AMYLIN AGONISTS – Anti-hyperglycemic Synthetic Analogs

Mechanism of Action
SYMLIN, by acting as an amylinomimetic agent, has the following effects: 1) modulation of gastric emptying; 2) prevention of the postprandial rise in plasma glucagon; and 3) satiety leading to decreased caloric intake and potential weight loss.

Gastric Emptying:
The gastric-emptying rate is an important determinant of the postprandial rise in plasma glucose. SYMLIN slows the rate at which food is released from the stomach to the small intestine following a meal and, thus, it reduces the initial postprandial increase in plasma glucose. This effect lasts for approximately 3 hours following SYMLIN administration. SYMLIN does not alter the net absorption of ingested carbohydrate or other nutrients.

Postprandial Glucagon Secretion:
In patients with diabetes, glucagon concentrations are abnormally elevated during the postprandial period, contributing to hyperglycemia. SYMLIN has been shown to decrease postprandial glucagon concentrations in insulin-using patients with diabetes.

Satiety:
SYMLIN administered prior to a meal has been shown to reduce total caloric intake. This effect appears to be independent of the nausea that can accompany SYMLIN treatment

INDICATIONS AND USAGE
SYMLIN is given at mealtimes and is indicated for:

Type 1 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy.

Type 2 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy, with or without a concurrent sulfonylurea agent and/or metformin.

CONTRAINDICATIONS
SYMLIN is contraindicated in patients with any of the following:
-a known hypersensitivity to SYMLIN or any of its components, including metacresol;
-a confirmed diagnosis of gastroparesis;
-hypoglycemia unawareness.

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.

DOSAGE AND ADMINISTRATION:

SYMLIN dosage differs depending on whether the patient has type 2 or type 1 diabetes (see below). When initiating therapy with SYMLIN, initial insulin dose reduction is required in all patients (both type 2 and type 1) to reduce the risk of insulin-induced hypoglycemia. As this reduction in insulin can lead to glucose elevations, patients should be monitored at regular intervals to assess SYMLIN tolerability and the effect on blood glucose, so that individualized insulin adjustments can be initiated. If SYMLIN therapy is discontinued for any reason (e.g., surgery or illnesses), the same initiation protocol should be followed when SYMLIN therapy is re-instituted (see below). 
 
Initiation of SYMLIN therapy:

Patients With Insulin-Using Type 2 Diabetes

In patients with insulin-using type 2 diabetes, SYMLIN should be initiated at a dose of 60 mcg and increased to a dose of 120 mcg as tolerated.

Patients should be instructed to:

• Initiate SYMLIN at 60 mcg subcutaneously, immediately prior to major meals;
• Reduce preprandial, rapid-acting or short-acting insulin dosages, including fixed-mix insulins (70/30) by 50%;
• Monitor blood glucose frequently, including pre- and post-meals and at bedtime;
• Increase the SYMLIN dose to 120 mcg when no clinically significant nausea has occurred for 3-7 days. SYMLIN dose adjustments should be made only as directed by the healthcare professional. If significant nausea persists at the 120 mcg dose, the SYMLIN dose should be decreased to 60 mcg;
• Adjust insulin doses to optimize glycemic control once the target dose of SYMLIN is achieved and nausea (if experienced) has subsided. Insulin dose adjustments should be made only as directed by the healthcare professional;
• Contact a healthcare professional skilled in the use of insulin to review SYMLIN and insulin dose adjustments at least once a week until a target dose of SYMLIN is achieved, SYMLIN is well-tolerated, and blood glucose concentrations are stable.

Patients With Type 1 Diabetes

In patients with type 1 diabetes, SYMLIN should be initiated at a dose of 15 mcg and titrated at 15-mcg increments to a maintenance dose of 30 mcg or 60 mcg as tolerated.

Patients should be instructed to:

• Initiate SYMLIN at a starting dose of 15 mcg subcutaneously, immediately prior to major meals;
• Reduce preprandial, rapid-acting or short-acting insulin dosages, including fixed-mix insulins (e.g., 70/30) by 50%;
• Monitor blood glucose frequently, including pre- and post-meals and at bedtime;
• Increase the SYMLIN dose to the next increment (30 mcg, 45 mcg, or 60 mcg) when no clinically significant nausea has occurred for at least 3 days. SYMLIN dose adjustments should be made only as directed by the healthcare professional. 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;
• Adjust insulin doses to optimize glycemic control once the target dose of SYMLIN is achieved and nausea (if experienced) has subsided. Insulin dose adjustments should be made only as directed by the healthcare professional;
• Contact a healthcare professional skilled in the use of insulin to review SYMLIN and insulin dose adjustments at least once a week until a target dose of SYMLIN is achieved, SYMLIN is well-tolerated, and blood glucose concentrations are stable.

Once Target Dose of SYMLIN is Achieved in Type 2 or Type 1 Patient:

After a maintenance dose of SYMLIN is achieved, both insulin-using patients with type 2 diabetes and patients with type 1 diabetes should be instructed to:

• Adjust insulin doses to optimize glycemic control once the target dose of SYMLIN is achieved and nausea (if experienced) has subsided. Insulin dose adjustments should be made only as directed by a healthcare professional;
• Contact a healthcare professional in the event of recurrent nausea or hypoglycemia. An increased frequency of mild to moderate hypoglycemia should be viewed as a warning sign of increased risk for severe hypoglycemia.

 Administration:
SYMLIN should be administered subcutaneously immediately prior to each major meal (≥250 kcal or containing ≥30 g 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.

SymlinPen® pen-injector

The SymlinPen® pen-injector is available in two presentations:

• SymlinPen® 60 pen-injector for doses of 15 mcg, 30 mcg, 45 mcg, 60 mcg.
• SymlinPen® 120 pen-injector for doses of 60 mcg and 120 mcg.

See the accompanying Patient Instructions for Use for instructions for using the SymlinPen® pen-injector.

The patient should be advised:

• to confirm they are using the correct pen-injector that will deliver their prescribed dose;
• on proper use of the pen-injector, emphasizing how and when to set up a new pen-injector;
• not to transfer SYMLIN from the pen-injector to a syringe. Doing so could result in a higher dose than intended, because SYMLIN in the pen-injector is a higher concentration than SYMLIN in the SYMLIN vial;
• not to share the pen-injector and needles with others;
• that needles are not included with the pen-injector and must be purchased separately;
• which needle length and gauge should be used;
• to use a new needle for each injection.

SYMLIN vials

To administer SYMLIN from vials, use a U-100 insulin syringe (preferably a 0.3 mL [0.3 cc] size) for optimal accuracy. If using a syringe calibrated for use with U-100 insulin, use the chart below (Table 8) to measure the microgram dosage in unit increments.

Always use separate, new syringes and needles to give SYMLIN and insulin injections.

Discontinuation of Therapy:
SYMLIN therapy should be discontinued if any of the following occur:

• 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 professional contacts or recommended clinic visits.

Preparation and Handling
SYMLIN should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and the container permit.

HOW SUPPLIED:

SYMLIN is supplied as a sterile injection in the following dosage forms:

• 1.5 mL disposable multidose SymlinPen® 60 pen-injector containing 1000 mcg/mL pramlintide (as acetate).
• 2.7 mL disposable multidose SymlinPen® 120 pen-injector containing 1000 mcg/mL pramlintide (as acetate).
• 5 mL vial, containing 600 mcg/mL pramlintide (as acetate), for use with an insulin syringe.

To administer SYMLIN from vials, use a U-100 insulin syringe (preferably a 0.3 mL [0.3 cc] size). If using a syringe calibrated for use with U-100 insulin, use the chart (Table 8) in the DOSAGE AND ADMINISTRATION section to measure the microgram dosage in unit increments.

Do not mix SYMLIN with insulin.

SYSYMLIN Injection is available in the following package sizes:

• SymlinPen® 60 pen-injector, containing 1000 mcg/mL pramlintide (as acetate)
  2 X 1.5 mL disposable multidose pen-injector
  (NDC 66780-115-02)
• SymlinPen® 120 pen-injector, containing 1000 mcg/mL pramlintide (as acetate)
  2 X 2.7 mL disposable multidose pen-injector
  (NDC 66780-121-02)
• 5 mL vial, containing 600 mcg/mL pramlintide (as acetate), for use with an insulin syringe
  (NDC 66780-110-01)

STORAGE:
SYMLIN pen-injectors and vials not in use: Refrigerate (36°F to 46°F; 2°C to 8°C), 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 and vials 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.

The SymlinPen® pen-injectors and SYMLIN vials are manufactured for:
Amylin Pharmaceuticals, Inc.
San Diego, CA 92121 USA
1-800-349-8919
https://www.SYMLIN.com

Rx only

The SYMLIN mark, SYMLIN design mark, and SymlinPen are registered trademarks of Amylin Pharmaceuticals, Inc. Copyright © 2005-2008, Amylin Pharmaceuticals, Inc. All rights reserved.
Literature Revised July 2008