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.