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Prescribing Information changes occur within a month of initiating drug therapy at recommended doses. NAME OF THE MEDICINAL PRODUCT Prescribing Information Lucrin PDS Depot 3.75 mg ® NAME OF THE MEDICINAL PRODUCT ® (Leuprorelin Acetate for Depot Suspension Lucrin PDS Depot 3.75 mg 3.75 mg) (Leuprorelin Acetate for Depot Suspension 3.75 mg) DESCRIPTION DESCRIPTION Leuprorelin acetate is a synthetic nonapeptide analog of naturally Leuprorelin acetate is a synthetic nonapeptide analogue of naturally occurring occurring gonadotropin releasing hormone (GnRH or LHRH). The analogue gonadotrophin hormonethan (GnRH LHRH). hormone. The analogue possesses greater possesses releasing greater potency theornatural potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-LThe chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucylL-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) and the structural formula is as follows: NH2 N H N O N H N O CH2 H N O O CH2 H OH CH3 H3C CH CH2 H O N N H O CH2 H N CH2 H O N Serum levels of leuprorelin acetate 3.75 mg measured in 11 patients H CH2 N N CH2 H O H3C CH O N 1-2 CH3CO O CH3 N H C NH NH CH2 CH2 Pharmacokinetics For patients at risk, the physician may consider initiating therapy with daily leuprorelin acetate injection for the weeks to given facilitate withdrawal of treatment Leuprorelin acetate is first not two active when orally. Bioavailability of thisif that isagent considered necessary. following subcutaneous administration is comparable to that after Patients with metastatic vertebral lesions and/or urinary tract obstruction should be intramuscular administration. closely observed during the first few weeks of therapy. Absorption Hyperglycemia and an increased risk of developing diabetes have been reported in Following single administration of Leuprorelin Acetate for Depot men receivingaGnRH agonists. Hyperglycemia may represent development of diabetes Suspension in prostatic carcinoma patients, doses of diabetes. 3.75 mg Monitor and 7.5blood mellitus or worsening of glycemic control in patients with mg by and/or subcutaneous and intramuscular routes provided mean leuprorelin glucose glycosylated hemoglobin (HbA1c) periodically in patients receiving GnRH agonists, and manage with current practice for treatment acetate plasma concentrations at the end of one month of of 0.7hyperglycemia ng/mL orand diabetes. 1.0 ng/mL, respectively. There was no indication of any drug accumulation. Intramuscular injectioninfarction, of the depot formulation (7.5and mg)stroke Increased risk of developing myocardial sudden cardiac death has been reported in association use of GnRHof agonists in men. The risk appears was shown to provide plasmawith concentrations leuprorelin acetate over low based on reported be evaluated carefully along with a period ofthe one monthodds in aratios, studyand of should orchiectomized male patients. cardiovascular risk factors whenacetate determining a treatment for patients with prostate Similarly, mean leuprorelin levels were detectable after four cancer. Patients receiving GnRH agonists should be monitored for symptoms and signs weeks of a single 7.5 mg, I.M., Leuprorelin Acetate for Depot Suspension suggestive of development of cardiovascular disease and be managed according to in a study involving current clinical practice.stage D2 prostatic carcinoma patients. OH Leuprorelin Acetate for Depot Suspension is a formulation of leuprorelin Leuprorelin Acetate for Depot Suspension is a formulation of leuprorelin acetate acetate supplied as sterile lyophilizedWhen microspheres. with a supplied as sterile lyophilized microspheres. mixed withWhen diluent,mixed it becomes diluent, it becomes a suspension which is administered as an intramuscular suspension for injection, which is administered as an intramuscular or subcutaneous injection once a month. or subcutaneous injection once a month. Active/Inactive Ingredients Active/Inactive Ingredients Leuprorelin Acetate for Depot Suspension 3.75 mg contains the following Leuprorelin Acetate for Depot Suspension 3.75 mg ingredients: Leuprorelin Acetate for Depot 3.75 mg contains following Leuprorelin acetate (3.75 mg), gelatinSuspension (0.65 mg), DL-lactic and glycolicthe acids copolymer leuprorelin acetate (3.75 mg), purified gelatin (0.65 mg), (33.1ingredients: mg), and mannitol (6.6 mg). DL-lactic and glycolic acids copolymer (33.1 mg), and D-mannitol During the manufacture of Leuprorelin Acetate for Depot Suspension 3.75 mg, acetic (6.6 mg). acid is lost, leaving the peptide. The accompanying diluent contains carboxymethylcellulose sodium mg), mannitol During the manufacture of Leuprorelin Acetate for Depot(5Suspension (50 mg), (1 mg), water for injection (1 mL). 3.75polysorbate mg, acetic80 acid is lost, leaving the peptide. The accompanying diluent contains carboxymethylcellulose sodium CLINICAL (5 mg),PHARMACOLOGY D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection (1 mL), and glacial acetic acid, to control pH. Pharmacodynamics Leuprorelin acetate, a GnRH agonist, acts as a potent inhibitor of gonadotrophin CLINICAL PHARMACOLOGY secretion when given on a continuous basis and in therapeutic doses. Animal and human studies indicate that following an initial stimulation, chronic administration Pharmacodynamics of leuprorelin acetate results in suppression of ovarian and testicular steroidogenesis. Leuprorelin acetate, a GnRH agonist, acts as a potent inhibitor of This effect is reversible on discontinuation of therapy. gonadotropin secretionacetate when has given on aincontinuous and inof Administration of leuprorelin resulted inhibition ofbasis the growth therapeutic Animal and (prostatic human studies an certain hormone doses. dependent tumors tumorsindicate in Nobelthat andfollowing Dunning male initial stimulation, mammary chronic administration of rats), leuprorelin results rats and DMBA-induced tumors in female as wellacetate as atrophy of the reproductive organs. of ovarian and testicular steroidogenesis. This effect is in suppression reversible on discontinuation ofacetate therapy. In humans, administration of leuprorelin results in an initial increase in circulating levelsAdministration of luteinizing hormone (LH) and acetate follicle stimulating hormone (FSH), leading to a of leuprorelin has resulted in inhibition of the transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone growth of certain hormone dependent tumors (prostatic tumors in Nobel in males, and estrone and estradiol in pre-menopausal females). and Dunning male rats and DMBA-induced mammary tumors in female However, administration of leuprorelinorgans. acetate results in decreased rats), continuous as well as atrophy of the reproductive levels of LH and FSH and sex steroids. In males, testosterone is reduced to castrate In humans, administration of leuprorelin in an initial or prepubertal levels. In pre-menopausal females, acetate estrogensresults are reduced to postmenopausal These hormonal occur within a month of and initiating drug increaselevels. in circulating levelschanges of luteinizing hormone (LH) follicle therapy at recommended doses. stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, Pharmacokinetics and estrone and estradiol in pre-menopausal females). Leuprorelin acetate is not active when given orally. Bioavailability of this agent However, continuous administration of leuprorelin results in following subcutaneous administration is comparable to thatacetate after intramuscular decreased levels of LH and FSH and sex steroids. In males, testosterone administration. is reduced to castrate or prepubertal levels. In pre-menopausal females, Absorption estrogens are reduced to post-menopausal levels. These hormonal Following a single administration of Leuprorelin Acetate for Depot Suspension in prostatic carcinoma patients, doses of 3.75 mg and 7.5 mg by subcutaneous and intramuscular routes provided mean leuprorelin acetate plasma concentrations at the end of one month of 0.7 ng/mL and 1.0 ng/mL, respectively. There was no indication of any drug accumulation. Intramuscular injection of the depot formulation (7.5 mg) was shown to provide plasma concentrations of leuprorelin acetate over a period of one month in a study of orchiectomized male patients. Similarly, mean leuprorelin acetate levels were detectable after four weeks of a single 7.5 mg, I.M., Leuprorelin Acetate for Depot Suspension in a study involving stage D2 prostatic carcinoma patients. Serum levels of leuprorelin acetate 3.75 mg measured in 11 patients with pre-menopausal breast cancer over 12 weeks. Mean leuprorelin acetate levels were above 0.1 ng/mL after four weeks and remained stable after re-injection (at 8 and 12 weeks). There was no tendency for drug accumulation. Distribution The mean steady-state volume of distribution of leuprorelin 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 leuprorelin administered intravenously, revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately three hours based on a two compartment model. Animal studies have shown 14C-labeled leuprorelin was metabolized into smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further metabolized. The major metabolite (M-I) plasma concentrations measured in five prostate cancer patients given leuprorelin acetate depot suspension reached a maximum concentration two to six 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 leuprorelin concentrations. Excretion Following administration of Leuprorelin Acetate for Depot Suspension 3.75 mg to three patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine over 27 days. Special Populations The pharmacokinetics of the drug in hepatic- and renal-impaired patients has not been determined. INDICATIONS Prostate Cancer Leuprorelin Acetate for Depot Suspension 3.75 mg is indicated in the palliative treatment of advanced prostatic cancer. It offers an alternative treatment of prostatic cancer when orchiectomy or estrogen administration are either not indicated or unacceptable to the patient. Endometriosis Leuprorelin Acetate for Depot Suspension 3.75 mg is indicated in the treatment of endometriosis for a period of six months. It can be used as sole therapy or as an adjunct to surgery. Uterine Fibroids Leuprorelin Acetate for Depot Suspension 3.75 mg is also indicated in the treatment of leiomyoma uteri (uterine fibroids) for a period up to six months. Therapy may be preoperative prior to myomectomy or hysterectomy, or it may provide symptomatic relief for the perimenopausal woman who does not desire surgery. Breast Cancer Leuprorelin Acetate for Depot Suspension 1 month 3.75 mg is indicated for the treatment of breast cancer in pre- and peri-menopausal women in whom hormone therapy is specified. CONTRAINDICATIONS Leuprorelin Acetate for Depot Suspension is contraindicated in patients with known hypersensitivity to leuprorelin acetate, similar nonapeptides, or any of the excipients. Isolated cases of anaphylaxis have been reported with the monthly formulation of Leuprorelin Acetate for Depot Suspension. Undiagnosed abnormal vaginal bleeding. Leuprorelin Acetate for Depot Suspension is contraindicated in women who are, or may become pregnant while receiving the drug. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with the two higher doses of leuprorelin acetate in rabbits and with the highest dose in rats. The effects on fetal mortality are logical consequences of the alterations in hormonal levels brought about by this drug. Therefore, the possibility exists that fetal abnormalities and spontaneous abortion may occur if the drug is administered during pregnancy. Use in women who are breastfeeding (see Lactation section). WARNINGS and PRECAUTIONS All Populations During the early phase of therapy, gonadotrophins 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. Worsening of pre-existing signs and symptoms during the first weeks of treatment may occur. Worsening of symptoms may contribute to paralysis with or without fatal complications. Bone Mineral Density Bone mineral density changes can occur during any hypoestrogenic state in women and in long-term use in prostate cancer in men. There is no data in men regarding reversibility after withdrawal of leuprorelin acetate. In women, bone mineral density loss may be reversible after withdrawal of leuprorelin acetate (see ADVERSE REACTIONS). Convulsions Postmarketing reports of convulsions have been observed in patients on leuprorelin acetate therapy. These included patients in the female and pediatric populations, 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. Effect on QT/QTc Interval with pre-menopausal breast cancer over 12 weeks. Mean leuprorelin QT-prolongation been observed during long-term deprivation therapy. acetate levels has were above 0.1 ng/mL after fourandrogen weeks and remained Physicians should consider whether the benefits of androgen deprivation therapy stable after re-injection 8 and 12with weeks). Therelong wasQT nosyndrome, tendencyelectrolyte for outweigh the potential risks(at in patients congenital drug accumulation. abnormalities, or congestive heart failure and in patients taking Class IA (e.g., quinidine, procainamide) Distribution or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications. Prostate Cancer Post Marketing Breast Cancer 3.75 mg Leuprorelin Acetate Depot Suspension 1 month 3.75 mg isFrequency indicated System Organ ClassforPreferred Term Frequency for the treatment of breast cancer in pre- and peri-menopausal women in whom hormone Endocrine disorders therapy Goiter is specified. Not known Pituitary apoplexy Not known CONTRAINDICATIONS Metabolism and Anorexia Common Leuprorelin Acetate for Depot Suspension is contraindicated in patients nutrition disorders Diabetes mellitus Not known with known hypersensitivity to leuprorelin acetate, similar nonapeptides, Increased appetite Not known or any of the excipients. Hyperglycaemia Isolated cases of anaphylaxis have beenUncommon reported with the monthly Hypoglycaemia formulation of Leuprorelin Acetate for Depot Suspension. Not known Dehydration Not known Undiagnosed abnormal vaginal bleeding. Notwomen known Leuprorelin Acetate forHyperlipidaemia Depot Suspension is contraindicated in who may become pregnant while receiving the drug. Hyperphosphatemia Not known Use in women who areHypoproteinemia breastfeeding (see Nursing Mothers section). Not known Abnormal weight Uncommon WARNINGS gain Prostate Cancer Psychiatric disorders Mood swings Not known Isolated cases of worsening signs and symptoms during theNot first few Nervousness known weeks of treatment have been reported with GnRH analogs. Worsening Libido decreased Common The mean steady-state volume of distribution of leuprorelin following of symptoms may contribute to paralysis with or without fatal Laboratory Tests Libido increased Not known intravenous bolus administration to healthy male volunteers was 27 L. complications. For patients at risk, the physician may consider initiating Response to leuprorelin acetate shouldproteins be monitored measuring serum levels of Insomnia Uncommon Not known In vitro binding to human plasma rangedbyfrom 43% to 49%. testosterone, as well as prostate specific antigen and prostatic acid phosphatase. therapy with daily leuprorelin acetate injection for the first two weeks disorder Uncommon Not known of treatment if that is considered necessary. InMetabolism the majority of patients, testosterone levels increased above baseline during the to facilitate withdrawalSleep In healthy male volunteers, a baseline 1 mg bolus first week, declining thereafter to levelsof orleuprorelin below by theadministered end of the second Depression Uncommon Not known Endometriosis/Uterine Fibroids week of treatment. Castrate were reached two to four intravenously, revealed thatlevels the mean systemicwithin clearance was 7.6weeks L/h, and Anxiety Not known once were maintainedhalf-life for as long as the patientsthree received their injections During the early phase of therapy, sex steroids temporarily rise above withachieved a terminal elimination of approximately hours based Delusion Not known on Transient increases in acid phosphatase levels sometimes occurred early baseline because of the physiological effect of the drug. Therefore, an ontime. a two compartment model. in treatment. However, by the fourth week, the elevated levels usually decrease to increase in clinical signs andideation symptoms may be observed during the Suicidal Not known 14 Animal studies have shown C-labeled leuprorelin was metabolized values at or near baseline. initial days of therapy,Suicidal but these will dissipate with continued attempt Nottherapy known into smaller inactive peptides, a pentapeptide (Metabolite I) tripeptides at adequate doses. However, reports of heavy vaginal bleeding requiring Women (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments Nervous system Dizziness Uncommon Not known medical or surgical intervention with continued therapy have been disorders may be further metabolized. Endometriosis/Uterine Fibroids Headache reported in the treatment of submucous leiomyoma uteri. Not known The major metabolite (M-I) plasma concentrations in five During the early phase of therapy, sex steroids temporarily risemeasured above baseline because Paraesthesia Uncommon Not known Safe use of leuprorelin acetate in pregnancy has not been established ofprostate the physiological effect ofgiven the drug. Therefore, an increase clinical signs and cancer patients leuprorelin acetate depotinsuspension known clinically. Before startingLethargy treatment with leuprorelin acetate, it isNot advisable symptoms may be observed during the initial days of therapy, but these will dissipate reached a maximum concentration two to six hours after dosing and patient is pregnant. Leuprorelin acetate is not with continued therapy at adequate reports of heavy vaginal bleeding to establish whether the Somnolence Uncommon were approximately 6% of thedoses. peak However, parent drug concentration. One is required, a nonhormonal method of requiring medical or surgical with continued therapy have been reported a contraceptive. If contraception Memory impairment Not known week after dosing, mean intervention plasma M-I concentrations were approximately in the treatment of submucous leiomyoma uteri. contraception should be used. 20% of mean leuprorelin concentrations. Dysgeusia Not known Safe use of leuprorelin acetate in pregnancy has not been established clinically. Before Excretion Hypoaesthesia Not known starting treatment with leuprorelin acetate, it is advisable to establish whether the PRECAUTIONS Following administration of Leuprorelin Acetate for Depot Suspension patient is pregnant. Syncope Not known Bone Mineral Density 3.75 mg to threeis patients, less than If5% of the dose was recovered as Leuprorelin acetate not a contraceptive. contraception is required, a nonhormonal Neuropathy Not known Bone mineral density changes can occur during any hypoestrogenic state. parent of and M-I metabolite in be theused. urine over 27 days. method contraception should peripheral may be reversible after withdrawal of leuprorelin Since bonePopulations loss can be anticipated as part of natural menopause, it may also be expected Bone mineral density loss Special Cerebrovascular Not known toThe occur during a medically-induced Bone loss has been found acetate. pharmacokinetics of the drughypoestrogenic in hepatic- andstate. renal-impaired patients accident tohas be not reversible after completion of a six month course of leuprorelin acetate. been determined. Prostate Cancer Loss of consciousness Not known Experience with Leuprorelin Acetate for Depot Suspension in females has been limited Patients with metastatic vertebral lesions and/or urinary tract obstruction Transient ischemic Not known toINDICATIONS women 18 years of age and older, treated for 6 months. attack during the first few weeks of therapy (see should be closely observed Prostate Cancer Laboratory Tests WARNINGS). Paralysis Not known Response to leuprorelin acetate should be monitored oneistoindicated two months after the Leuprorelin Acetate for Depot Suspension 3.75 mg in the Neuromyopathy Not known Laboratory Tests start of therapy with a GnRH stimulation test and sex steroid levels. Measurement of palliative treatment of advanced prostatic cancer. It offers an alternative Not known bone age forofadvancement should be orchiectomy done every 6or toestrogen 12 months. Response to leuprorelinConvulsion acetate should be monitored by measuring serum treatment prostatic cancer when administration Eye of disorders blurred known testosterone, Vision as well as prostate specific antigen andNot prostatic Sex steroids may increase or or unacceptable rise above pre-pubertal levels if the dose is inadequate. levels is either not indicated to the patient. Once a therapeutic dose has been established, gonadotrophin and sex steroid levels acid phosphatase. In the majority increased Eye disorder of patients, testosterone levelsNot known Endometriosis will decline to pre-pubertal levels. above baseline duringVisual the first week, declining thereafter toNotbaseline impairment known levels or below by the end of the second week of treatment. Castrate Leuprorelin Acetate for Depot Suspension 3.75 mg is indicated in the Drug Interactions Amblyopia Uncommon Not known levels were reached within two to four weeks and once achieved were treatment of endometriosis for a period of six months. It can be used No pharmacokinetic-based drug-drug interaction studies have been conducted with Dry eye Not known as sole therapy orfor as Depot an adjunct to surgery. Leuprorelin Acetate Suspension. However, because leuprorelin acetate is a maintained for as long as the patients received their injections on time. increases in acid phosphatase levels sometimes occurred early Ear and labyrinth Ear pain Uncommon peptide thatFibroids is primarily degraded by peptidase and not by cytochrome P-450 enzymes Transient Uterine disorders However,Tinnitus by the fourth week, the elevated levels usually as noted in specific studies, and the drug is only about 46% bound to plasma proteins, in treatment. Uncommon Not known Leuprorelin Acetate Suspension 3.75 mg is also indicated in decrease to values at or near baseline. drug interactions wouldfor notDepot be expected to occur. Hearing impaired Not known the treatment of leiomyoma uteri (uterine fibroids) for a period up to Drug/Laboratory Test Interactions Administration of leuprorelin acetate depot in women results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after leuprorelin acetate depot treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotrophic and gonadal functions conducted during treatment and for up to three months after discontinuation of leuprorelin acetate depot may be misleading. Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was 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 leuprorelin 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 leuprorelin 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 leuprorelin acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential. Clinical and pharmacologic studies in adults with leuprorelin acetate and similar analogues have shown full reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks. Pregnancy and Lactation Pregnancy See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS. Lactation It is not known whether leuprorelin acetate is excreted in human milk. Therefore, it should not be used by nursing mothers. Cardiac disorders Vascular disorders Women Metabolism and nutrition disorders: weight gain, weight loss Psychiatric disorders: loss of or decreased libido, increased libido, affects lability Nervous system disorders: headache Vascular disorders: hot flushes, vasodilatation, hypotension Skin and subcutaneous tissue disorders: acne, seborrhea, dry skin, urticaria, skin odour abnormal, hyperhidrosis, hair growth abnormal, hirsutism, hair disorder, eczema, nail disorder, night sweats Reproductive system and breast disorders: vaginal haemorrhage, dysmenorrhea, menstrual disorder, breast enlargement, breast engorgement, breast atrophy, genital discharge, vaginal discharge, galactorrhea, breast pain, metrorrhagia, menopausal symptoms, dyspareunia, uterine disorder, vaginitis, menorrhagia General disorders and administration site conditions: feeling hot, irritability Investigations: bone density decreased Long exposure (6 to 12 months): diabetes mellitus, glucose tolerance impaired, total cholesterol increased, LDL increased, triglycerides increased, osteoporosis. System Organ Class Preferred Term Infections and infestations Infection Rhinitis Post Marketing Frequency Frequency Not known Uncommon Urinary tract infection Not known Angina pectoris Uncommon Not known Ventricular extrasystoles Uncommon Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders Not known Bradycardia Not known Sudden cardiac death Not known Hot flushes Very common Vasodilatation Very common Angiopathy Uncommon Skin and subcutaneous tissue disorders Thrombosis Not known Hypotension Not known Varicose vein Not known Not known Pulmonary fibrosis Not known Inflammation dehydrogenase increased/ALT Aspartate aminotransferase increased/AST Common Gammaglutamyltransferase increased Uncommon Electrocardiogram abnormal Not known ECG signs of myocardial ischemia Not known Liver function test abnormal Not known Platelet count decreased Uncommon Uncommon Prothrombin time prolonged Not known Activated partial thromboplastin time prolonged Not known Cardiac murmur Not known Low density lipoprotein increased Not known Blood triglycerides increased Not known Not known Haemoptysis Uncommon Not known Blood bilirubin increased Emphysema Uncommon Cough Not known Reticulocyte count increased Pleural effusion Not known Lung infiltration Not known Respiratory disorder Not known Sinus congestion Not known Pulmonary embolism Not known Interstitial lung disease Not known Not known Common Not known Vomiting Common Not known Gastrointestinal haemorrhage Not known Abdominal distention Not known Not known Dysphagia Not known Dry mouth Not known Duodenal ulcer Not known Gastrointestinal disorder Not known Peptic ulcer Not known Rectal polyp Not known Hepatic function abnormal Not known Jaundice Not known Alopecia Uncommon Injury, poisoning and procedural complications Not known Changes in Bone Density In controlled clinical studies, patients with endometriosis (six months of therapy) or uterine fibroids (three months of therapy) were treated with leuprorelin depot 3.75 mg. In endometriosis patients, vertebral bone density as measured by dual energy x-ray absorptiometry (DEXA) decreased by an average of 3.9% at six months compared with the pretreatment value. For those patients who were tested at six or twelve months after discontinuation of therapy, mean bone density returned to within 2% of pretreatment. When leuprorelin depot 3.75 mg was administered for three months in uterine fibroid patients, vertebral trabecular bone mineral density as assessed by quantitative digital radiography (QDR) revealed a mean decrease of 2.7% compared with baseline. Six months after discontinuation of therapy, a trend toward recovery was observed. Table 2: Women Indications ADRs Endo (3.75 mg) System Organ Class Dry skin Not known Infections and infestations Photosensitivity reaction Not known Uncommon Uncommon Fibroids (3.75 mg) Not known Infection Uncommon Rhinitis Not known Uncommon Uncommon Pyelonephritis Uncommon Furuncle Uncommon Not known Urinary tract infection Hair growth abnormal Not known Vulvovaginal candidiasis Uncommon Influenza Uncommon Uncommon Common Night sweats Uncommon Pigmentation disorder Not known Skin lesion Uncommon Myalgia Uncommon Bone swelling Not known Not known Arthropathy Not known Arthralgia Common Muscular weakness Uncommon Pain in extremity Uncommon Not known Not known Nasopharyngitis Neoplasms benign, malignant and unspecified (incl cysts and polyps) Not known Not known Pneumonia Not known Bone pain Common Pharyngitis Not known Post Marketing Frequency Frequency Frequency Frequency Dermatitis Pruritus BC (3.75 mg) Preferred Term Upper respiratory tract infection Common Hair disorder Endometriosis In two clinical trials treating endo Acetate for Depot Suspension wi the following adverse reactions probable relationship to study dru in 5% or more of the patients re not drug related are excluded. Women Table 2 presents ADRs and frequencies (very common [≥1/10]; common [≥1/100 to <1/10]; uncommon [≥1/1,000 to <1/100]; not known [unable to estimate frequency based upon available data]) from endometriosis, uterine fibroid and breast cancer clinical studies and post-marketing experience. A blank indicates that the ADR was not seen from that particular source. Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack. Although a temporal relationship was reported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH agonist and these events. Not known Rash Rash maculo-papular Endometriosis/Uterine Fibroid Estradiol levels may increase duri injection, but then decline to me in estradiol can be associated wit symptoms (see WARNINGS). Uncommon Spinal fracture Not known Not known In this same study, the following than 5% of the patients on Leup Cardiovascular System - angina System - anorexia, diarrhea; End decrease; Musculoskeletal Central/Peripheral Nervous Respiratory System - hemoptysi local skin reactions, hair growth; U urgency, hematuria, testicular pain hard nodule in throat, increased acid. Not known Not known Not known Cardiovascular System Edema Gastrointestinal System Nausea/vomiting Endocrine System Decreased Testicular Size* Hot Flashes/sweats* Impotence* Central/Peripheral Nervous S General Pain Respiratory System Dyspnea Miscellaneous Asthenia *Physiologic effect of decreased Not known White blood cell count decreased Not known ADVERSE REACTIONS Prostate Cancer In the majority of patients testos during the first week, declining th the end of the second week of tr Potential exacerbations of signs an of treatment is a concern in pati urinary obstruction or hematur neurological problems such as te of the lower limbs or worsening o In a clinical trial of Leuprorelin Acet adverse reactions were reported to to drug as ascribed by the trea patients receiving the drug. Oft patients with metastatic prostate related are excluded. T MOST COMMON (Intention T Not known White blood cell count increased Uncommon Ecchymosis Uncommon Protein urine present Common Common Not known Nursing Mothers increased Alanin It is not known whether leuprorelin acetate isUncommon excreted in human milk. aminotransferase Therefore, it should be administered with caution to a nursing mother. Epistaxis Nausea Not known Pregnancy Pelvic fibrosis Not known Leuprorelin Acetate for Depot Suspension is contraindicated in women Investigations Haemoglobin Uncommon who are or may becomedecreased pregnant while receiving the drug. When administered on day six of Blood pregnancy at test dosages of 0.00024, 0.0024 urea increased Uncommon Not known and 0.024 mg/kg (1/600 to 1/6 the human dose) to rabbits, it produced Blood uric acid UncommonSimilar studies Not known a dose-related increase inincreased major fetal abnormalities. in rats failed to demonstrate an increase in fetal malformations. There was Blood creatinine fetal weights with the twoNot known increased fetal mortality and decreased higher increased doses of the monthly formulation of leuprorelin acetate in rabbits and Blood calcium Uncommon Not known with the highest dose in rats. increased The effects on fetal mortality are logical consequences of the alterations Common Blood alkaline in hormonal levels broughtphosphatase about by this drug. Therefore, the possibility increased may occur if the drug is administered exists that spontaneous abortion during pregnancy. Very common Blood lactic Dyspnoea Constipation Uncommon Carcinogenesis, Mutagenesis, Impairment of Fertility Fatigue Common A two-year carcinogenicity study was conducted in rats and mice. In Pyrexia Not known rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas wasInjection notedsite at reaction 24 months when the drug Notwas known administered subcutaneously at high (0.6 to 4 mg/kg).Not There Injection site daily doses Uncommon known was a significant but notinflammation dose-related increase of pancreatic islet-cell adenomas in females and Injection of testicular interstitial cell adenomas inNot males site pain Common known (highest incidence in the low dose group). In mice, no leuprorelin acetateInjection site Common Not known induced tumors or pituitary abnormalities were observed at a dose as induration high as 60 mg/kg for two years. Patients have been treated with leuprorelin Injection site Uncommon acetate for up to three years with doses as high as 10 mg/day and for erythema two years with doses as high as 20 mg/day without demonstrable pituitary Injection site abscess Not known abnormalities. sterile Mutagenicity studies have Injection been performed with leuprorelin acetateNot using site known bacterial and mammalianhematoma systems. These studies provided no evidence of a mutagenic potential.Injection site irritation Uncommon Clinical and pharmacologicChills studies in adults with leuprorelin acetate Uncommon Not and known similar analogs have shown full reversibility of fertility suppressionNot when Nodule known the drug is discontinued after continuous administration for periods of Thirst Not known up to 24 weeks. Uncommon Pleural rub Hyperhidrosis Renal and urinary disorders Asthenia Not known Not known Urticaria Musculoskeletal and connective tissue disorders Penile swelling Not known Drug/Laboratory Test Interactions Penis disorder Not known Administration of leuprorelin acetate depot in women results in suppression of the pituitary gonadal Prostatic system.pain Normal function is usually restored Not known withinGeneral threedisorders months depot treatment is Pain leuprorelin acetate Common Not known andafter discontinued. Therefore, diagnostic tests of pituitary gonadotropic and administration site Chest pain Uncommon conditions gonadal functions conducted during treatment and for up to three Oedemaof leuprorelin acetate depot may Not known months after discontinuation be Oedema peripheral Common misleading. Not known Uncommon Not known Blood potassium decreased Phlebitis Diarrhea Hepato-biliary disorders Breast tenderness Drug Interactions Erectile dysfunction Common No pharmacokinetic-based drug-drug been Testicular atrophy interaction Commonstudies haveNot known conducted with Leuprorelin Acetate Depot Suspension. However, because Testicular pain Not known leuprorelin acetate is a peptide that is primarily degraded by peptidase Breastenzymes enlargement Uncommon and not by cytochrome P-450 as noted in specific studies, and Breast pain to plasma proteins, drug interactions Not known the drug is only about 46% bound would not be expected toTesticular occur. disorder Not known Not known Tachycardia Poor peripheral circulation Table 1: Prostate Cancer Prostate Cancer 3.75 mg Not known Lymphoedema Clinical and Postmarketing The following sections present adverse events seen in clinical studies or postmarketing experience. They are arranged by patient populations: Men, Women. Men Prostate Cancer 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). Table 1 presents all adverse drug reactions (ADR) and frequencies (very common [≥1/10]; common [≥1/100 to <1/10]; uncommon [≥1/1,000 to <1/100]; not known [unable to estimate frequency based upon available data]) from prostate cancer clinical studies and post marketing experience. A blank indicates that the ADR was not seen from that particular source. Uncommon Hypertension Endometriosis/Uterine Fibroids Since bone loss can be anticipated as part of natural menopause, it may also be expected to occur during a medically-induced hypoestrogenic Prostate Cancer PostofMarketing state. Bone loss has been found to be reversible after completion a 3.75 mg six month course of leuprorelin acetate. System Organ Class Preferred Term Frequency Frequency Experience with Leuprorelin Acetate for Depot Suspension in females has been limited to women 18 years of ageUncommon and older, treatedNotfor 6 Reproductive system Gynaecomastia known months. and breast disorders Not known Myocardial infarction The following adverse events are commonly associated with the pharmacological actions of leuprorelin acetate on the steroidogenesis: Men Neoplasm benign, malignant and unspecified (including cysts and polyps): prostate tumor flare, aggravation of prostate cancer Metabolism and nutrition disorders: weight gain, weight loss Psychiatric disorders: loss of or decreased libido, increased libido Nervous system disorders: headache, muscular weakness Vascular disorders: vasodilatation, hot flushes, hypotension, orthostatic hypotension Skin and subcutaneous tissue disorders: dry skin, hyperhidrosis, rash, urticaria, hair growth abnormal, hair disorder, night sweats, hypotrichosis, pigmentation disorder, cold sweat, hirsutism Reproductive system and breast disorders: gynaecomastia, breast tenderness, erectile dysfunction, testicular pain, breast enlargement, breast pain, prostate pain, penile swelling, penis disorder, testis atrophy General disorders and administration site conditions: mucosal dryness Investigations: PSA increased, bone density decreased Long exposure (6 to 12 months): diabetes mellitus, glucose tolerance impaired, total cholesterol increased, LDL increased, triglycerides increased, osteoporosis. Cardiac failure congestive Arrhythmia ADVERSE REACTIONS Men Prostate Cancer Initially, leuprorelin 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 Leuprorelin Acetate for Depot Suspension 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 ureteric obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Worsening of symptoms may contribute to paralysis with or without fatal complications. six months. Therapy may be preoperative prior to myomectomy or hysterectomy, or it may provide symptomatic relief for the perimenopausal woman who does not desire surgery. Common Skin cancer Not known Leukopenia Blood and lymphatic Anaemia system disorders Iron deficiency anaemia Uncommon Not known Common Ankylosing spondylitis Not known Immune system disorder Anaphylactic reaction Not known Tenosynovitis Not known Not known Not known Endocrine disorders Goiter Urinary incontinence Metabolism and nutrition disorders Anorexia Dysuria Uncommon Pollakiuria Uncommon Pharyngitis Not known Micturition urgency Pneumonia Not known Haematuria Uncommon Uncommon Not known Not known Not known Fungal skin infection Uncommon Urinary retention Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm Uncommon Bladder spasm Not known Urinary tract disorder Not known Skin cancer Not known Not known Blood and lymphatic system disorder Anaemia Not known Urinary tract obstruction Immune system disorder Anaphylactic reaction Not known Polyuria Uncommon Pituitary apoplexy Not known Uncommon Uncommon Diabetes mellitus Increased appetite Not known Uncommon Uncommon Very common Decreased appetite Not known Common Hypoglycaemia Not known Dehydration Not known Hyperlipidaemia Not known Hypercholesterolaemia Common Hyperphosphatemia Not known Hypoproteinemia Not known Endo (3.75 mg) System Organ Class Psychiatric disorders Preferred Term Fibroids (3.75 mg) BC (3.75 mg) Frequency Frequency Frequency Frequency Abnormal weight gain Very common Common Abnormal loss of weight Common Common Very common Affect lability Very common Common Common Uncommon Nervousness Very common Common Libido decreased Very common Common Very common Common Very common Libido increased Sleep disorder Nervous system disorders Major depression Common Anxiety Common Delusion Uncommon Thinking abnormal Uncommon Confusional state Common Euphoric mood Uncommon Hostility Common Apathy Uncommon Nervousness/anxiety Very common Common Not known Common Not known Very common Not known Suicide attempt Not known Common Very common Not known Skin discolouration Uncommon Uncommon Pigmentation disorder Uncommon Common Arthropathy Common Common Arthralgia Common Common Very common Back pain Common Common Very common Arthritis Uncommon Common Neck pain Common Common Common Periarthritis Common Uncommon Dysuria Common Pollakiuria Uncommon Not known Not known Uncommon Hypertonia Common Common Ataxia Uncommon Reproductive system and breast disorders Not known Common Not known Common HOW SUPPLIED Urinary tract obstruction Not known Gynaecomastia Not known Breast tenderness Not known Vaginal haemorrhage Not known Common Uncommon Breast enlargement Uncommon Breast engorgement Uncommon Breast atrophy Common Genital discharge Common Common Common Uncommon Transient ischemic attack Not known Metrorrhagia Paralysis Not known Menopausal symptoms Neuromyopathy Not known Vaginitis Convulsion Not known Eye disorder Uncommon Not known Visual impairment Common Not known Amblyopia Common Not known Eye pain Uncommon Conjunctivitis Uncommon Common Dry eye Vertigo Not known Common Tinnitus Common Not known Hearing impaired Not known Cardiac failure congestive Not known Arrhythmia Not known Myocardial infarction Not known Angina pectoris Not known Tachycardia Uncommon Uncommon Palpitations Common Vasodilatation Very common Very common Uncommon Common Common Common Chest pain Common Uncommon Common Oedema Common Uncommon Common Oedema peripheral Common Common Common Face oedema Uncommon Common Very common Generalised oedema Uncommon Asthenia Common Uncommon Injection site mass Uncommon Uncommon Injection site pain Common Not known Injection site induration Very common Not known Injection site pruritus Common Injection site erythema Common Common Not known Injection site haemorrhage Common Phlebitis Not known Injection site hematoma Thrombosis Not known Chills Hypotension Not known Nodule Varicose vein Not known Uncommon Pleural rub Not known Injection site hypersensitivity Common Not known Common Common Not known Not known Not known Thirst Common Not known Common Not known General physical health deterioration Very common Feeling hot Very common Irritability Common Haemoptysis Dysphonia Not known Common Not known Not known Dyspnoea Common Very common Not known Uncommon Not known Uncommon Not known Not known Hypertension Pulmonary fibrosis Not known Common Lymphoedema Epistaxis Not known Injection site abscess sterile Very common Not known Common Injection site inflammation Not known Hot flush Very common Pyrexia Common Bradycardia Very common Fatigue Not known Not known Not known Malaise Pleural effusion Not known Condition aggravated Lung infiltration Not known Inflammation Not known Respiratory disorder Not known Pelvic fibrosis Not known Sinus congestion Not known Blood urea increased Not known Blood uric acid increased Not known Cough Common Oropharyngeal pain Common Investigations Common Uncommon Pulmonary embolism Not known Interstitial lung disease Not known Blood creatinine increased Not known Blood calcium increased Not known Constipation Common Uncommon Common Not known Nausea Very common Common Very common Not known Body temperature increased Uncommon Common Not known Electrocardiogram abnormal Not known Not known ECG signs of myocardial ischemia Not known Not known Liver function test abnormal Vomiting Nausea and vomiting Common Uncommon Gastrointestinal haemorrhage Abdominal distention Uncommon Diarrhoea Common Dyspepsia Uncommon Flatulence Uncommon Common Gastritis Uncommon Common Common Not known Not known Gingival bleeding Uncommon Dry mouth Common Uncommon Abdominal pain Common Common Not known Common Abdominal pain upper Common Abdominal pain lower Common Stomatitis Common Retching Common Uncommon Common Not known Platelet count decreased Not known Blood potassium decreased Not known White blood cell count increased Not known White blood cell count decreased Not known Prothrombin time prolonged Not known Activated partial thromboplastin time prolonged Not known Uncommon Duodenal ulcer Not known Laboratory test abnormal Gastrointestinal disorder Not known Cardiac murmur Not known Low density lipoprotein increased Not known Blood triglycerides increased Not known Not known Blood bilirubin increased Not known Hepatic function abnormal Not known Injury, poisoning Spinal fracture and procedural complications Not known Serious liver injury Not known Abdominal discomfort Common Tongue disorder Common Peptic ulcer Not known Rectal polyp Liver tenderness Uncommon Jaundice Not known Erythema Common Alopecia Common Ecchymosis Common Acne Very common Seborrhoea Common Rash Common Rash maculo-papular Uncommon Dry skin Common Photosensitivity reaction Uncommon Common Not known Common Hyperhidrosis Common Not known Common Not known Not known Common Uncommon Common OVERDOSAGE There is no clinical experience with the effects of an acute overdose of leuprorelin acetate depot suspension. In animal studies, doses of approximately 133 times the recommended human dose resulted in dyspnea, decreased activity and local irritation at the injection site. In cases of overdosage, the patients should be monitored closely and management should be symptomatic and supportive. DOSAGE AND ADMINISTRATION Urticaria Skin odour abnormal Not known License Holder Common Pain Injection site reaction Takeda Japan, for Abbott Laboratories, Spain Not known Uncommon Common Menorrhagia General disorders and administration site conditions Manufacture The format of this leaflet was determined by the Ministry of Health and its content was checked and approved. Pelvic pain Not known Not known Leuprorelin Acetate Prefilled Dual Chamber Syringe (PDS) 3.75 mg - is available in a single dose administration kit of a syringe containing sterile lyophilized microspheres which are leuprorelin acetate incorporated in a biodegradable polymer of polylactic acid. When mixed with 1 mL of diluent leuprorelin acetate is administered as a single intramuscular or subcutaneous injection. Abbott Medical Laboratories Ltd., P.O.B. 58099, Tel-Aviv 61580, Israel Not known Common STORAGE Not known Uncommon Vision blurred Leuprorelin Acetate Prefilled Dual Chamber Syringe (PDS): For optimal performance of the Prefilled Dual Chamber Syringe (PDS), read and follow the following instructions: 1.To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn. 2.Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first stopper is at the blue line in the middle of the barrel. 3.Keep the syringe UPRIGHT. Gently mix the microspheres (particles) thoroughly to form a uniform suspension. The suspension will appear milky. 4.Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. 5.Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. 6.Inject the entire contents of the syringe intramuscularly or subcutaneously at the time of the reconstitution. The suspension settles very quickly following reconstitution; therefore, leuprorelin acetate should be mixed and used immediately. NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is accidentally penetrated. If present, blood can be seen through the transparent hub of the needle. Not known Common Loss of consciousness Use in Treatment of Uterine Fibroids Recommended duration of therapy is up to 6 months. Urinary tract disorder Breast pain Not known Use in Treatment of Endometriosis It is recommended that the therapy begins with the first day of the menstrual cycle after pregnancy has been ruled out. Development of amenorrhea is usually evidence of a clinical response, although spotting or bleeding from the atrophic endometrium can still occur. Therapy should be continued uninterrupted for 6 months. Bladder spasm Galactorrhoea Cerebrovascular accident Endometriosis Uterine fibroids Prostate cancer Breast cancer Not known Common Menstrual disorder Neuropathy peripheral Not known Not known Dysmenorrhea Common Convulsions local Not known Hematuria Uncommon Indication 3.75 Store below 25°C. Once reconstituted with the sterile diluent, the suspension should be administered immediately. Protect from freezing. Not known Common Not known Urinary incontinence Nocturia Migraine Not known Micturition urgency Not known Not known Common Musculoskeletal stiffness Not known Uncommon Not known Muscular weakness Common Syncope Not known Not known Nuchal rigidity Dose (mg) Preparation for Administration Common Uncommon Uncommon Tenosynovitis Common Not known Not known Bone pain Common Uncommon Common Dermatitis bullous Common Uncommon Not known Uncommon Myalgia The recommended dose of Leuprorelin Acetate for Depot Suspension is summarized below: Uncommon Nail disorder Paraesthesia Tremor Skin and subcutaneous tissue disorders Uncommon Not known Hypoaesthesia Hepato-biliary disorders Common Very common Dysgeusia Gastrointestinal disorders Hirsutism Hair disorder Very common Amnesia Respiratory, thoracic and mediastinal disorders Not known Very common Memory impairment Vascular disorders Not known Hair growth abnormal Headache Somnolence Cardiac disorders Dermatitis Ankylosing spondylitis Renal and urinary disorders Post Marketing Frequency Frequency Frequency Frequency Bone swelling Common Lethargy Ear and labyrinth disorders Musculoskeletal and connective tissue disorders Not known Not known Very common BC (3.75 mg) Skin lesion Not known Suicide ideation Dizziness Preferred Term Fibroids (3.75 mg) Night sweats Not known Very common Uncommon Common Dizziness postural Eye disorders Not known Not known Very common System Organ Class Very common Very common Personality disorder Depression Endo (3.75 mg) Pruritus Mood swings Insomnia Post Marketing Common Very common Not known General Leuprorelin Acetate for Depot Suspension - 1 Month 3.75 mg must be administered under the supervision of a physician. As with other drugs administered by injection, the injection sites should be varied periodically. Upon reconstitution, the suspension should be discarded if not used immediately. Administration Guidelines Reconstitute the microspheres immediately prior to administration and administer as a single intramuscular or subcutaneous injection once a month. SH LUC PDS 3.75 API Apr 2012