Drug Criteria & Outcomes

Exenatide (Byetta) Drug Evaluation

Part 1 of 2: Mechanism of action, Indications, Dosing and Administration, Special populations, Contraindications, Warnings/precautions, Potential for error, Adverse effects, Pregnancy/Lactation

By Steven Higginbotham, PharmD Candidate, Harrison School of Pharmacy
Auburn (AL) University

Injectable noninsulin antihyperglycemics

Exenatide (Byetta) — Amylin Pharmaceuticals & Eli Lilly;

• Pramlintide (Symlin) — Amylin Pharmaceuticals

Mechanism of action

Exenatide is an incretin mimetic that is similar to the glucagon-like peptide-1(GLP-1) in the body, and acts by binding to GLP-1 receptors. It improves glycemic control by increasing glucose-dependent insulin secretion, improving first-phase insulin response, decreasing glucagon secretion, slowing gastric emptying, and reducing food intake.

Pramlintide is a synthetic analogue of human amylin that is synthesized by pancreatic beta cells and contributes to postprandial glucose control. Pramlintide is co-secreted with insulin in response to food intake. Pramlintide acts as an amylinomimetic agent, and controls glucose levels by slowing gastric emptying, decreasing postprandial glucagon secretion, and causing satiety leading to decreased caloric intake and weight loss.

Indications

Exenatide — An adjunctive therapy in patients with Type 2 diabetes who cannot achieve glycemic control with metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea.

Pramlintide — An adjunctive therapy in Type 1 diabetics who have failed to achieve adequate glucose control with optimal insulin therapy. It is also used in Type 2 diabetics who use insulin and have failed to achieve adequate glucose control with or without concomitant use of a sulfonylurea and/or metformin.

Dosing and administration

• Exenatide should be initiated at 5 mcg twice daily and can be increased to 10 mcg twice daily after one month of therapy. The dose can be given anytime during the 60 minutes prior to breakfast or dinner. Do not administer after a meal. Each dose should be administered as a SQ injection into the thigh, upper arm, or abdomen. When added to sulfonylurea therapy, a dose reduction of the sulfonylurea may be considered to reduce chances of hypoglycemia. Dose reductions are typically unnecessary for metformin.

• Pramlintide should be given SQ in the abdomen or thigh, and the injection site should be rotated. Do not inject insulin concomitantly into the same site.

Pramlintide dosage differs depending on whether the patient has Type 2 or Type 1 diabetes.

In patients with Type 2 diabetes mellitus (DM):

• Initiate at 60 mcg SQ immediately prior to major meals.

• Reduce insulin doses by 50%.

• May increase the dose to 120 mcg in 3-7 days if no significant nausea has occurred.

• If nausea occurs, reduce dose to 60 mcg.

• Once the target pramlintide dose is reached (120 mcg), adjust insulin doses to achieve optimal glycemic control.

In patients with Type 1 DM:

• Initiate at 15 mcg SQ immediately prior to major meals (> 250 kcal or > 30 g of carbohydrate).

• Reduce insulin doses by 50%.

• May increase dose by increments of 15 mcg to a target dose of 30-60 mcg when no significant nausea has occurred in three days.

• If significant nausea occurs with the 45-60 mcg dose, decrease to 30 mcg.

• If the 30-mcg dose cannot be tolerated, discontinuation should be considered.

• Once the patient is stable on the target dose, adjust insulin levels for optimal therapy.

Dose adjustments

• Exenatide — No dose adjustments are necessary in mild-to-moderate renal impairment. However, exenatide is not recommended for use in severe renal failure patients. No adjustments are necessary in hepatic insufficiency.

• Pramlintide — No dose adjustments are necessary in renal and hepatic insufficient patients.

Special populations

No differences were noted for the dosage and effectiveness of exenatide and pramlintide based on age, race, gender, or body mass. Neither drug has been studied for use in the pediatric population.

Contraindications

Exenatide is contraindicated in patients with a known hypersensitivity to the drug or any of its components. Pramlintide is contraindicated in patients with a known hypersensitivity to the drug or any of its components including metacresol. Pramlintide also is contraindicated in patients with gastroparesis and hypoglycemia unawareness.

Warnings/precautions

Exenatide is not a substitute for insulin in insulin-dependent patients. This drug should not be used to treat patients with Type 1 diabetes or patients with diabetic ketoacidosis. Exenatide has not been evaluated for concurrent use with insulin, thiazolidinediones, D-phenylalanine derivatives, meglitinides, or a-glucosidase inhibitors. Patients with severe gastrointestinal disease should not use exenatide. This drug is not indicated for use as monotherapy. Patients using exenatide and a sulfonylurea concomitantly should be warned of the increased risk of hypoglycemia associated with this combination.

Pramlintide has a black box warning pertaining to hypoglycemia. This warning is associated with the increased risk of hypoglycemia in patients who use pramlintide and insulin, particularly those with Type 1 diabetes. Patients should be warned and educated about the signs of hypoglycemia. Patients with a history of noncompliance, HbA1c > 9%, recurrent severe hypoglycemia, gastroparesis, or who require the use of gastrointestinal motility stimulant should not use pramlintide.

The addition of other antihyperglycemics and drugs such as angiotensin-converting enzyme inhibitors (ACEIs), diisopyramide, fibrates, monoamine oxidase inhibitors (MAOIs), pentoxifylline, propoxyphene, salicylates, and sulfonamide antibiotics can increase the risk of hypoglycemia. Patients should be informed that pramlintide and insulin cannot be mixed and they must be administered at different sites. Pramlintide can delay the absorption of concomitantly administered oral drugs. Patients should be instructed to take any oral medications one hour before or two hours after the pramlintide injection. Pramlintide is not indicated for use as monotherapy.

Potential for medication error

• Exenatide — The drug is supplied in a pen delivery device and could potentially be mistaken for insulin or other injectable medications. Some potential look- and sound-alike drugs include Bextra, Biaxin, exemestane, exidine, eptifibatide, ezetimibe, ethosuximide, and ethionamide.

• Pramlintide — The drug is supplied in a vial that could potentially be confused with insulin or other injectable products. A small volume of the drug will need to be drawn out of the vial prior to injection so patients need to be skilled with syringes. Some potential look- and sound-alike drugs include Synvisc, Synalar, Similac, pralidoxime, and pramoxine.

Pregnancy and lactation

• Exenatide is pregnancy Category C. It has been shown to reduce fetal growth in mice but no studies have been conducted in humans. Exenatide only should be used in pregnant women if the benefit outweighs the risks. It is unknown if and to what extent exenatide is secreted in human milk. However, it should be assumed that exenatide will be present in the breast milk and proper precautions should be taken.

• Pramlintide is pregnancy Category C. Fetal abnormalities have been observed in rats, but similar studies in rabbits have shown that pramlintide has no effect on fetal growth. Pramlintide should only be used in pregnancy if the benefit outweighs the potential risk. It is unknown if and to what extent pramlintide is secreted in human milk. However, it should be assumed that pramlintide will be present in the breast milk and proper precautions should be taken.

Adverse effects

Exenatide — The most serious side effect of exenatide is the possibility of hypoglycemia. Exenatide alone does not cause hypoglycemia; it results from a combination of antihyperglycemic drugs. The incidence is particularly higher in patients who also use a sulfonylurea. The more common but less severe side effects were nausea, vomiting, diarrhea, feeling jittery, dizziness, headache, and dyspepsia. Nausea was the most frequently seen and was typically mild to moderate. Most of the adverse events were resolved with continued use of exenatide. Patents should be aware that a decrease in appetite and weight loss are expected, and do not warrant a dose reduction.

Pramlintide — As with exenatide, the most serious adverse effect of pramlintide use is hypoglycemia, which was observed more frequently in patients with Type 1 diabetes. Again, hypoglycemia is a result of a combination of drugs and is not due to the pramlintide alone. Most of the other adverse events involved the gastrointestinal system and typically improved as the pramlintide dose was gradually titrated to goal. Other adverse events include nausea, headache, anorexia, vomiting, abdominal pain, fatigue, dizziness, coughing, pharyngitis, allergic reaction, and arthralgia.

The adverse event profiles of exenatide and pramlintide are similar. They both are associated with hypoglycemia, but clinical trials seem to demonstrate more frequent episodes in patients taking pramlintide. The two drugs have similar gastrointestinal (GI) and central nervous system (CNS) side effects, with nausea being the most common. Clinical trials indicate that these GI and CNS side effects improve with continued use of either drug. No comparative studies have been conducted, so it is unknown which drug is better tolerated.

Drug interactions

• Exenatide is a peptide drug that is metabolized by enzymes outside of the liver so there are few direct drug interactions. One potential interaction would be due to additive effects from other antihyperglycemic agents, which could lead to hypoglycemia. Other drug interactions are related to the slowing action that exenatide has on gastric motility.

Some of the drugs that have been studied are digoxin, lovastatin, lisinopril, and acetaminophen. When used concomitantly, exenatide decreased the Cmax of digoxin by 17% and delayed the Tmax by approximately 2.5 hours, but did not change the overall AUC. Exenatide decreases the AUC and Cmax of lovastatin by 40% and 28%, respectively, and delayed the Tmax by about four hours but did not appear to consistently change lipid profiles. When given with lisinopril, the Tmax of lisinopril was delayed by two hours, but no effect on blood pressure was noted. Exenatide decreased the AUC and Cmax of acetaminophen, and increased the Tmax. The best way to manage these interactions is to give the oral drugs one hour prior or two hours after the exenatide injection.

• Pramlintide is a peptide drug that is metabolized by enzymes outside of the liver so there are few direct drug interactions. One potential interaction would be due to additive effects from other antihyperglycemic agents, which could lead to hypoglycemia. Other drug interactions are related to the slowing action that pramlintide has on gastric motility. Pramlintide should not be used in patients who take drugs that alter gastrointestinal motility such as metoclopramide and atropine. Patients who take drugs such as a-glucosidase inhibitors, which slow intestinal absorption, should also avoid pramlintide. Because pramlintide can decrease the rate and extent of absorption of some oral drugs, they should be administered one hour prior or two hours after the pramlintide injection.

Monitoring parameters

Patients receiving exenatide and pramlintide should have glucose and HbA1c levels checked regularly. Patients should be educated about the symptoms of hypoglycemia (blurred vision, confusion, sweating, cool pale skin, excessive hunger, and drowsiness) so that they can take the necessary precautions. Patients should also be evaluated to check for nausea and overall quality of life.

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