and because of the potential for serious adverse reactions in a breastfed child from LUTRATE DEPOT, a decision should
be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.
Females And Males Of Reproductive Potential
Based on findings in animals and mechanism of action, LUTRATE DEPOT may impair fertility in males of reproductive potential
[see Nonclinical Toxicology].
The safety and effectiveness of LUTRATE DEPOT in pediatric patients have not been established.
In the clinical trials for LUTRATE DEPOT in prostate cancer 74% of the patients studied were at least 65 years of age. Hot flushes
occurred with equal frequency in those less than or at least 65 years of age.