WARNING SYMLIN is used with insulin and has been associated with an increased risk of insulin-induced severe hypoglycemia, particularly in patients with type 1 diabetes. When severe hypoglycemia associated with SYMLIN use occurs, it is seen within 3 hours following a SYMLIN injection. If severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries may occur. Appropriate patient selection, careful patient instruction, and insulin dose adjustments are critical elements for reducing this risk.
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WARNINGS Patient Selection Proper patient selection is critical to safe and effective use of SYMLIN Before initiation of therapy, the patient's HbA1c, recent blood glucose monitoring data, history of insulin-induced hypoglycemia, current insulin regimen, and body weight should be reviewed. SYMLIN therapy should only be considered in patients with insulin-using type 2 or type 1 diabetes who fulfill the following criteria: have failed to achieve adequate glycemic control despite individualized insulin management; are receiving ongoing care under the guidance of a healthcare professional skilled in the use of insulin and supported by the services of diabetes educator(s). Patients meeting any of the following criteria should NOT be considered for SYMLIN therapy: poor compliance with current insulin regimen; poor compliance with prescribed self-blood glucose monitoring; have an HbA1c > 9%; recurrent severe hypoglycemia requiring assistance during the past 6 months; presence of hypoglycemia unawareness; confirmed diagnosis of gastroparesis; require the use of drugs that stimulate gastrointestinal motility; pediatric patients. Hypoglycemia SYMLIN alone does not cause hypoglycemia. However, SYMLIN is indicated to be co-administered with insulin therapy and in this setting SYMLIN increases the risk of insulin-induced severe hypoglycemia, particularly in patients with type 1 diabetes. Severe hypoglycemia associated with SYMLIN occurs within the first 3 hours following a SYMLIN injection. If severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries may occur. Therefore, when introducing SYMLIN therapy, appropriate precautions need to be taken to avoid increasing the risk for insulin-induced severe hypoglycemia. These precautions include frequent pre- and post-meal glucose monitoring combined with an initial 50% reduction in pre-meal doses of short-acting insulin (see DOSAGE and ADMINISTRATION ). Symptoms of hypoglycemia may include hunger, headache, sweating, tremor, irritability, or difficulty concentrating. Rapid reductions in blood glucose concentrations may induce such symptoms regardless of glucose values. More severe symptoms of hypoglycemia include loss of consciousness, coma, or seizure. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes; diabetic nerve disease; use of medications such as beta-blockers, clonidine, guanethidine, or reserpine; or intensified diabetes control. The addition of any antihyperglycemic agent such as SYMLIN to an existing regimen of one or more antihyperglycemic agents (e.g., insulin, sulfonylurea), or other agents that can increase the risk of hypoglycemia may necessitate further insulin dose adjustments and particularly close monitoring of blood glucose. The following are examples of substances that may increase the blood glucose-lowering effect and susceptibility to hypoglycemia: oral anti-diabetic products, ACE inhibitors, diisopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates, and sulfonamide antibiotics. Clinical studies employing a controlled hypoglycemic challenge have demonstrated that SYMLIN does not alter the counter-regulatory hormonal response to insulin-induced hypoglycemia. Likewise, in SYMLIN-treated patients, the perception of hypoglycemic symptoms was not altered with plasma glucose concentrations as low as 45 mg/dL.
ADVERSE REACTIONS Adverse events (excluding hypoglycemia, discussed below) commonly associated with SYMLIN when co-administered with a fixed dose of insulin in the long-term, placebo-controlled trials in insulin-using type 2 patients and type 1 patients are presented in Table 4 and Table 5, respectively. The same adverse events were also shown in the open-label clinical practice study, which employed flexible insulin dosing. Table 4: Treatment-Emergent Adverse Events Occurring With ≥5% Incidence and Greater Incidence With SYMLIN Compared With Placebo in Long-Term, Placebo-Controlled Trials. Incidence of the Same Events in the Open-Label Clinical Practice Study (Patients With Insulin-Using Type 2 Diabetes, 120 mcg) Long-Term, Placebo-Controlled Studies Open-Label, Clinical Practice Study Placebo + Insulin (n(%)) (N=284) SYMLIN + Insulin (n(%)) (N=292) SYMLIN + Insulin (n(%)) (N=166) Nausea 34 (12) 81 (28) 53 (30) Headache 19 (7) 39 (13) 8 (5) Anorexia 5 (2) 27 (9) 1 (<1) Vomiting 12 (4) 24 (8) 13 (7) Abdominal Pain 19 (7) 23 (8) 3 (2) Fatigue 11 (4) 20 (7) 5 (3) Dizziness 11 (4) 17 (6) 3 (2) Coughing 12 (4) 18 (6) 4 (2) Pharyngitis 7 (2) 15 (5) 6 (3) Table 5: Treatment-Emergent Adverse Events Occurring With ≥5% Incidence and Greater Incidence With SYMLIN Compared to Placebo in Long-Term, Placebo-Controlled Studies. Incidence of the Same Events in the Open-Label Clinical Practice Study (Patients With Type 1 Diabetes, 30 or 60 mcg) Long-Term, Placebo-Controlled Studies Open-Label, Clinical Practice Study Placebo + Insulin (n(%)) (N=538) SYMLIN + Insulin (n(%)) (N=716) SYMLIN + Insulin (n(%)) (N=265) Nausea 92 (17) 342 (48) 98 (37) Anorexia 12 (2) 122 (17) 0 (0) Inflicted Injury 55 (10) 97 (14) 20 (8) Vomiting 36 (7) 82 (11) 18 (7) Arthralgia 27 (5) 51 (7) 6 (2) Fatigue 22 (4) 51 (7) 12 (4.5) Allergic Reaction 28 (5) 41 (6) 1 (<1) Dizziness 21 (4) 34 (5) 5 (2) Most adverse events were gastrointestinal in nature. In patients with type 2 or type 1 diabetes, the incidence of nausea was higher at the beginning of SYMLIN treatment and decreased with time in most patients. The incidence and severity of nausea are reduced when SYMLIN is gradually titrated to the recommended doses (see DOSAGE and ADMINISTRATION ). Severe Hypoglycemia SYMLIN alone (without the concomitant administration of insulin) does not cause hypoglycemia. However, SYMLIN is indicated as an adjunct treatment in patients who use mealtime insulin therapy and co-administration of SYMLIN with insulin can increase the risk of insulin-induced hypoglycemia, particularly in patients with type 1 diabetes (see Boxed Warning ). The incidence of severe hypoglycemia during the SYMLIN clinical development program is summarized in Table 6 and Table 7. Table 6: Incidence and Event Rate of Severe Hypoglycemia in Long-Term, Placebo-Controlled and Open-Label, Clinical Practice Studies in Patients With Insulin-Using Type 2 Diabetes Long-Term, Placebo-Controlled Studies (No Insulin Dose-Reduction During Initiation) Open-Label, Clinical Practice Study (Insulin Dose-Reduction During Initiation) Placebo + Insulin SYMLIN + Insulin SYMLIN + Insulin Severe Hypoglycemia 0-3 Months (n=284) >3-6 Months (n=251) 0-3 Months (n=292) >3-6 Months (n=255) 0-3 Months (n=166) >3-6 Months (n=150) Patient-Ascertained Event Rate (event rate/patient year) 0.24 0.13 0.45 0.39 0.05 0.03 Incidence (%) 2.1 2.4 8.2 4.7 0.6 0.7 Medically Assisted Event Rate (event rate/patient year) 0.06 0.07 0.09 0.02 0.05 0.03 Incidence (%) 0.7 1.2 1.7 0.4 0.6 0.7 Table 7: Incidence and Event Rate of Severe Hypoglycemia in Long-Term, Placebo-Controlled and Open-Label, Clinical Practice Studies in Patients With Type 1 Diabetes Long-Term, Placebo-Controlled Studies (No Insulin Dose-Reduction During Initiation) Open-Label, Clinical Practice Study (Insulin Dose-Reduction During Initiation) Placebo + Insulin SYMLIN + Insulin SYMLIN + Insulin Severe Hypoglycemia 0-3 Months (n=538) >3-6 Months (n=470) 0-3 Months (n=716) >3-6 Months (n=576) 0-3 Months (n=265) >3-6 Months (n=213) Patient-Ascertained Event Rate (event rate/patient year) 1.33 1.06 1.55 0.82 0.29 0.16 Incidence (%) 10.8 8.7 16.8 11.1 5.7 3.8 Medically Assisted Event Rate (event rate/patient year) 0.19 0.24 0.50 0.27 0.10 0.04 Incidence (%) 3.3 4.3 7.3 5.2 2.3 0.9 Post Marketing Experience Since market introduction of SYMLIN, the following adverse reactions have been reported. Because these events 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. General: Injection site reactions.