SymlinPen Uncovered: How It Works, Key Uses, and Must-Know Tips

Symlin (pramlintide acetate) is an injectable medication used in conjunction with insulin to help manage blood sugar levels in adults with type 1 and type 2 diabetes mellitus. It is particularly helpful for those who have not achieved their desired glucose control despite optimal insulin therapy. Pramlintide is a synthetic analog of human amylin, a naturally occurring hormone that is secreted by pancreatic beta cells along with insulin.

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.

How Symlin Works: The Mechanism of Action

Pramlintide, by acting as an amylinomimetic agent, has the following effects:

Modulation of Gastric Emptying: 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. The gastric-emptying rate is an important determinant of the postprandial rise in plasma glucose. Gastric emptying in patients with diabetes is often accelerated compared with healthy individuals. This may, at least in part, be due to deficient amylin secretion in response to meals. Since gastric emptying is the rate-limiting step for glucose entering the circulation, accelerated gastric emptying may exacerbate postprandial glucose excursions in patients with diabetes. This effect lasts for approximately 3 hours following SYMLIN administration.
Prevention of Postprandial Rise in Plasma Glucagon: In patients with diabetes, glucagon concentrations are abnormally elevated during the postprandial period, contributing to hyperglycemia. Pramlintide also suppresses the inappropriately elevated postprandial glucagon secretion that is often seen in patients with diabetes. Glucagon, secreted from pancreatic alpha cells, is a catabolic hormone that stimulates hepatic glucose production in the fasting state to protect against hypoglycemia. Normally, glucagon secretion is suppressed after meals. However, in patients with type 1 and type 2 diabetes, postprandial glucagon secretion is abnormally elevated. This inappropriate secretion of glucagon leads to excess hepatic glucose production and is an important contributor to postprandial hyperglycemia in patients with diabetes.
Satiety: SYMLIN administered prior to a meal has been shown to reduce total caloric intake.

By mimicking the actions of the naturally occurring hormone amylin, pramlintide complements insulin by regulating the appearance of glucose into the circulation after meals via three primary mechanisms of action: slowing gastric emptying, suppressing inappropriate post-meal glucagon secretion, and increasing satiety.

In simpler terms: Symlin works by:

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Slowing down how quickly food leaves your stomach, which helps prevent blood sugar spikes after eating.
Reducing the amount of sugar released by your liver after meals.
Helping you feel fuller, so you eat less.

Indications for Symlin

SYMLIN is indicated as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy in:

Type 1 diabetes
Type 2 diabetes, with or without a concurrent sulfonylurea agent and/or metformin.

Dosage and Administration

Initial Considerations

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.

General Guidelines

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. See the accompanying Patient Instructions for Use for instructions for using the SymlinPen® pen-injector.
Pramlintide is indicated for use in combination with insulin, however, per the manufacturer, they should be administered as separate injections. The site of injection should be distinct from the site of the insulin injection (i.e., at least 2 inches apart).
Double-check dosage prior to administration.
Rotate administration sites with each injection to prevent lipodystrophy.
Diabetes medication pens should never be shared among patients. Even if the disposable needle is changed, sharing may result in transmission of hepatitis viruses, HIV, or other blood-borne pathogens. Do not share pens among multiple patients in an inpatient setting; use multidose vials instead.
Patients should be advised not to transfer pramlintide from the pen-injector into a syringe. The concentration of the pramlintide solution in the pen-injector is 1,000 mcg/mL.

Dosage for 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. 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. Adjust insulin doses to optimize glycemic control once the target dose of SYMLIN is achieved and nausea (if experienced) has subsided. Adjust insulin doses to optimize glycemic control once the target dose of SYMLIN is achieved and nausea (if experienced) has subsided. Contact a healthcare professional in the event of recurrent nausea or hypoglycemia.

Dosage for 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. 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. Adjust insulin doses to optimize glycemic control once the target dose of SYMLIN is achieved and nausea (if experienced) has subsided.

Insulin Dose Adjustment

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.

SymlinPen Availability

The SymlinPen is available in 2 sizes.

The SymlinPen 60 should be used for doses of 15 mcg, 30 mcg, 45 mcg, and 60 mcg.
The SymlinPen 120 should be used for doses of 60 mcg and 120 mcg.

Instruct patients to buy needles separately; needles are not included with the pen-injector. Either 29, 30, or 31-gauge needles are recommended.

Preparation and Administration Instructions for Patients

To prepare a dose using the pen-injector:

If stored in the refrigerator, allow it to warm to room temperature before injecting.
If using the pen-injector for the first time, it should be primed before using. If the pen is dropped at any time, repeat the priming process to ensure that it works.
Prior to injecting each dose, make sure that you are using the correct pen strength.
Attach a needle to the pen-injector device.
Turn the dial until the correct dose appears in the window.
Pull out the knob as far as it will go; you should hear a clicking noise.

To inject a dose:

Select an injection site on the stomach or thigh, and clean with an alcohol wipe. Make sure the injection site for pramlintide is at least 2 inches away from the site for your insulin injection.
Pinch the skin up with your fingers about 3 inches apart, and insert the needle at an angle of 45 to 90 degrees.
Release the skin and press the knob for pen-injectors all the way down to deliver the dose.
When using the pen-injector, keep the needle in the skin for 10 seconds so that all of the pramlintide is injected.
Remove the needle from the skin and press gently on the injection site for a moment (but do not rub or massage).
Rotate your injection site so that each site is not used more than once every 1 to 2 months. Do not use injection sites that are thickened, red, or bumpy. Never inject pramlintide into a vein.
Remove the needle after each injection to help prevent leakage, keep out air bubbles, reduce needle clogs, and reduce the risk of infection.
Discard the used needles in an appropriate sharps container after injection.

Important Considerations and Precautions

Hypoglycemia Risk

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. 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. Clinical studies employing a controlled hypoglycemic challenge have demonstrated that SYMLIN does not alter the counter-regulatory hormonal response to insulin-induced hypoglycemia.

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Patient Selection

Careful patient selection is critical to successful pramlintide therapy. Pramlintide use is contraindicated in patients with hypoglycemia unawareness. Further, patients with recurrent severe hypoglycemia who have required assistance during the past 6 months should not receive pramlintide.

Monitoring and Education

Monitor blood glucoses frequently, including pre- and post-meals and at bedtime, particularly when initiating SYMLIN or increasing the SYMLIN dose.
After the initial 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).
Discuss the risk and consequences of hypoglycemia and approaches to minimize its occurrence.
Inform patients about the importance of self-management practices including glucose monitoring and timing of dosing.
Show patients how to administer SYMLIN using the pen-injector.
Instruct patients on the proper injection technique and proper storage of SYMLIN.

Contraindications

Allergies to Pramlintide or any of the ingredients in the specific product dispensed
Unawareness of Low Blood Sugar
Slowed Stomach Emptying

Potential Side Effects

Nausea and vomiting
Stomach pain
Headache
Loss of appetite
Injection site reactions (erythema, edema, or pruritus)
Hypoglycemia

Drug Interactions

SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. 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). 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.

Special Populations

Pregnancy: Available data from a small number of reports in the manufacturer’s safety database on SYMLIN use in pregnant women are not sufficient to determine a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes.
Geriatric Use: SYMLIN has been studied in patients ranging in age from 15 to 84 years of age, including 769 patients ≥65 to 75 years of age and 87 patients ≥75 years of age. No consistent differences in the efficacy and safety of SYMLIN have been observed in older patients, but greater sensitivity in some older individuals cannot be ruled out.

Storage

SYMLIN pen-injectors 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.
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.

Benefits of Pramlintide

Improved Glycemic Control: Pramlintide treatment also improved overall glycemic control as measured by A1C. Pramlintide significantly reduced A1C over 26 weeks with mean reductions of approximately 0.6% in patients with type 2 diabetes at the 120 μg dose (p<0.0001) and 0.4% in patients with type 1 diabetes at 30 μg to 60 μg doses (p<0.0001).
Weight Reduction: Improved glycemic control in pramlintide-treated patients is not accompanied by weight gain, and instead is associated with a sustained and significant reduction in body weight. Combined data from pramlintide clinical trials showed significant (p<0.0001) reductions in body weight at 26 weeks of approximately 1.5 kg in patients with type 2 diabetes and 1.2 kg in patients with type 1 diabetes compared with an average gain of 0.2 kg to 0.5 kg, respectively, in placebo-treated patients.

Pramlintide in the Management of Diabetes

In patients with diabetes, dysregulation of multiple glucoregulatory hormones results in chronic hyperglycemia and an array of associated microvascular and macrovascular complications. Optimization of glycemic control, both overall (glycosylated hemoglobin [A1C]) and in the postprandial period, may reduce the risk of long-term vascular complications. However, despite significant recent therapeutic advances, most patients with diabetes are unable to attain and/or maintain normal or near-normal glycemia with insulin therapy alone. Pramlintide, an analog of amylin, is the first in a new class of pharmaceutical agents and is indicated as an adjunct to mealtime insulin for the treatment of patients with type 1 and type 2 diabetes.

Diabetes results from the dysregulation of multiple glucoregulatory hormones that normally act to maintain glucose homeostasis. These hormonal imbalances lead to chronic hyperglycemia, which results in an array of microvascular complications including retinopathy, nephropathy, and neuropathy. The Diabetes Control and Complications Trial (DCCT 1993) and the UK Prospective Diabetes Study (UKPDS 1998) demonstrated that in patients with type 1 and type 2 diabetes, respectively, improved overall glycemic control, as measured by glycosylated hemoglobin (A1C), reduced the risk of development and progression of microvascular complications . Importantly, there does not appear to be a discernable glycemic threshold, indicating that any reduction in A1C conveys clinical benefits .

In addition to microvascular complications, patients with diabetes also have at least a 2- to 10-fold greater risk for cardiovascular disease than individuals without diabetes. Cardiovascular disease is the leading cause of morbidity and mortality in this patient population. Unfortunately, despite intensive insulin therapy, many insulin-treated patients are unable to achieve and maintain normal or near-normal glycemic control on a long-term basis. This is due to a number of limitations of exogenously administered insulin, including weight gain and difficulty controlling postprandial glucose excursions. Intensification of insulin therapy almost inevitably results in weight gain. This is not only a cosmetic deterrent to optimal therapy for many patients, but it has been associated with various components of the metabolic syndrome and increased cardiovascular risk.

A second important limitation of insulin therapy is its frequent inability to adequately control post-meal glucose excursions. Investigation of additional therapies to optimize glycemic control in patients with diabetes has led to the development of pramlintide, an agent that mimics the actions of the neuroendocrine hormone amylin. Amylin is co-secreted with insulin from pancreatic beta cells in response to nutrient intake. Insulin and amylin have complementary effects on glucose metabolism. During the postprandial period, insulin facilitates glucose disappearance from the circulation by stimulating peripheral glucose uptake. Amylin regulates glucose appearance into the circulation by three principal mechanisms: regulation of gastric emptying, suppression of postprandial glucagon secretion, and regulation of food intake. Both insulin and amylin are absent in patients with type 1 diabetes and deficient in later stages of type 2 diabetes.

Pramlintide, the active ingredient in SYMLIN® (pramlintide acetate) injection, is a soluble, non-aggregating, synthetic analog of amylin. It mimics the glucoregulatory effects of amylin, which collectively limit postprandial glucose excursions. Pramlintide is indicated for use as an adjunct to mealtime insulin in patients with type 1 and type 2 diabetes who are unable to achieve glycemic goals with insulin therapy alone.

Gastric emptying in patients with diabetes is often accelerated compared with healthy individuals. This may, at least in part, be due to deficient amylin secretion in response to meals. Since gastric emptying is the rate-limiting step for glucose entering the circulation, accelerated gastric emptying may exacerbate postprandial glucose excursions in patients with diabetes. Pramlintide slows gastric emptying, limiting the rate at which nutrients are delivered from the stomach to the small intestine and subsequently, the rate at which glucose enters the circulation following meals.

Pramlintide also suppresses the inappropriately elevated postprandial glucagon secretion that is often seen in patients with diabetes. Glucagon, secreted from pancreatic alpha cells, is a catabolic hormone that stimulates hepatic glucose production in the fasting state to protect against hypoglycemia. Normally, glucagon secretion is suppressed after meals. However, in patients with type 1 and type 2 diabetes, postprandial glucagon secretion is abnormally elevated. This inappropriate secretion of glucagon leads to excess hepatic glucose production and is an important contributor to postprandial hyperglycemia in patients with diabetes.

Finally, pramlintide affects satiety, which leads to a reduced caloric intake.

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