use of gnrh analogs in men. monitor for cardiovascular disease and manage according to current clinical practice. ( 5.3 ) effect on qt/qtc interval: androgen deprivation therapy may prolong the qt interval. consider risks and benefits. ( 5.4 ) convulsions have been observed in patients with or without a history of predisposing factors. manage convulsions according to the current clinical practice. ( 5.5 ) embryo-fetal toxicity: lupron depot may cause fetal harm. ( 5.7 , 8.1 ) 5.1 tumor flare initially, lupron 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 therapy. 5.2 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. 5.3 cardiovascular diseases 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. 5.4 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. 5.5 convulsions 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. 5.6 laboratory tests monitor serum levels of testosterone following injection of lupron depot 7.5 mg for 1-month administration, 22.5 mg for 3-month administration, 30 mg for 4-month administration, or 45 mg for 6-month administration. in the majority of patients, testosterone levels increased above baseline, and then declined thereafter to castrate levels (< 50 ng/dl) within four weeks. [see clinical studies ( 14 ) and adverse reactions ( 6 ) ] . 5.7 embryo-fetal toxicity based on findings in animal studies, lupron 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 ( 8.1 )].

injection every 12 weeks. ( 2.2 ) lupron depot 30 mg for 4-month administration, given as a single intramuscular injection every 16 weeks. ( 2.3 ) lupron depot 45 mg for 6-month administration, given as a single intramuscular injection every 24 weeks. ( 2.4 ) figure 1 figure 2 figure 3 figure 4 figure 5 figure 6 figure 7 2.1 lupron depot 7.5 mg for 1-month administration the recommended dose of lupron depot 7.5 mg for 1-month administration is one injection every 4 weeks. do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 4 weeks as a single intramuscular injection. for optimal performance of the prefilled dual chamber syringe (pds), read and follow the instructions in section 2.5 . 2.2 lupron depot 22.5 mg for 3-month administration the recommended dose of lupron depot 22.5 mg for 3-month administration is one injection every 12 weeks. do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 12 weeks as a single intramuscular injection. for optimal performance of the prefilled dual chamber syringe (pds), read and follow the instructions in section 2.5 . 2.3 lupron depot 30 mg for 4-month administration the recommended dose of lupron depot 30 mg for 4-month administration is one injection every 16 weeks. do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 16 weeks as a single intramuscular injection. for optimal performance of the prefilled dual chamber syringe (pds), read and follow the instructions in section 2.5 . 2.4 lupron depot 45 mg for 6-month administration the recommended dose of lupron depot 45 mg for 6-month administration is one injection every 24 weeks. do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 24 weeks as a single intramuscular injection. for optimal performance of the prefilled dual chamber syringe (pds), read and follow the instructions in section 2.5 . 2.5 reconstitution and administration for injection of lupron depot reconstitute and administer the lyophilized microspheres as a single intramuscular injection. inject the suspension immediately or discard if not used within two hours, because lupron depot does not contain a preservative. 1. visually inspect the lupron depot powder. do not use the syringe if clumping or caking is evident. a thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. the diluent should appear clear and colorless. 2. to prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn (see figure 1 and figure 2). figure 1 figure 2 3. hold the syringe upright. release the diluent by slowly pushing (6 to 8 seconds) the plunger until the first middle stopper is at the blue line in the middle of the barrel (see figure 3). figure 3 4. keep the syringe upright. mix the microspheres (powder) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. the suspension will appear milky. if the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. do not use if any of the powder has not gone into suspension (see figure 4). figure 4 5. keep the syringe upright. with the opposite hand pull the needle cap upward without twisting. 6. keep the syringe upright. advance the plunger to expel the air from the syringe. now the syringe is ready for injection. 7. after cleaning the injection site with an alcohol swab, administer the intramuscular injection by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid; injection sites should be alternated (see figure 5). figure 5 note: if a blood vessel is accidentally penetrated, aspirated blood will be visible just below the luer lock (see figure 6) and can be seen through the transparent luproloc ® safety device. if blood is present, remove the needle immediately. do not inject the medication. figure 6 8. inject the entire contents of the syringe intramuscularly. 9. withdraw the needle. once the syringe has been withdrawn, immediately activate the luproloc® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a click is heard or felt (see figure 7). figure 7 10. dispose of the syringe according to local regulations/procedures.

weats, gi disorders, joint disorders, testicular atrophy, urinary disorders. ( 6.2 ) lupron depot 30 mg for 4-month administration: the most common adverse reactions (>10%) were asthenia, flu syndrome, general pain, headache, injection site reaction, hot flashes/sweats, gi disorders, edema, skin reaction, urinary disorders. ( 6.3 ) lupron depot 45 mg for 6-month administration: the most common adverse reactions (>10%) were hot flush, injection site pain, upper respiratory infection, and fatigue. ( 6.4 ) in postmarketing experience, mood swings, depression, rare reports of suicidal ideation and attempt, rare reports of pituitary apoplexy, and rare reports of serious drug-induced liver injury have been reported. ( 6.5 ) to report suspected adverse reactions, contact abbvie inc. at 1-800-633-9110 or fda at 1-800-fda-1088 or www.fda.gov/medwatch 6.1 lupron depot 7.5 mg for 1-month administration 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. 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 or hematuria which, if aggravated, may lead to neurological problems such as temporary weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms [see warnings and precautions ( 5.1 ) ] . in a clinical trial of lupron depot 7.5 mg for 1-month administration, the following adverse reactions were reported in 5% or more of the patients during the initial 24-week treatment period. table 2. adverse reactions reported in ≥ 5% of patients lupron depot 7.5 mg for 1-month administration (n=56) n (%) body as a whole general pain 13 (23.2) infection 3 (5.4) cardiovascular system hot flashes/sweats* 32 (57.1) digestive system gi disorders 8 (14.3) metabolic and nutritional disorders edema 8 (14.3) nervous system libido decreased* 3 (5.4) respiratory system respiratory disorder 6 (10.7) urogenital system urinary disorder 7 (12.5) impotence* 3 (5.4) testicular atrophy* 3 (5.4) * due to the expected physiologic effect of decreased testosterone levels. in this same study, the following adverse reactions were reported in less than 5% of the patients on lupron depot 7.5 mg for 1-month administration. body as a whole - asthenia, cellulitis, fever, headache, injection site reaction, neoplasm cardiovascular system - angina, congestive heart failure digestive system - anorexia, dysphagia, eructation, peptic ulcer hemic and lymphatic system - ecchymosis musculoskeletal system - myalgia nervous system - agitation, insomnia/sleep disorders, neuromuscular disorders respiratory system - emphysema, hemoptysis, lung edema, sputum increased skin and appendages - hair disorder, skin reaction urogenital system - balanitis, breast enlargement, urinary tract infection laboratory abnormalities abnormalities of certain parameters were observed, but their relationship to drug treatment are difficult to assess in this population. the following were recorded in ≥5% of patients at final visit: decreased albumin, decreased hemoglobin/hematocrit, decreased prostatic acid phosphatase, decreased total protein, decreased urine specific gravity, hyperglycemia, hyperuricemia, increased bun, increased creatinine, increased liver function tests (ast, ldh), increased phosphorus, increased platelets, increased prostatic acid phosphatase, increased total cholesterol, increased urine specific gravity, leukopenia. 6.2 lupron depot 22.5 mg for 3-month administration in two clinical trials of lupron depot 22.5 mg for 3-month administration, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician in 5% or more of the patients receiving the drug. often, causality is difficult to assess in patients with metastatic prostate cancer. reactions considered not drug-related are excluded. table 3. adverse reactions reported in ≥ 5% of patients lupron depot 22.5 mg for 3-month administration body system/reaction n=94 (%) body as a whole asthenia 7 (7.4) general pain 25 (26.6) headache 6 (6.4) injection site reaction 13 (13.8) cardiovascular system hot flashes/sweats 55 (58.5) digestive system gi disorders 15 (16.0) musculoskeletal system joint disorders 11 (11.7) central/peripheral nervous system dizziness/vertigo 6 (6.4) insomnia/sleep disorders 8 (8.5) neuromuscular disorders 9 (9.6) respiratory system respiratory disorders 6 (6.4) skin and appendages skin reaction 8 (8.5) urogenital system testicular atrophy 19 (20.2) urinary disorders 14 (14.9) in these same studies, the following adverse reactions were reported in less than 5% of the patients on lupron depot 22.5 mg for 3-month administration. body as a whole - enlarged abdomen, fever cardiovascular system - arrhythmia, bradycardia, heart failure, hypertension, hypotension, varicose vein digestive system - anorexia, duodenal ulcer, increased appetite, thirst/dry mouth hemic and lymphatic system - anemia, lymphedema metabolic and nutritional disorders - dehydration, edema central/peripheral nervous system - anxiety, delusions, depression, hypesthesia, libido decreased*, nervousness, paresthesia respiratory system - epistaxis, pharyngitis, pleural effusion, pneumonia special senses - abnormal vision, amblyopia, dry eyes, tinnitus urogenital system - gynecomastia, impotence*, penis disorders, testis disorders. * physiologic effect of decreased testosterone. laboratory abnormalities abnormalities of certain parameters were observed, but are difficult to assess in this population. the following were recorded in ≥5% of patients: increased bun, hyperglycemia, hyperlipidemia (total cholesterol, ldl-cholesterol, triglycerides), hyperphosphatemia, abnormal liver function tests, increased pt, increased ptt. additional laboratory abnormalities reported were: decreased platelets, decreased potassium and increased wbc. 6.3 lupron depot 30 mg for 4-month administration the 4-month formulation of lupron depot 30 mg was utilized in clinical trials that studied the drug in 49 nonorchiectomized prostate cancer patients for 32 weeks or longer and in 24 orchiectomized prostate cancer patients for 20 weeks. in the above described clinical trials, the following adverse reactions were reported in ≥ 5% of the patients during the treatment period. table 4. adverse reactions reported in ≥ 5% of patients lupron depot 30 mg for 4-month administration body system/events nonorchiectomized orchiectomized study 013 study 012 n=49 (%) n=24 (%) body as a whole asthenia 6 (12.2) 1 (4.2) flu syndrome 6 (12.2) 0 (0.0) general pain 16 (32.7) 1 (4.2) headache 5 (10.2) 1 (4.2) injection site reaction 4 (8.2) 9 (37.5) cardiovascular system hot flashes/sweats 23 (46.9) 2 (8.3) digestive system gi disorders 5 (10.2) 3 (12.5) metabolic and nutritional disorders dehydration 4 (8.2) 0 (0.0) edema 4 (8.2) 5 (20.8) musculoskeletal system joint disorder 8 (16.3) 1 (4.2) myalgia 4 (8.2) 0 (0.0) nervous system dizziness/vertigo 3 (6.1) 2 (8.3) neuromuscular disorders 3 (6.1) 1 (4.2) paresthesia 4 (8.2) 1 (4.2) respiratory system respiratory disorder 4 (8.2) 1 (4.2) skin and appendages skin reaction 6 (12.2) 0 (0.0) urogenital system urinary disorders 5 (10.2) 4 (16.7) in these same studies, the following adverse reactions were reported in less than 5% of the patients on lupron depot 30 mg for 4-month administration. body as a whole - abscess, accidental injury, allergic reaction, cyst, fever, generalized edema, hernia, neck pain, neoplasm cardiovascular system - atrial fibrillation, deep thrombophlebitis, hypertension digestive system - anorexia, eructation, gastrointestinal hemorrhage, gingivitis, gum hemorrhage, hepatomegaly, increased appetite, intestinal obstruction, periodontal abscess hemic and lymphatic system - lymphadenopathy metabolic and nutritional disorders - healing abnormal, hypoxia, weight loss musculoskeletal system - leg cramps, pathological fracture, ptosis nervous system - abnormal thinking, amnesia, confusion, convulsion, dementia, depression, insomnia/sleep disorders, libido decreased*, neuropathy, paralysis respiratory system - asthma, bronchitis, hiccup, lung disorder, sinusitis, voice alteration skin and appendages - herpes zoster, melanosis urogenital system - bladder carcinoma, epididymitis, impotence*, prostate disorder, testicular atrophy*, urinary incontinence, urinary tract infection. * physiologic effect of decreased testosterone. laboratory abnormalities abnormalities of certain parameters were observed, but their relationship to drug treatment is difficult to assess in this population. the following were recorded in ≥ 5% of patients: decreased bicarbonate, decreased hemoglobin/hematocrit/rbc, hyperlipidemia (total cholesterol, ldl-cholesterol, triglycerides), decreased hdl-cholesterol, eosinophilia, increased glucose, increased liver function tests (alt, ast, ggtp, ldh), increased phosphorus. additional laboratory abnormalities were reported: increased bun and pt, leukopenia, thrombocytopenia, uricaciduria. 6.4 lupron depot 45 mg for 6-month administration one open label, multicenter study was conducted with lupron depot 45 mg for 6-month administration in 151 prostate cancer patients. patients were treated for 48 weeks, with 139/151 receiving two injections 24 weeks apart. in the above described clinical trial, the following adverse events were reported in ≥ 5% of the patients during the treatment period. the table 5 includes all adverse events reported in ≥ 5% of patients as well as the incidences of these adverse events that were considered, by the treating physician, to have a definite or possible relationship to lupron. table 5. adverse events in ≥ 5% of patients lupron depot 45 mg for 6-month administration treatment emergent treatment related adverse event n = 151 (%) n = 151 (%) hot flush/flushing 89 58.9 88 58.3 injection site pain/discomfort 29 19.2 16 10.6 upper respiratory tract infection/influenza-like illness 1 32 21.2 0 0 fatigue/lethargy 20 13.2 18 11.9 constipation 15 9.9 5 3.3 arthralgia 14 9.3 2 1.3 insomnia/sleep disorder 13 8.6 5 3.3 headache/sinus headache 12 7.9 3 2.0 musculoskeletal pain/ myalgia 12 7.9 3 2.0 second primary neoplasm 2 11 7.3 0 0 cough 10 6.6 2 1.3 hematuria/hemorrhagic cystitis 10 6.6 0 0 hypertension/bp increased 10 6.6 3 2.0 rash 9 6.0 3 2.0 dysuria 9 6.0 1 0.7 urinary tract infection/cystitis 9 6.0 0 0 anemia/hemoglobin decreased 10 6.6 2 1.3 back pain 8 5.3 0 0 copd 8 5.3 0 0 dizziness 8 5.3 3 2.0 dyspnea/dyspnea on exertion 8 5.3 2 1.3 nocturia 8 5.3 2 1.3 peripheral/pitting edema 8 5.3 2 1.3 coronary artery disease/angina 8 5.3 1 0.7 1 includes influenza, nasal congestion, nasopharyngitis, rhinorrhea, upper respiratory tract infection, and viral upper respiratory tract infection 2 includes basal cell carcinoma, bladder transitional cell carcinoma, lung neoplasm, malignant melanoma, non-hodgkin’s lymphoma, and squamous cell carcinoma the following adverse events led to discontinuation; fatigue, hot flush, second primary neoplasm, asthenia, coronary artery disease, constipation, hyperkalemia, and sleep disorder. serious adverse events in ≥ 2% of patients, regardless of causality, included chronic obstructive pulmonary disease, coronary artery disease/angina, cerebrovascular accident/transient ischemic attack, pneumonia, and second primary neoplasms. laboratory abnormalities at baseline, 13.9% of patients had a ctcae v4.0 grade 1 or 2 decreased hemoglobin. during the study, 42.4% of subjects had grade 1 decreased hemoglobin (10 - <12-5 g/dl), 2.0% had grade 2 (8 - <10 g/dl) and 1.3% of subjects had grade 3 or 4 (<8 g/dl). likewise, 28.5% of patients had a grade 1 or 2 increased cholesterol at baseline while 55.0% had grade 1 increased cholesterol (>199- 300 mg/dl), 3.3% had a grade 2 increase (>300-400 mg/dl), and 0.7% of subjects had grade 3 (>400 mg/dl) during the study. 6.5 postmarketing the following adverse reactions have been identified during post-approval use of lupron depot. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. during postmarketing surveillance, which includes other dosage forms and other patient populations, the following adverse reactions were reported. like other drugs in this class, mood swings, including depression, have been reported. there have been very rare reports of suicidal ideation and attempt. many, but not all, of these patients had a history of depression or other psychiatric illness. patients should be counseled on the possibility of development or worsening of depression during treatment with lupron. 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. 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 a gnrh 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 post-marketing 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. 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 respiratory, thoracic and mediastinal disorder - interstitial lung disease hepato-biliary disorder - serious drug-induced liver injury hemic and lymphatic system - decreased wbc central/peripheral nervous system - convulsion, peripheral neuropathy, spinal fracture/paralysis endocrine system - diabetes musculoskeletal system - tenosynovitis-like symptoms urogenital system - prostate pain see other lupron depot and lupron injection package inserts for other reactions reported in women and pediatric populations.

roughout 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. data animal data 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. 8.2 lactation the safety and efficacy of lupron depot have not been established in females. there is no information regarding the presence of lupron depot in 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 lupron depot, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. 8.3 females and males of reproductive potential infertility males based on findings in animals and mechanism of action, lupron depot may impair fertility in males of reproductive potential [see nonclinical toxicology ( 13.1 )] . 8.4 pediatric use see lupron depot-ped ® (leuprolide acetate for depot suspension) labeling for the safety and effectiveness in children with central precocious puberty. 8.5 geriatric use in the clinical trials for lupron depot in prostate cancer 80% of the subjects studied were at least 65 years of age. therefore, the labeling reflects the efficacy and safety of lupron depot in this population.

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.

males). however, continuous administration of leuprolide acetate results in decreased concentrations of lh and fsh. in males, testosterone is reduced to castrate concentrations. in premenopausal females, estrogens are reduced to postmenopausal concentrations. these decreases occur within two to four weeks after initiation of treatment, and castrate concentrations of testosterone in prostatic cancer patients have been demonstrated for more than five years. leuprolide acetate is not active when given orally. 12.3 pharmacokinetics absorption lupron depot 7.5 mg for 1-month administration following a single injection of lupron depot 7.5 mg for 1-month administration to patients, mean plasma measured concentrations were 20 ng/ml at 4 hours and 0.36 ng/ml at 4 weeks. however, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. lupron depot 22.5 mg for 3-month administration following a single injection of lupron depot 22.5 mg for 3-month administration in patients, mean peak plasma concentrations were 48.9 ng/ml at 4 hours and then declined to 0.67 ng/ml at 12 weeks. leuprolide appeared to be released at a constant rate following the onset of steady-state concentrations during the third week after dosing, providing steady plasma concentrations through the 12-week dosing interval. however, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. the initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the monthly formulation. lupron depot 30 mg for 4-month administration following a single injection of lupron depot 30 mg for 4-month administration in sixteen orchiectomized prostate cancer patients, mean plasma concentrations were 59.3 ng/ml at 4 hours and then declined to 0.30 ng/ml at 16 weeks. mean plasma concentrations from weeks 3.5 to 16 was 0.44 ± 0.20 ng/ml (range: 0.20-1.06). leuprolide appeared to be released at a constant rate following the onset of steady-state concentrations during the fourth week after dosing, providing steady plasma concentrations throughout the 16-week dosing interval. however, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. the initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the other depot formulations. lupron depot 45 mg for 6-month administration following a single injection of lupron depot 45 mg for 6-month administration in 26 prostate cancer patients, mean peak plasma concentration of 6.7 ng/ml was observed at 2 hours and then declined to 0.07 ng/ml at 24 weeks. leuprolide appeared to be released continuously following the onset of steady-state concentrations during the third week after dosing providing steady plasma concentrations through the 24-week dosing interval. the initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the other depot formulations. in this study, mean plasma concentration-time profiles were similar after the first and second dose. 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%. elimination the mean systemic clearance of leuprolide following intravenous bolus administration to healthy male volunteers was 7.6 l/h, and terminal elimination half-life was approximately 3 hours based on a two compartment model. 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.

burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the monthly formulation. lupron depot 30 mg for 4-month administration following a single injection of lupron depot 30 mg for 4-month administration in sixteen orchiectomized prostate cancer patients, mean plasma concentrations were 59.3 ng/ml at 4 hours and then declined to 0.30 ng/ml at 16 weeks. mean plasma concentrations from weeks 3.5 to 16 was 0.44 ± 0.20 ng/ml (range: 0.20-1.06). leuprolide appeared to be released at a constant rate following the onset of steady-state concentrations during the fourth week after dosing, providing steady plasma concentrations throughout the 16-week dosing interval. however, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. the initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the other depot formulations. lupron depot 45 mg for 6-month administration following a single injection of lupron depot 45 mg for 6-month administration in 26 prostate cancer patients, mean peak plasma concentration of 6.7 ng/ml was observed at 2 hours and then declined to 0.07 ng/ml at 24 weeks. leuprolide appeared to be released continuously following the onset of steady-state concentrations during the third week after dosing providing steady plasma concentrations through the 24-week dosing interval. the initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the other depot formulations. in this study, mean plasma concentration-time profiles were similar after the first and second dose. 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%. elimination the mean systemic clearance of leuprolide following intravenous bolus administration to healthy male volunteers was 7.6 l/h, and terminal elimination half-life was approximately 3 hours based on a two compartment model. 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.

hese 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.

vidence 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.

testosterone increased by 50% or more above baseline during the first week of treatment. serum testosterone suppressed to the castrate range within 30 days of the initial depot injection in 94% (51/54) of patients for whom testosterone suppression was achieved (2 patients withdrew prior to onset of suppression) and within 66 days in all 54 patients. mean serum testosterone suppressed to castrate level by week 3. the median dosing interval between injections was 28 days. one escape from suppression (2 consecutive testosterone values greater than 50 ng/dl after achieving castrate level) was noted at week 18, associated with a substantial dosing delay. in this patient, serum testosterone returned to the castrate range at the next monthly measurement. serum testosterone was minimally above the castrate range on a single occasion for 4 other patients. no clinical significance was attributed to these rises in testosterone. figure 8. lupron depot 7.5 mg for 1-month administration mean serum testosterone concentrations secondary efficacy endpoints evaluated included objective tumor response, assessed by clinical evaluations of tumor burden (complete response, partial response, objectively stable, and progression), as well as changes in local disease status, assessed by digital rectal examination, and changes in prostatic acid phosphatase (pap). these evaluations were performed at weeks 12 and 24. the objective tumor response analysis showed a "no progression" (ie. complete or partial response, or stable disease) in 77% (40/52) of patients at week 12, and in 84% (42/50) of patients at week 24. local disease improved or remained stable in all (42) patients evaluated at week 12 and in 98% (41/42) of patients elevated at week 24. pap normalized or decreased at week 12 and/or 24 in the majority of patients with elevated baseline pap. periodic monitoring of serum testosterone and 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. 14.2 lupron depot 22.5 mg for 3-month administration in clinical studies, serum testosterone was suppressed to castrate within 30 days in 87 of 92 (95%) patients and within an additional two weeks in three patients. two patients did not suppress for 15 and 28 weeks, respectively. suppression was maintained in all of these patients with the exception of transient minimal testosterone elevations in one of them, and in another an increase in serum testosterone to above the castrate range was recorded during the 12 hour observation period after a subsequent injection. this represents stimulation of gonadotropin secretion. figure 9. lupron depot 22.5 mg for 3-month administration mean serum testosterone concentrations an 85% rate of "no progression" was achieved during the initial 24 weeks of treatment. a decrease from baseline in serum psa of ≥90% was reported in 71% of the patients and a change to within the normal range (≤3.99 ng/ml) in 63% of the patients. periodic monitoring of serum testosterone and 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. 14.3 lupron depot 30 mg for 4-month administration in an open-label, noncomparative, multicenter clinical study of lupron depot 30 mg for 4-month administration, 49 patients with stage d2 prostatic adenocarcinoma (with no prior treatment) were enrolled. the objectives were to determine whether a 30 mg depot formulation of leuprolide injected once every 16 weeks would reduce and maintain serum testosterone levels at castrate levels (≤ 50 ng/dl), and to assess the safety of the formulation. the study was divided into an initial 32-week treatment phase and a long-term treatment phase. serum testosterone levels were determined biweekly or weekly during the first 32 weeks of treatment. once the patient completed the initial 32-week treatment period, treatment continued at the investigator's discretion with serum testosterone levels being done every 4 months prior to the injection. in the majority of patients, testosterone levels increased 50% or more above the baseline during the first week of treatment. mean serum testosterone subsequently suppressed to castrate levels within 30 days of the first injection in 94% of patients and within 43 days in all 49 patients during the initial 32-week treatment period. the median dosing interval between injections was 112 days. one escape from suppression (two consecutive testosterone values greater than 50 ng/dl after castrate levels achieved) was noted at week 16. in this patient, serum testosterone increased to above the castrate range following the second depot injection (week 16) but returned to the castrate level by week 18. no adverse reactions were associated with this rise in serum testosterone. a second patient had a rise in testosterone at week 17, then returned to the castrate level by week 18 and remained there through week 32. in the long-term treatment phase two patients experienced testosterone elevations, both at week 48. testosterone for one patient returned to the castrate range at week 52, and one patient discontinued the study at week 48 due to disease progression. secondary efficacy endpoints evaluated in the study were the objective tumor response as assessed by clinical evaluations of tumor burden (complete response, partial response, objectively stable and progression) and evaluations of changes in prostatic involvement and prostate-specific antigen (psa). these evaluations were performed at weeks 16 and 32 of the treatment phase. the long-term treatment phase monitored psa at each visit (every 16 weeks). the objective tumor response analysis showed "no progression" (i.e. complete or partial response, or stable disease) in 86% (37/43) of patients at week 16, and in 77% (37/48) of patients at week 32. local disease improved or remained stable in all patients evaluated at week 16 and/or 32. for patients with elevated baseline psa, 50% (23/46) had a normal psa (less than 4.0 ng/ml) at week 16, and 51% (19/37) had a normal psa at week 32. periodic monitoring of serum testosterone and 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. using historical comparisons, the safety and efficacy of lupron depot 30 mg for 4-month administration appear similar to the other lupron depot formulations. figure 10. lupron depot 30 mg for 4-month administration mean serum testosterone concentrations 14.4 lupron depot 45 mg for 6-month administration an open-label, non-comparative, multicenter clinical study of lupron depot 45 mg for 6-month administration enrolled 151 patients with prostate cancer. the study drug was administered as two intramuscular injections of lupron depot 45 mg at 24 week intervals (139/151 received 2 injections), and patients were followed for a total of 48 weeks. among 148 patients who had testosterone value at week 4, serum testosterone was suppressed to castrate levels (< 50 ng/dl) from week 4 through week 48 in an estimated 93.4% (two-sided 95% ci: 89.2%, 97.6%) of patients. one patient failed to achieve testosterone suppression by week 4, and eight patients had escapes from suppression (any testosterone value > 50 ng/dl after castrate levels were achieved). mean testosterone levels increased to 608 ng/dl from a baseline of 435 ng/dl during the first week of treatment. by week 4, the mean testosterone concentration had decreased to below castrate levels (16 ng/dl). periodic monitoring of serum testosterone levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. testosterone determinations are dependent on assay methodology and it is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions. figure 11 below shows the mean testosterone concentration at various time points. figure 11. lupron depot 45 mg for 6-month administration serum testosterone concentrations (mean + se)

ot 7.5 mg for 1-month administration is administered as a single monthly intramuscular injection. when mixed with 1.5 ml of accompanying diluent, lupron depot 22.5 mg for 3-month administration is administered as a single intramuscular injection every 12 weeks . when mixed with 1.5 ml of accompanying diluent, lupron depot 30 mg for 4-month administration is administered as a single intramuscular injection every 16 weeks . when mixed with 1.5 ml of accompanying diluent, lupron depot 45 mg for 6-month administration is administered as a single intramuscular injection every 24 weeks . store at 25°c (77°f); excursions permitted to 15°c–30°c (59°f–86°f) [see usp controlled room temperature].

e is an increased risk of myocardial infarction, sudden cardiac death, and stroke with lupron depot treatment. advise patients to immediately report signs and symptoms associated with these events to their healthcare provider for evaluation [see warnings and precautions ( 5.3 )]. urogenital disorders advise patients that lupron depot may cause impotence. infertility inform patients that lupron depot may cause infertility [see use in specific populations ( 8.3 )]. continuation of lupron depot treatment inform patients that lupron depot is usually continued, often with additional medication, after the development of non-metastatic and metastatic castration-resistant prostate cancer [see dosage and administration ( 2.1 )]. manufactured for abbvie inc. north chicago, il 60064 by takeda pharmaceutical company limited osaka, japan 540-8645 20071816 april 2022