Pramlintide acetate (Symlin) is a new antihyperglycemic drug that was approved by the Food and Drug Administration (FDA) for use in adult diabetic patients currently treated with insulin. 1 Amylin Pharmaceuticals developed the drug after 18 years of research into the pathophysiology and treatment of diabetes. The primary therapeutic effect of pramlintide is to improve postprandial glucose control in diabetics using insulin. The drug also induces patient satiety, leading to potential weight loss by reducing caloric intake.
Indications
Pramlintide was evaluated in clinical studies with both type 1 (N = 2,375) and type 2 (N = 1,688) diabetics. The drug is indicated for type 1 and type 2 diabetes in patients that are unable to achieve desired glucose control with optimal insulin therapy. 2 Pramlintide may be used in type 2 diabetic patients that are using insulin with or without concurrent metformin or sulfonylureas. This new medication is not indicated for non-insulin-using diabetics or in patients that are able to achieve and maintain adequate glucose control.
Mechanism of Action
Pramlintide mimics the effects of endogenous amylin. Amylin is secreted, along with insulin, by normal functioning pancreatic beta cells in response to food intake. The physiological effects of endogenous amylin and the administered pramlintide are similar. These include: 1) Slowed gastric emptying, resulting in reduced rate of glucose absorption. 2) Suppressed glucagon secretion, which reduces postprandial hepatic glucose output. 3) Modulated appetite, resulting in reduced food intake. 2
By slowing the rate of gastric emptying after a meal, pramlintide reduces the postprandial rise in plasma glucose for approximately 3 hours. This slowing of the gastric emptying time does not change the final amount of carbohydrate or other nutrient absorption. 2 In patients with damaged pancreatic beta cells, the amount of insulin and amylin secretions is reduced. 2
Drug Metabolism
Pramlintide is absorbed systemically after a subcutaneous injection in the thigh or abdomen. The body mass index or amount of adipose tissue in the patient does not appear to affect absorption or bioavailability. 2 Pramlintide is not extensively bound to blood cells or albumin, and the drug's distribution is minimally affected by the availability of binding sites. The drug is metabolized predominantly in the kidneys with a half-life of approximately 48 minutes. 2 Although metabolized in the kidney, renal function does not appear to have a significant affect on drug clearance. In clinical trials, patients with moderate or severe impairment of renal function did not appear to have reduced drug clearance or increased effects of pramlintide.
Contraindications
Pramlintide is contraindicated for patients with any sensitivity to the drug or its components. Specific contraindications are limited to those patients with confirmed gastroparesis. The drug is also contra-indicated for patients unable to self-monitor for hypoglycemic events.
Practitioner screening and selection of appropriate patients for therapy is necessary for maintaining the safe and effective use of pramlintide. Amylin Pharmaceuticals suggests patients with the following criteria are inappropriate for pramlintide therapy: 2
* poor compliance with current insulin regimens;
* poor compliance with prescribed self-blood glucose monitoring;
* hemoglobin A1c > 9%;
* recurrent severe hypoglycemia requiring assistance during the past 6 months;
* presence of hypoglycemia unawareness;
* confirmed diagnosis of gastroparesis;
* patients who require the use of drugs that stimulate gastrointestinal motility;
* pediatric patients.
Patients currently using a medication that alters gastrointestinal motility or slows intestinal absorption should not use pramlintide. Pramlintide may also delay the absorption of other medications taken at the same time. If rapid absorption of the oral medication is critical, it should be administered at least 1 hour before or 2 hours after the pramlintide injection. 2
Special population patients with renal insufficiency (ClCr > 20 to < 50 mL/min) did not have significant pharmacotherapeutic differences from patients with normal renal function during clinical studies. In addition, patients > 65 years of age (N = 539), of both genders (N = 2,799 males, N = 2,085 females), and of different races/ethnicity had no significant differences in the efficacy or adverse effects of pramlintide during the clinical trials. 2 The drug was not specifically studied in pediatric patients or those with hepatic insufficiency. However, Amylin Pharmaceuticals does expect to start clinical trials with pediatric patients in 2007. Pramlintide has not been studied in pregnant women, is listed as a Pregnancy Category C drug, and it is unknown whether it is excreted in human milk. Practitioners should carefully weigh the benefits of pramlintide use in pregnancy against the risks of potential harm to the fetus.
Pramlintide may delay the absorption of other medications taken at the same time.
Adverse Reactions
Nausea is the most common adverse event reported by patients using pramlintide, and dosing is initially adjusted by monitoring the level of nausea. Pramlintide-induced nausea generally decreases with time and when the dose is titrated gradually. Other reported adverse events in both type 1 and type 2 diabetic patients include anorexia, vomiting, fatigue, and dizziness.
The drug insert for pramlintide contains a black box warning related to its potential for severe hypoglycemic events; particularly in type 1 diabetics. In the first 3 months, hypoglycemic events (as ascertained by the patient) occurred in 16.8% and required medical assistance in 7.3% of type 1 diabetic patients enrolled in the clinical studies. 2 Patients unable to monitor for hypoglycemic episodes are unsuitable for pramlintide therapy.
Dosage and Administration
The dosing of pramlintide is different for type 1 and type 2 diabetes. For both types it is necessary to reduce the patient's insulin dose when starting therapy with pramlintide to avoid potential hypoglycemic events. When initiating pramlintide therapy, the preprandial, rapid-acting, or short-acting insulin dosages should be reduced by one-half. With a reduction of the insulin dose, a corresponding increase in blood sugar may occur and therefore, patients must be monitored carefully at regular intervals. Diabetic therapy with insulin and pramlintide must be individualized. Pramlintide dosing should be adjusted based on home glucose levels and side effects (primarily nausea). Pramlintide should be initiated at 15 mcg sub-Q and titrated at 15 mcg increments to a maintenance dose of 30 mcg to 60 mcg as tolerated. This drug is given just before the meal.
For insulin-using type 2 diabetics, pramlintide should be started at a dose of 60 mcg sub-Q just prior to each meal and increased to a dose of 120 mcg when the patient has no nausea for 3 to 7 days. 2 For patients with type 1 diabetes, the initial dose of pramlintide is 15 mcg sub-Q just prior to each meal, and is titrated in 15-mcg increments when there is no nausea for 3 days to a maintenance dose of 30 mcg or 60 mcg as tolerated. 2 Once the target dose of pramlintide has been achieved, and the nausea has subsided or is controlled, insulin doses may then be readjusted to achieve optimal glycemic control. It is important to inform the patient that insulin dose adjustments should be made only by a healthcare professional. Detailed dosing guidelines are available in the drug insert.
Pramlintide is administered subcutaneously in the abdomen or thigh before a large meal. It should not be given in the arm. The injection sites should be rotated and distinct from the insulin injection site. A U-100 insulin syringe (preferably 0.3 mL size) is used for measuring and administering the pramlintide dose (see Table: "Pramlintide Doses"). 2
Special Instructions
When initiating pramlintide therapy, the drug manufacturer recommends practitioners give patients the following important administration guidelines: 2
* Pramlintide and insulin should always be administered as separate injections.
* Pramlintide should not be mixed with any type of insulin.
* If a pramlintide dose is missed, do not give an additional injection.
* Always use a new syringe and needle to give pramlintide and insulin injections.
Pramlintide is supplied in 5 mL vials that contain 0.6 mg/mL. Unopened vials should be kept refrigerated and protected from light. Opened vials may be kept at room temperature (< 77[degrees]F) or refrigerated but must be used or discarded within 28 days.
Discontinuation of pramlintide therapy should be considered if the patient experiences recurrent hypoglycemic episodes or clinically significant nausea. In addition, if the patient is noncompliant with self-monitoring blood glucose, insulin dose adjustments, or scheduled follow-up visits, the practitioner should stop pramlintide drug therapy. 2
As with most diabetic patients, those using pramlintide should be carefully monitored with frequent follow-up visits to the practitioner's clinic. It is important to review and verify that the patient understands the correct administration technique. Patients should not only receive verbal instructions, but should be given a medication guide for review at home. Amylin Pharmaceuticals provides 24-hour customer service at 1-800-349-8919 and further drug information is available at http://www.Symlin.com.
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