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warnings and cautions
5 WARNINGS AND PRECAUTIONS Tumor Flare: Increased serum testosterone (~50% above baseline) during first week of treatment; monitor serum testosterone and PSA. (5.6) Isolated cases of transient worsening of symptoms, or additional signs and symptoms of prostate cancer during the first few weeks of treatment. (5.1) A small number of patients may experience a temporary increase in bone pain which can be managed symptomatically. (5.1) Isolated cases of ureteral obstruction and spinal cord compression have been reported with GnRH agonists, which may contribute to paralysis with or without fatal complications. (5.1) Hyperglycemia and Diabetes: Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH analogs. Monitor blood glucose level and manage according to current clinical practice. (5.2) Cardiovascular Diseases: Increased risk of myocardial infarction, sudden cardiac death and stroke has been reported in association with 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 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) Monitor serum levels of testosterone following injection of LUTRATE DEPOT 22.5 mg for 3-month administration. (5.6) Embryo-Fetal Toxicity: LUTRATE DEPOT may cause fetal harm. (5.7, 8.1) 5.1 Tumor Flare Initially, LUTRATE DEPOT, like other GnRH agonists, causes increases in serum levels of testosterone to approximately 50% above baseline during the first weeks of treatment. Isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Transient worsening of symptoms may develop. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of 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 LUTRATE DEPOT 22.5 mg for 3-month administration. In the majority of patients, testosterone levels increased above baseline during the first week, and then declined thereafter to castrate levels ( 50 ng/dL) within four weeks. [ see Clinical Studies (14) and Adverse Reactions (6) ]. 5.7 Embryo-Fetal Toxicity Based on findings in animal studies, LUTRATE DEPOT may cause fetal harm when administered to a pregnant woman. In animal developmental and reproductive toxicology studies, administration of the monthly formulation of leuprolide acetate on day 6 of pregnancy (sustained exposure was expected throughout the period of organogenesis) caused adverse embryo-fetal toxicity in animals at doses less than the human dose, based on body surface area, using an estimated daily dose. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus [ see Use in Specific Populations (8.1) ] .
6 ADVERSE REACTIONS The following is discussed in more detail in other sections of the labeling: Tumor Flare [ see Warnings and Precautions (5.1) ] HyperglycemiaandDiabetes [ see Warnings and Precautions (5.2) ] Cardiovascular Disease [ see Warnings and Precautions (5.3) ] Effect on QT/QTc Interval [ see Warnings and Precautions (5.4) ] Convulsions [ see Warnings and Precautions (5.5) ] Most common adverse reactions (incidence > 10%) are hot flushes, upper respiratory infection, fatigue, diarrhea, pollakiuria, arthralgia, and injection site pain (6) . As with other GnRH agonist, other adverse reactions, including decreased bone density and rare cases of pituitary apoplexy may occur. (6) To report SUSPECTED ADVERSE REACTIONS, contact GP-Pharm at 1 800 xxx-xxxx or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. LUTRATE DEPOT 22.5 mg for 3-Month Administration In a clinical trial of LUTRATE DEPOT 22.5 mg for 3-month administration, patients were treated for 24 weeks with 157/163 receiving two injections. The table includes adverse reactions were reported in 5% or more of the patients during the treatment period as well as the incidence of these adverse reaction that were considered, by the treating physician, to be at least possibly related to Lutrate Depot. Grade 3-4 adverse reactions reported as treatment-emergent in 13% of patients and treatment-related 4% of patients. Table 2. Adverse Reactions Reported in ≥ 5% of Patients LUTRATE DEPOT 22.5 mg for 3-Month Administration N = 163 (%) Grade 1-4 Treatment-Emergent Treatment-Related Hot Flush/Flushing 1 128 (79) 127 (78) Upper Respiratory Infection 2 28 (17) 0 Fatigue/Asthenia 24 (15) 22 (13) Diarrhea 21 (13) 2 (1) Pollakiuria 20 (12) 3 (2) Arthralgia/Arthritis 18 (11) 2 (1) Injection Site Pain/Discomfort 18 (11) 15 (9) Constipation 15 (9) 1 (0.6) Extremity Pain 14 (9) 0 Nausea 14 (9) 4 (2) Nocturia 14 (9) 3 (2) Abdominal Pain/Discomfort 13 (8) 1 (0.6) Urinary Tract Pain 13 (8) 2 (1) Dizziness 12 (7) 2 (1) Headache/Sinus Headache 12 (7) 1 (0.6) Urinary Tract Infection 12 (7) 0 Bone Pain 11 (7) 4 (2) Back Pain 10 (6) 1 (0.6) Hypertension/Blood Pressure Increased 10 (6) 0 Pruritus/Generalized Pruritus 9 (6) 3 (2) CTCAE v.3 1 Includes cold sweat, flushing, hot flush, hyperhidrosis, and night sweats 2 Includes influenza, influenza-like illness, nasal congestion, nasopharyngitis, rhinorrhea, upper respiratory tract infection and congestion In the same study, erectile dysfunction and testicular atrophy were reported in patients on LUTRATE DEPOT 22.5 mg. Laboratory abnormalities During the treatment period, at least a one grade change in laboratory values was seen (>10%) in the following: anemia, increased triglyceride, hyperglycemia, increased cholesterol, increased creatine kinase, leukopenia, increased AST, increased creatinine, and increased ALT. 6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of gonadotropin releasing hormone agonists. 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. Pituitary apoplexy: During postmarketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. 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. Immune Disorders: Anaphylaxis Psychiatric Disorders: Depression Respiratory Disorders: Pneumonitis, Interstitial Lung Disease
adverse reactions
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. LUTRATE DEPOT 22.5 mg for 3-Month Administration In a clinical trial of LUTRATE DEPOT 22.5 mg for 3-month administration, patients were treated for 24 weeks with 157/163 receiving two injections. The table includes adverse reactions were reported in 5% or more of the patients during the treatment period as well as the incidence of these adverse reaction that were considered, by the treating physician, to be at least possibly related to Lutrate Depot. Grade 3-4 adverse reactions reported as treatment-emergent in 13% of patients and treatment-related 4% of patients. Table 2. Adverse Reactions Reported in ≥ 5% of Patients LUTRATE DEPOT 22.5 mg for 3-Month Administration N = 163 (%) Grade 1-4 Treatment-Emergent Treatment-Related Hot Flush/Flushing 1 128 (79) 127 (78) Upper Respiratory Infection 2 28 (17) 0 Fatigue/Asthenia 24 (15) 22 (13) Diarrhea 21 (13) 2 (1) Pollakiuria 20 (12) 3 (2) Arthralgia/Arthritis 18 (11) 2 (1) Injection Site Pain/Discomfort 18 (11) 15 (9) Constipation 15 (9) 1 (0.6) Extremity Pain 14 (9) 0 Nausea 14 (9) 4 (2) Nocturia 14 (9) 3 (2) Abdominal Pain/Discomfort 13 (8) 1 (0.6) Urinary Tract Pain 13 (8) 2 (1) Dizziness 12 (7) 2 (1) Headache/Sinus Headache 12 (7) 1 (0.6) Urinary Tract Infection 12 (7) 0 Bone Pain 11 (7) 4 (2) Back Pain 10 (6) 1 (0.6) Hypertension/Blood Pressure Increased 10 (6) 0 Pruritus/Generalized Pruritus 9 (6) 3 (2) CTCAE v.3 1 Includes cold sweat, flushing, hot flush, hyperhidrosis, and night sweats 2 Includes influenza, influenza-like illness, nasal congestion, nasopharyngitis, rhinorrhea, upper respiratory tract infection and congestion In the same study, erectile dysfunction and testicular atrophy were reported in patients on LUTRATE DEPOT 22.5 mg. Laboratory abnormalities During the treatment period, at least a one grade change in laboratory values was seen (>10%) in the following: anemia, increased triglyceride, hyperglycemia, increased cholesterol, increased creatine kinase, leukopenia, increased AST, increased creatinine, and increased ALT.