SYMLINPEN

SYMLIN ® (pramlintide acetate) injection is an anti-diabetic medication for use in patients with diabetes treated with insulin. Pramlintide is a synthetic analog of human amylin, a naturally occurring neuroendocrine hormone synthesized by pancreatic beta cells that contributes to glucose control during the postprandial period. Pramlintide is provided as an acetate salt of the synthetic 37-amino acid polypeptide, which differs in amino acid sequence from human amylin by replacement with proline at positions 25 (alanine), 28 (serine), and 29 (serine). The structural formula of pramlintide acetate is shown below: Pramlintide acetate is a white powder that has a molecular formula of C 171 H 267 N 51 O 53 S 2 • × C 2 H 4 O 2 (3≤ × ≤8); the molecular weight is 3949.4. Pramlintide acetate is soluble in water. SYMLIN is formulated as a clear, isotonic, sterile solution for subcutaneous administration. The disposable multidose SymlinPen ® pen-injector contains 1000 mcg/mL of pramlintide (as acetate). The formulation contains 2.25 mg/mL of metacresol as a preservative, D-mannitol as a tonicity modifier, acetic acid, sodium acetate as pH modifiers, and water for injection. SYMLIN has a pH of approximately 4.0. Pramlintide Acetate Chemical Structure

SYMLIN is indicated as an adjunctive treatment in patients with type 1 or type 2 diabetes who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy. SYMLIN is an amylin analog indicated for patients with type 1 or type 2 diabetes who use mealtime insulin and have failed to achieve desired glycemic control despite optimal insulin therapy (1) .

• Upon initiation of SYMLIN, reduce mealtime insulin dose by 50%. Monitor glucoses frequently and individualize subsequent insulin dose adjustments (2.1) . • Type 1 Diabetes: Start at 15 mcg subcutaneously before major meals. Increase in 15 mcg increments to a maximum premeal dose of 30 or 60 mcg; if not tolerated, reduce to 30 mcg, as tolerated (2.2) . • Type 2 Diabetes: Start at 60 mcg subcutaneously before major meals then increase to 120 mcg before meals, as tolerated (2.2) . • Wait at least 3 days between dose titrations to minimize nausea (2.1) . 2.1 Important Considerations Pertaining to SYMLIN and Insulin Dose Adjustments SYMLIN dosage differs depending on whether the patient has type 1 or type 2 diabetes [see Dosage and Administration (2.2 , 2.3) ]. SYMLIN should be used only in patients who can fully understand and adhere to proper insulin adjustments and glucose monitoring. Insulin and SYMLIN dose adjustments should be made only as directed by a healthcare professional skilled in the use of insulin. When initiating SYMLIN, reduce mealtime insulin doses, including premixed insulins, by 50% to reduce the risk of hypoglycemia. To reduce the risk of nausea, wait at least 3 days before titrating SYMLIN to the next dose increment. Monitor blood glucoses frequently, including pre- and post-meals and at bedtime, particularly when initiating SYMLIN or increasing the SYMLIN dose. After the initial 50% reduction in mealtime insulin dose, individualize insulin dose adjustments based on glycemic control and tolerability (e.g., if nausea occurs it may affect the dose of insulin required). An increased frequency of mild-to-moderate hypoglycemia should be viewed as a warning sign of increased risk for severe hypoglycemia. If SYMLIN therapy is discontinued for any reason (e.g., surgery or illnesses), the same initiation protocol should be followed when SYMLIN therapy is reinstituted [see Dosage and Administration (2.2) ]. 2.2 Patients with Type 2 Diabetes Using Mealtime Insulin Reduce mealtime insulin doses (including premixed insulins) by 50%, then initiate SYMLIN at 60 mcg subcutaneously, injecting immediately prior to each major meal. Increase the SYMLIN dose from 60 to 120 mcg prior to each major meal when no clinically significant nausea has occurred for at least 3 days. If significant nausea persists at the 120 mcg dose, the SYMLIN dose should be decreased to 60 mcg. 2.3 Patients with Type 1 Diabetes Reduce mealtime insulin doses by 50%, then initiate SYMLIN at 15 mcg subcutaneously, injecting immediately prior to each major meal. Increase the SYMLIN dose to the next increment (30, 45, or 60 mcg) when no clinically significant nausea has occurred for at least 3 days. If significant nausea persists at the 45 or 60 mcg dose level, the SYMLIN dose should be decreased to 30 mcg. If the 30 mcg dose is not tolerated, discontinuation of SYMLIN therapy should be considered. 2.4 Administration SYMLIN should be administered subcutaneously immediately prior to each major meal (≥250 kcal or containing ≥30 grams of carbohydrate). SYMLIN should be at room temperature before injecting to reduce potential injection site reactions. Each SYMLIN dose should be administered subcutaneously into the abdomen or thigh. Administration into the arm is not recommended because of variable absorption. Injection sites should be rotated so that the same site is not used repeatedly. The injection site selected should also be distinct from the site chosen for any concomitant insulin injection. SYMLIN and insulin should always be administered as separate injections. SYMLIN should not be mixed with any type of insulin. If a SYMLIN dose is missed, wait until the next scheduled dose and administer the usual amount. 2.5 Discontinuation of Therapy SYMLIN therapy should be discontinued if there is: • recurrent unexplained hypoglycemia that requires medical assistance. • persistent clinically significant nausea. • noncompliance with self-monitoring of blood glucose concentrations. • noncompliance with insulin dose adjustments. • noncompliance with scheduled healthcare provider contacts or recommended clinic visits. 2.6 Preparation and Handling SYMLIN should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and the container permit.

SYMLIN is contraindicated in patients with any of the following: • serious hypersensitivity reaction to SYMLIN or to any of its product components. • hypoglycemia unawareness. • confirmed gastroparesis. • Prior serious hypersensitivity reaction to SYMLIN or its ingredients (4) • Hypoglycemia unawareness (4) • Confirmed gastroparesis (4)

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

7.1 Insulin The pharmacokinetic parameters of pramlintide are altered when SYMLIN is mixed in the same syringe with regular, NPH, and 70/30 premixed formulations of recombinant human insulin. SYMLIN and insulin must not be mixed and must be administered as separate injections [see Dosage and Administration (2.4) , Warnings and Precautions (5.4) , and Clinical Pharmacology (12.3) ]. 7.2 Oral Medications SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset or threshold concentration of a concomitant orally administered medication is a critical determinant of effectiveness (such as with analgesics, antibiotics, and oral contraceptives), the medication should be administered at least 1 hour prior to SYMLIN injection or 2 hours after SYMLIN injection [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3) ]. 7.3 Drugs Affecting Gastrointestinal Motility Due to its effects on gastric emptying, SYMLIN should not be considered for patients taking medications that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) or medications that slow the intestinal absorption of nutrients (e.g., alpha-glucosidase inhibitors). Patients using these medications have not been studied in SYMLIN clinical trials [see Warnings and Precautions (5.6) ]. 7.4 Drugs Affecting Glucose Metabolism The following are examples of medications that may increase the susceptibility to hypoglycemia when administered with SYMLIN: anti-diabetic products, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, salicylates, somatostatin analogs, and sulfonamide antibiotics. SYMLIN and these drugs should be coadministered with caution.

Storage and Handling SYMLIN pen-injectors not in use: Refrigerate (2°C to 8°C; 36°F to 46°F), and protect from light. Do not freeze. Do not use if product has been frozen. Unused SYMLIN (opened or unopened) should not be used after the expiration (EXP) date printed on the carton and the label. SYMLIN pen-injectors in use: After first use, refrigerate or keep at a temperature not greater than 86°F (30°C) for 30 days. Use within 30 days, whether or not refrigerated. Storage conditions are summarized in Table 9. Table 9: Storage Conditions Dosage Form Unopened (not in use) Refrigerated Open (in use) Refrigerated or Temperature up to 86°F (30°C) 1.5 mL pen-injector Until Expiration Date Use Within 30 Days 2.7 mL pen-injector