LEUPROLIDE ACETATE 1 mg/.2mL Injection, 1 kit — NDC 42023-259-00 (Billing 42023-0259-00)

WARNINGS Initially, leuprolide acetate, 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 leuprolide acetate 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. Leuprolide acetate may cause fetal harm.

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.

ADVERSE REACTIONS Clinical Trials 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. This transient increase was occasionally associated with a temporary worsening of signs and symptoms, usually manifested by an increase in bone pain (see WARNINGS section). In a few cases a temporary worsening of existing hematuria and urinary tract obstruction occurred during the first week.

Temporary weakness and paresthesia of the lower limbs have been reported in a few cases. Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction which, if aggravated, may lead to neurological problems or increase the obstruction. In a comparative trial of leuprolide acetate injection versus DES, in 5% or more of the patients receiving either drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician.

Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug related are excluded. Leuprolide Acetate (N=98) DES (N=101) Number of Reports Cardiovascular System Congestive heart failure 1 5 ECG changes/ischemia 19 22 High blood pressure 8 5 Murmur 3 8 Peripheral edema 12 30 Phlebitis/thrombosis 2 10 Gastrointestinal System Anorexia 6 5 Constipation 7 9 Nausea/vomiting 5 17 Endocrine System *Decreased testicular size 7 11 *Gynecomastia/breast tenderness or pain 7 63 *Hot flashes 55 12 *Impotence 4 12 Hemic and Lymphatic System Anemia 5 5 Musculoskeletal System Bone pain 5 2 Myalgia 3 9 Central/Peripheral Nervous System Dizziness/lightheadedness 5 7 General pain 13 13 Headache 7 4 Insomnia/sleep disorders 7 5 Respiratory System Dyspnea 2 8 Sinus congestion 5 6 Integumentary System Dermatitis 5 8 Urogenital System Frequency/urgency 6 8 Hematuria 6 4 Urinary tract infection 3 7 Miscellaneous Asthenia 10 10 * Physiologic effect of decreased testosterone.

In this same study, the following adverse reactions were reported in less than 5% of the patients on leuprolide acetate. Cardiovascular System —Angina, Cardiac arrhythmias, Myocardial infarction, Pulmonary emboli; Gastrointestinal System —Diarrhea, Dysphagia, Gastrointestinal bleeding, Gastrointestinal disturbance, Peptic ulcer, Rectal polyps; Endocrine System —Libido decrease, Thyroid enlargement; Musculoskeletal System —Joint pain; Central/Peripheral Nervous System —Anxiety, Blurred vision, Lethargy, Memory disorder, Mood swings, Nervousness, Numbness, Paresthesia, Peripheral neuropathy, Syncope/blackouts, Taste disorders; Respiratory System —Cough, Pleural rub, Pneumonia, Pulmonary fibrosis; Integumentary System — Carcinoma of skin/ear, Dry skin, Ecchymosis, Hair loss, Itching, Local skin reactions, Pigmentation, Skin lesions; Urogenital System —Bladder spasms, Dysuria, Incontinence, Testicular pain, Urinary obstruction; Miscellaneous —Depression, Diabetes, Fatigue, Fever/chills, Hypoglycemia, Increased BUN, Increased calcium, Increased creatinine, Infection/inflammation, Ophthalmologic disorders, Swelling (temporal bone).

In an additional clinical trial and from long-term observation of both studies, the following additional adverse events (excluding those considered not drug related) were reported for patients receiving leuprolide acetate. Cardiovascular System —Bradycardia, Carotid bruit, Extrasystole, Palpitations, Perivascular cuffing (eyes), Ruptured aortic aneurysm, Stroke, Tachycardia, Transient ischemic attack; Gastrointestinal System —Flatus, Dryness of mouth and throat, Hepatitis, Hepatomegaly, Occult blood (rectal exam), Rectal fistula/erythema; Endocrine System —Libido increase, Thyroid nodule; Musculoskeletal System —Ankylosing spondylosis, Arthritis, Blurred disc margins, Bone fracture, Muscle stiffness, Muscle tendernes… [Excerpted — this section continues on DailyMed.]

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.

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. 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. Based on findings in animal studies, leuprolide acetate 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. 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.

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 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 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 ye… [Excerpted — this section continues on DailyMed.]