osterone 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.

ctions 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 physiologic effect of decreased testosterone. 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 in this same study, the following adverse reactions were reported in less than 5% of the patients on leuprolide acetate injection. 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 injection. 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 tenderness, pelvic fibrosis, spasms/cramps; central/peripheral nervous system - auditory hallucinations/tinnitus, decreased hearing, decreased reflexes, euphoria, hyperreflexia, loss of smell, motor deficiency; respiratory system - chest tightness, decreased breathing sounds, hemoptysis, pleuritic chest pain, pulmonary infiltrate, rales/rhonchi, rhinitis, strep throat, wheezing/bronchitis; integumentary system - boil (pubic), bruises, hives, keratosis, mole, shingles, spiders; urogenital system - blisters on penis, inguinal hernia, penile swelling, post void residual, prostatic pain, pyuria; miscellaneous - abdominal distention, facial swelling/edema, feet burning, flu, eyelid growth, hypoproteinemia, accidental injury, knee effusion, mass, pallid, sallow, weakness. postmarketing during postmarketing surveillance which includes other dosage forms and other patient populations, the following adverse events were reported. symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. rash, urticaria, and photosensitivity reactions have also been reported. localized reactions including induration and abscess have been reported at the site of injection. symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively. cardiovascular system - hypotension, myocardial infarction, pulmonary embolism; endocrine system – diabetes; gastrointestinal system - hepatic dysfunction; hepato-biliary disorder – serious drug-induced liver injury; hemic and lymphatic system - decreased wbc; integumentary system - hair growth; central/peripheral nervous system - convulsion, peripheral neuropathy, spinal fracture/paralysis, hearing disorder; miscellaneous - hard nodule in throat, weight gain, increased uric acid; musculoskeletal system - tenosynovitis-like symptoms; respiratory system - respiratory disorders, interstitial lung disease; urogenital system – prostate pain. changes in bone density: decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an lh-rh agonist analog. in a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. the leuprolide-treated group had lower bone density scores than the nontreated control group. it can be anticipated that long periods of medical castration in men will have effects on bone density. pituitary apoplexy: during postmarketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. in a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. in these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. immediate medical attention has been required. see other lupron depot* and leuprolide acetate injection package inserts for other events reported in the same and different patient populations.

mg/kg, and 0.024 mg/kg (approximately 1/600 to 1/6 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 in rats.

ily administration of leuprolide acetate results in decreased levels of lh and fsh. in males, testosterone is reduced to castrate levels. in pre-menopausal females, estrogens are reduced to post-menopausal levels. these decreases occur within two to four weeks after initiation of treatment, and castrate levels of testosterone in prostatic cancer patients have been demonstrated for periods of up to five years. leuprolide acetate is not active when given orally. pharmacokinetics absorption bioavailability by subcutaneous administration is comparable to that by intravenous administration. distribution the mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 l. in vitro binding to human plasma proteins ranged from 43% to 49%. metabolism in healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 l/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. in rats and dogs, administration of 14 c-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (metabolite i), tripeptides (metabolites ii and iii) and a dipeptide (metabolite iv). these fragments may be further catabolized. the major metabolite (m-i) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. one week after dosing, mean plasma m-i concentrations were approximately 20% of mean leuprolide concentrations. excretion following administration of lupron depot* 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and m-i metabolite in the urine. special populations the pharmacokinetics of the drug in hepatically and renally impaired patients has not been determined. drug interactions no pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide acetate. however, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by cytochrome p-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur.

. leuprolide may reduce male and female fertility. administration of leuprolide acetate to male and female rats at dose of 0.024 mg/kg, 0.24 mg/kg, 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.