WARNING: SEVERE HYPOGLYCEMIA SYMLIN use with insulin increases the risk of severe hypoglycemia, particularly in patients with type 1 diabetes. When severe hypoglycemia occurs, it is seen within 3 hours following a SYMLIN injection. Serious injuries may occur if severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities. Appropriate patient selection, careful patient instruction, and insulin dose reduction are critical elements for reducing this risk. WARNING: SEVERE HYPOGLYCEMIA See full prescribing information for complete boxed warning. • SYMLIN use with insulin has been associated with an increased risk of severe hypoglycemia, particularly in patients with type 1 diabetes. • Hypoglycemia risk may be reduced by appropriate patient selection, careful patient instruction, and insulin dose reduction (5.1 , 5.2) .
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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Severe hypoglycemia: Increased risk particularly for type 1 diabetes. Upon initiation of SYMLIN, reduce mealtime insulin dose by 50% and frequently monitor blood glucoses (5.2) . • Never share a SymlinPen between patients, even if the needle is changed (5.3) . • Do not mix SYMLIN and insulin: Mixing can alter the pharmacokinetics of both products. Administer as separate injections (5.4 , 7.1) . • Slows gastric emptying: Administer concomitant oral medications at least 1 hour before or 2 hours after SYMLIN if rapid onset or threshold concentration is critical (5.6 , 7.2) . 5.1 Patient Selection Proper patient selection is critical to the safe and effective use of SYMLIN. Before initiating SYMLIN, 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 type 1 diabetes or patients with type 2 diabetes using mealtime insulin 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 a 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. SYMLIN should be prescribed with caution to persons with visual or dexterity impairment. 5.2 Hypoglycemia SYMLIN alone does not cause hypoglycemia. However, SYMLIN is indicated to be coadministered with mealtime insulin therapy, and in this setting there is an increased risk of severe hypoglycemia, particularly in patients with type 1 diabetes. If severe hypoglycemia associated with SYMLIN occurs, it is usually seen within the first 2 to 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 or death may occur. Therefore, when introducing SYMLIN therapy, appropriate precautions need to be taken to avoid increasing the risk for severe hypoglycemia. These precautions include frequent monitoring of pre- and post-meal glucose combined with an initial 50% reduction in doses of mealtime insulin [see Dosage and Administration (2.1 , 2.2) ]. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes; diabetic neuropathy; use of medications such as beta-blockers, clonidine, guanethidine, or reserpine; or intensified glycemic control. The addition of any anti-diabetic medication, such as SYMLIN, to an existing regimen of one or more anti-diabetic medications (e.g., sulfonylurea), or other medications that can increase the risk of hypoglycemia may necessitate further insulin dose adjustments and particularly close monitoring of blood glucose. 5.3 Never Share a SymlinPen Between Patients SymlinPen should never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. 5.4 Never Mix SYMLIN and Insulin Mixing SYMLIN and insulin can alter the pharmacokinetics of both products which may result in inadequate glucose control or hypoglycemia. Therefore, SYMLIN and insulin must always be administered as separate injections and should never be mixed [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. 5.5 Concomitantly Administered Oral Medications SYMLIN slows gastric emptying, which may delay the absorption of concomitantly administered oral medications. Administer the concomitant oral medication at least 1 hour prior to SYMLIN injection or 2 hours after SYMLIN injection if the rapid onset or threshold concentration of the concomitant medication is a critical determinant of its effectiveness (such as with analgesics, antibiotics, and oral contraceptives) [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ]. 5.6 Medications that Affect Gastrointestinal Motility SYMLIN slows gastric emptying. SYMLIN is not recommended for patients taking other medications that alter gastrointestinal motility [see Drug Interactions (7.3) ]. 5.7 Allergy Local Allergy Patients may experience erythema, edema, or pruritus at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than SYMLIN, such as irritants in a skin cleansing agent or improper injection technique.
6 ADVERSE REACTIONS 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. • Most common adverse reactions (incidence ≥5% and higher incidence than placebo): nausea, vomiting, anorexia, headache (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Adverse Reactions (Excluding Hypoglycemia) Adverse reactions (excluding hypoglycemia, which is discussed separately below) commonly associated with SYMLIN when coadministered with a fixed dose of insulin in the 26- to 52-week, placebo-controlled trials in patients with type 1 diabetes and patients with type 2 diabetes on mealtime insulin are presented in Table 1 and Table 2, respectively. Table 1: Patients with Type 1 Diabetes: Common Adverse Reactions (Incidence ≥5% and Greater Incidence with SYMLIN Compared to Placebo) in 3 Pooled Placebo-Controlled Trials Long-Term, Placebo-Controlled Studies SYMLIN 30 or 60 mcg 3 Times Daily + Insulin Placebo + Insulin (N=716) % (N=538) % Nausea 48 17 Anorexia 17 2 Inflicted Injury Examples of inflicted injury included among others, abrasions, bruises, burns, fractures, lacerations, and muscle strains. 14 10 Vomiting 11 7 Arthralgia 7 5 Fatigue 7 4 Allergic Reaction 6 5 Dizziness 5 4 Table 2: Patients with Type 2 Diabetes on Insulin: Common Adverse Reactions (Incidence ≥5% and Greater Incidence with SYMLIN Compared to Placebo) in 2 Pooled Placebo-Controlled Trials Long-Term, Placebo-Controlled Studies SYMLIN 120 mcg 2 Times Daily + Insulin Placebo + Insulin (N=292) % (N=284) % Nausea 28 12 Headache 13 7 Anorexia 9 2 Vomiting 8 4 Abdominal pain 8 7 Fatigue 7 4 Dizziness 6 4 Cough 6 4 Pharyngitis 5 2 Most adverse reactions were gastrointestinal in nature. The incidence of nausea is higher at the beginning of SYMLIN treatment and decreases with time in most patients. Gradual titration of the SYMLIN dose minimizes the incidence and severity of nausea [see Dosage and Administration (2) ]. Severe Hypoglycemia Coadministration of SYMLIN with mealtime insulin increases the risk of severe hypoglycemia, particularly in patients with type 1 diabetes [see Boxed Warning and Warnings and Precautions (5.1) ]. Two definitions of severe hypoglycemia were used in the SYMLIN clinical trials. Patient-ascertained severe hypoglycemia was defined as an episode of hypoglycemia requiring the assistance of another individual (including help administering oral carbohydrate) or requiring the administration of glucagon, intravenous glucose, or other medical intervention. Medically-assisted severe hypoglycemia was defined as an episode of hypoglycemia that was classified as a serious event by the investigator or that required glucagon, intravenous glucose, hospitalization, paramedic assistance or an emergency room visit. The incidence of severe hypoglycemia during the SYMLIN clinical development program is summarized in Table 3 and Table 4. Table 3: Incidence and Event Rate of Severe Hypoglycemia in Six-Month, Placebo-Controlled Trials and Dose Titration Trial in Patients with Type 1 Diabetes Long-Term, Placebo-Controlled Studies (No Insulin Dose-Reduction During Initiation) Placebo-Controlled Dose Titration Study SYMLIN + Insulin Placebo + Insulin SYMLIN + Insulin Placebo + Insulin Severe Hypoglycemia 0 to 3 Months (n=716) >3 to 6 Months (n=576) 0 to 3 Months (n=538) >3 to 6 Months (n=470) 0 to 3 Months (n=148) >3 to 6 Months (n=133) 0 to 3 Months (n=147) >3 to 6 Months (n=138) Patient-Ascertained Patient-ascertained severe hypoglycemia: Requiring the assistance of another individual (including help ingesting oral carbohydrate) and/or requiring the administration of glucagon injection, intravenous glucose, or other medical intervention. Event Rate (events/patient-year) 1.55 0.82 1.33 1.06 0.69 0.49 0.28 0.3 Subject Incidence (%) 16.8 11.1 10.8 8.7 13.5 10.5 6.1 5.8 Medically-Assisted Medically-assisted severe hypoglycemia: Requiring glucagon, intravenous glucose, hospitalization, paramedic assistance, emergency room visit, and/or assessed as a serious adverse event by the investigator. Event Rate (events/patient-year) 0.50 0.27 0.19 0.24 0.14 0.20 0.08 0.15 Subject Incidence (%) 7.3 5.2 3.3 4.3 3.4 4.5 2.0 2.9 Table 4: Incidence and Event Rate of Severe Hypoglycemia in Six-Month, Placebo-Controlled Trials in Patients with Type 2 Diabetes Using Insulin Long-Term, Placebo-Controlled Studies (No Insulin Dose-Reduction During Initiation) SYMLIN + Insulin Placebo + Insulin Severe Hypoglycemia 0 to 3 Months (n=292) >3 to 6 Months (n=255) 0 to 3 Months (n=284) >3 to 6 Months (n=251) Patient-Ascertained Patient-ascertained severe hypoglycemia: Requiring the assistance of another individual (including help ingesting oral carbohydrate) and/or requiring the administration of glucagon injection, intravenous glucose, or other medical intervention. Event Rate (events/patient-year) 0.45 0.39 0.24 0.13 Subject Incidence (%) 8.2 4.7 2.1 2.4 Medically-Assisted Medically-assisted severe hypoglycemia: Requiring glucagon, intravenous glucose, hospitalization, paramedic assistance, emergency room visit, and/or assessed as a serious adverse event by the investigator. Event Rate (events/patient-year) 0.09 0.02 0.06 0.07 Subject Incidence (%) 1.7 0.4 0.7 1.2 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SYMLIN. 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. • Injection site reactions • Pancreatitis