warnings and cautions
5 WARNINGS AND PRECAUTIONS Hyperglycemia, Diabetes, and Ketoacidosis: Sometimes severe. Monitor glucose levels as clinically appropriate during therapy. Monitor glucose levels more frequently in the months that follow initiation or discontinuation of SIGNIFOR LAR therapy and following SIGNIFOR LAR dose adjustment. Use anti-diabetic treatment if indicated.If ketoacidosis is suspected, discontinue SIGNIFOR LAR and promptly evaluate and treat the patient. ( 2.1 , 5.1 ) Bradycardia and QT Prolongation: Use with caution in at-risk patients; evaluate ECG and electrolytes prior to dosing and periodically while on treatment. ( 2.1 , 5.2 , 7.1 ) Liver Test Elevations: Evaluate liver enzyme tests prior to and during treatment. ( 2.1 , 5.3 ) Cholelithiasis and Complications of Cholelithiasis: Monitor periodically. Discontinue if complications of cholelithiasis are suspected. ( 5.4 ) Pituitary Hormone Deficiency(ies): Monitor for occurrence periodically and treat if clinically indicated. ( 5.5 ) Steatorrhea and Malabsorption of Dietary Fats : New onset steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss may occur. If new occurrence or worsening of these symptoms are reported, evaluate for potential pancreatic exocrine insufficiency ( 5.6 ) 5.1 Hyperglycemia, Diabetes, and Ketoacidosis SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. There have been postmarketing cases of ketoacidosis with SIGNIFOR LAR in patients with history of diabetes and in patients without history of diabetes. In the acromegalic patient study, 5 patients naïve to drug therapy treated with SIGNIFOR LAR (2 of whom were normoglycemic at baseline) and none in the active comparator group were hospitalized for hyperglycemia (blood glucose range 359-506 mg/dL). Two additional patients who had received active comparator in the main trial and were switched to SIGNIFOR LAR in the extension trial, were hospitalized for elevated glucose levels while on SIGNIFOR LAR; one of those patients developed diabetic ketoacidosis. In the Cushing's disease study, 2 patients were hospitalized for elevated blood glucose. In clinical studies for acromegaly and Cushing's disease, SIGNIFOR LAR caused an increase in the incidence of diabetes and prediabetes. A majority of patients, including those with normal glucose tolerance, prediabetes and diabetes, experienced increased glucose levels within the first 3 months of treatment [see Adverse Reactions (6.1) ]. In the drug-naïve acromegaly study, the prevalence of diabetes increased from 30% at baseline to 60% at Month 12. In the study evaluating acromegaly patients previously treated with somatostatin analogs, the prevalence of diabetes increased from 71% at baseline to 87% at Month 6 in patients treated with SIGNIFOR LAR 40 mg, and from 60% to 84% in patients treated with SIGNIFOR LAR 60 mg. In the Cushing's disease study, the prevalence of diabetes increased from 40% at baseline to 56% at Month 12. Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia. Assess FPG and HbA1c prior to starting treatment with SIGNIFOR LAR [see Dosage and Administration (2.1)] . In patients with poorly controlled diabetes mellitus, optimize anti-diabetic treatment before SIGNIFOR LAR initiation. Monitor blood glucose weekly for the first 3 months after initiating SIGNIFOR LAR and the first 4- to 6 weeks after dose increases. Continue monitoring thereafter, as clinically appropriate. Patients who develop significant hyperglycemia on SIGNIFOR LAR may require initiation of anti-diabetic treatment or adjustment in their current anti-diabetic treatment. The optimal treatment for the management of SIGNIFOR LAR-induced hyperglycemia is not known. If hyperglycemia cannot be controlled despite medical management, reduce the dose of SIGNIFOR LAR or discontinue SIGNIFOR LAR. Assess FPG and HbA1c after SIGNIFOR LAR discontinuation, if indicated. Patients receiving anti-diabetic treatment may require more frequent blood glucose monitoring and dose adjustment to their anti-diabetic drug therapy to mitigate the risk of hypoglycemia after discontinuing SIGNIFOR LAR. Patients who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of diabetes history. In some reported post-marketing cases of ketoacidosis in patients taking SIGNIFOR LAR, factors predisposing to ketoacidosis such as acute illness, infection, pancreatic disorders (e.g., pancreatic malignancy or pancreatic surgery), and alcohol abuse were present. If ketoacidosis is suspected, discontinue SIGNIFOR LAR and promptly evaluate and treat the patient. 5.2 Bradycardia and QT Prolongation Bradycardia Bradycardia has been reported with the use of SIGNIFOR LAR [see Adverse Reactions (6.1)] . Patients with cardiac disease and/or risk factors for bradycardia, such as history of clinically significant bradycardia, high-grade heart block, or concomitant use of drugs associated with bradycardia, should be monitored. Adjustments in the dose of drugs known to slow the heart rate (e.g., beta-blockers, calcium channel blockers) and correction of electrolyte disturbances may be necessary when initiating or during the course of SIGNIFOR LAR treatment. QT Prolongation In cardiac electrophysiology studies (i.e., thorough QT studies) with pasireotide via subcutaneous route, QT prolongation occurred at therapeutic and supra-therapeutic doses [see Clinical Pharmacology (12.2)] . In the clinical studies, a corrected QT interval (i.e., QTcF) of greater than 480 ms was reported in 6 patients and an increase in the QTcF from baseline of greater than 60 ms was reported for seven patients on SIGNIFOR LAR. No patient on SIGNIFOR LAR had a QTcF value of greater than 500 ms [see Adverse Reactions (6.1) , Clinical Pharmacology (12.2) ] . SIGNIFOR LAR should be used with caution in patients who are at significant risk of developing prolongation of the QT interval, such as those listed below: with congenital long QT prolongation with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia on anti-arrhythmic therapy or other substances that are known to lead to QT prolongation with hypokalemia and/or hypomagnesemia A baseline ECG is recommended prior to initiating therapy with SIGNIFOR LAR. Monitoring for an effect on the QT interval at the time of maximum drug concentration (21 days after injection) should be obtained in patients at risk. Hypokalemia or hypomagnesemia must be corrected prior to initiating SIGNIFOR LAR and should be monitored periodically during therapy. 5.3 Liver Test Elevations Increases in liver enzymes have been observed with SIGNIFOR LAR. In all Phase 3 acromegaly studies and across all doses, alanine aminostransferase (ALT) or aspartate aminotransferase (AST) elevations greater than 3 times the upper limit of normal (ULN) were observed in 4% of acromegaly patients and ALT or AST elevations greater than 5 times the ULN were observed in 1% of acromegaly patients treated with SIGNIFOR LAR. In the Phase 3 Cushing's disease study and across all doses, ALT or AST elevations greater than 3 times the ULN were observed in 14% of Cushing's disease patients and ALT or AST elevations greater than 5 times the ULN were observed in 5% of Cushing's disease patients treated with SIGNIFOR LAR. Assessment of liver function is recommended prior to treatment with SIGNIFOR LAR , and after the first 2- to 3 weeks, then monthly for 3 months. Thereafter, liver function should be monitored as clinically indicated. Patients who develop increased transaminase levels, should be monitored until values return to pre-treatment levels. Treatment with SIGNIFOR LAR should be discontinued if signs or symptoms suggestive of clinically significant liver impairment develop. Following discontinuation of treatment with SIGNIFOR LAR, patients should be monitored until resolution. Treatment should not be restarted, if the liver function abnormalities are suspected to be related to SIGNIFOR LAR. 5.4 Cholelithiasis and Complications of Cholelithiasis Cholelithiasis was reported in 33% of drug-naïve and 10% of inadequately controlled (40 mg dose) acromegaly patients treated with SIGNIFOR LAR in clinical trials [see Adverse Reactions (6)] . Cholelithiasis was reported in 33% of Cushing's disease patients treated with SIGNIFOR LAR. There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications, including cholecystitis or cholangitis and requiring cholecystectomy in patients taking SIGNIFOR LAR. Patients should be monitored periodically. If complications of cholelithiasis are suspected, discontinue SIGNIFOR LAR and treat appropriately. 5.5 Pituitary Hormone Deficiency(ies) Suppression of anterior pituitary hormones may occur on SIGNIFOR LAR. Monitoring pituitary function (e.g., thyroid, adrenal, gonadal) prior to initiation of therapy with SIGNIFOR LAR, as well as periodically during treatment, as clinically appropriate, is recommended. Patients should be monitored for and instructed on the signs and symptoms of adrenal insufficiency during therapy. If adrenal insufficiency is suspected, it should be confirmed and treated per standard of care with exogenous glucocorticoids at replacement doses . 5.6 Steatorrhea and Malabsorption of Dietary Fats New onset steatorrhea, stool discoloration and loose stools have been reported in patients receiving somatostatin analogs, including pasireotide products. Somatostatin analogs reversibly inhibit secretion of pancreatic enzymes and bile acids, which may result in malabsorption of dietary fats and subsequent symptoms of steatorrhea, loose stools, abdominal bloating, and weight loss. If new occurrence or worsening of these symptoms are reported in patients receiving SIGNIFOR LAR, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly.