Exenatide - Uses, Dosage, Side Effects, Drug Warnings, and Precautions

Overview:

Exenatide is a GLP-1 (glucagon-like peptide-1) agonist approved since 2006 for treating type 2 diabetes mellitus (T2DM). It works by enhancing glucose-induced insulin release and lowering postprandial glucagon secretion. As a result, it increases insulin secretion and reduces blood glucose levels, particularly postprandially. It also decreases gastric emptying and promotes safety. In clinical practice, it lowers HbA1c (ranging from -0.4 percent to -1.3 percent), fasting, and postprandial blood glucose levels. It is the only antidiabetic drug that promotes weight loss (along with Liraglutide, a human GLP-1 analog) (ranging from -1.5 kg to -5.5 kg). It can be used alone or in combination with other drugs such as Metformin, Sulphonylureas, and Thiazolidinediones (TZD).

Indication of Exenatide:

Exenatide is indicated for:

• Type 2 Diabetes Mellitus: As an adjuvant therapy to diet and exercise to enhance glycemic control.

Dosage:

Dosage Form and Strength: This is available as a sterile solution for subcutaneous injection comprising 250 mcg/mL.

• 1.2 mL prefilled pen, five mcg per dose, 60 doses.

• 2.4 mL prefilled pen, ten mcg per dose, 60 doses.

Recommended Dose: Start with 5 mcg twice daily, 60 minutes before food at about six hours or more apart; Exenatide should not be taken after having meals. Depending on the clinical response to the drug after one month of therapy, the dose can be increased to 10 mcg twice daily. Starting with 5 mcg lowers the likelihood and severity of gastrointestinal side effects.

Site of Injection: Should be injected subcutaneously (SC) in the thigh, abdomen, or upper arm.

Contraindication: It is contraindicated in patients with a previous history of severe hypersensitivity reactions.

Warnings and Precautions:

• Acute Pancreatitis: Exenatide has been linked to fatal and non-fatal hemorrhagic or necrotizing acute pancreatitis. After starting Exenatide and increasing the dose, carefully monitor patients for signs and symptoms of pancreatitis (such as prolonged severe abdominal pain and back pain, which might be associated with vomiting). If pancreatitis is suspected, Exenatide should be stopped immediately, and proper management should begin. Exenatide should not be re-initiated if pancreatitis is confirmed. In patients with a history of pancreatitis, look for alternative diabetes treatments to Exenatide.

• Hypoglycemia: When Exenatide is combined with Sulfonylurea, the risk of hypoglycemia increases. As a result, patients taking Exenatide and Sulfonylurea may need to decrease the Sulfonylurea dose to minimize the chances of hypoglycemia. Exenatide may also elevate the risk of hypoglycemia when combined with other glucose-independent insulin secretagogues (for example- Meglitinides).

• Renal Impairment: Exenatide is not advised in patients with severe renal impairment (creatinine clearance of less than 30 mL/min) or end-stage renal disease. Single doses of Exenatide 5 micrograms are not tolerated in patients with end-stage renal disease undergoing dialysis due to gastrointestinal side effects. Exenatide may cause nausea, vomiting, and transient hypovolemia, impairing renal function.

• Gastrointestinal Disease: Exenatide is usually associated with gastrointestinal adverse reactions such as nausea, vomiting, and diarrhea. Hence, it is not recommended to use in patients with gastrointestinal diseases.

• Immune Reactions: Following treatment with Exenatide, few patients develop antibodies to the drug.

• Hypersensitivity: Few patients may develop serious hypersensitivity reactions (for example - anaphylaxis (severe allergic reaction) and angioedema (painless swelling in the whole part of the body).

• Macrovascular Outcomes: No clinical data show definitive proof of Exenatide or any other antidiabetic drug lowering the risk of macrovascular diseases.

For Patients:

What Is Type 2 Diabetes?

Type 2 diabetes is the most popular type of diabetes, which develops when the blood glucose levels are too high. Blood glucose is the primary energy source, derived mainly from consumed foods. Insulin, a hormone produced by the pancreas, aids in transporting glucose into cells for energy. In type 2 diabetes, the body fails to produce the required amount of insulin or does not use insulin effectively. Too much glucose remains in the blood without reaching the cells for energy requirements.

Who Is More Prone to Develop Type 2 Diabetes?

• Type 2 diabetes can affect any age, including childhood, and is more common in middle-aged and older people with a family history of diabetes, overweight or obese.

• Lack of physical activity and certain health issues, such as high blood pressure, increase the risk of developing type 2 diabetes.

• If the patient has suffered from prediabetes or had gestational diabetes during pregnancy, they are more likely to develop type 2 diabetes.

What Is Exenatide and What Is It Used For?

• Exenatide is an injectable medication often used to improve blood sugar levels in adults with type 2 diabetes (non-insulin-dependent). It should be taken with other diabetic medications such as Metformin, Sulphonylureas, and Thiazolidinediones. It is a supplemental medication that can help control blood sugar levels along with the patient's regular diet and exercises, as suggested by the physician.

• When the patient has high blood sugar levels, this medication helps to produce more insulin to compensate for the body's needs.

What to Know Before Using Exenatide?

1. Do Not Take Exenatide: If the patient is allergic to Exenatide or any other ingredient in the drug.

2. Warnings and Precautions:

• This medication is not advised if the patient has slow stomach emptying or poor food digestion. The active ingredient in this medication slows stomach emptying, allowing food to pass more slowly through the stomach.

• If the patient had pancreatitis (pancreas inflammation), severe kidney disease, or was under dialysis.

Who Should Not Use Exenatide?

This medication should not be given to children or adolescents under 18 years and during pregnancy.

How to Use Exenatide?

• Take the drug precisely as instructed by the doctor. Exenatide is available in two strengths: Five micrograms and ten micrograms. The doctor may advise taking five micrograms twice daily. After 30 days of using Exenatide five micrograms twice daily, the doctor may increase the dose of Exenatide to ten micrograms twice daily.

• The dose is delivered with a single injection of the prefilled pen. This medicine should be injected one hour before the morning and evening meals below the skin (subcutaneously) into the upper leg (thigh), stomach area (abdomen), or upper arm. Two injections must be taken separately if the patient uses Exenatide and insulin.

• To adjust the dose, the patient must regularly test sugar levels. If the patient uses insulin, the doctor will teach how to reduce the insulin dose and advise monitoring the blood sugar more frequently to avoid hyperglycemia (high blood sugar) and diabetic ketoacidosis.

What if the Patient Misses a Dose?

If the patient misses a dose of this medication, skip it and take the injection at the next planned time of the day. Do not take an additional dose or increase the amount of the next dose to compensate for the missed dose.

What Are the Possible Side Effects?

The Possible Side Effects Include:

• Severe Allergic Reactions (Anaphylaxis):

• Swelling (angioedema) of the face, tongue, or throat.

• Rashes, itching, and rapid swelling of the neck, face, mouth, or throat tissues.

• Difficulties in swallowing.

• Hives and breathing difficulties.

• Pancreatitis is a serious, potentially fatal medical condition.

The Most Common Side Effects Are:

• Nausea.

• Vomiting.

• Diarrhea.

• Hypoglycemia (decrease in blood glucose levels).

• Dizziness.

• Headache.

• Feeling jittery.

• Constipation.

• Pain in the stomach area.

• Bloating.

• Indigestion.

• Itching (with or without rash).

• Flatulence (passing gas).

• Increased sweating.

• Loss of energy and strength.

• Heartburn.

• Reduced appetite and loss of weight.

Uncommon Side Effects Include:

• Decreased function of the kidney.

• Dehydration is generally associated with nausea, vomiting, and diarrhea.

• Unusual taste in the mouth.

• Burping.

• Injection site reactions (redness).

• Sleepiness.

• Loss of hair.

• Decreased weight.

• Stomach emptying is delayed.

• Inflamed gallbladder.

• Gallstones.

Rare Side Effects Include:

• Intestinal obstruction (blockage in the intestine).

In addition, the following side effects have been documented:

• Because of a low level of blood platelets, the patient may bleed or bruise more easily than usual.

• When combined with Warfarin, there have been reports of changes in the international normalized ratio (blood thinning measurement).

How to Store Exenatide?

• Keep this medication out of children's sight and reach.

• Refrigerate between 36 to 46 degrees Fahrenheit (2 to 8 degrees Celsius). Keep the pen below 25º Celsius for 30 days after it has been used. Do not refrigerate.

• Regardless of how much medicine remains in the pen, dispose of it after 30 days.

• Protect the pen from light, and replace the cap.

• If the patient notices particles in the solution or if it is cloudy or colored, do not use it.

• Do not keep the needle connected to the pen. If the needle is left in the pen, the medicine may leak, or air bubbles may occur in the cartridge.

For Doctors:

What Is Exenatide?

Exenatide is a synthetic peptide first discovered in the lizard Heloderma suspectum. Exenatide varies from Insulin, Sulfonylureas, Biguanides, Thiazolidinediones, Alpha-glucosidase inhibitors, Amylinomimetics, and Dipeptidyl peptidase-4 inhibitors in its chemical structure and pharmacological action. Exenatide is a peptide amide with 39 amino acids. Exenatide has a molecular weight of 4186.6 Daltons. Exenatide is made available as a sterile, preserved isotonic solution in a glass cartridge assembled in a pen injector for subcutaneous injection (pen). Two prefilled pens deliver unit doses of five micrograms or ten micrograms. Each prefilled pen contains 60 doses, sufficient for 30 days of treatment.

Each Milliliter (ML) Of the Exenatide Contains:

• 250 micrograms (mcg) of synthetic Exenatide.

• 2.2 milligrams Metacresol as an antimicrobial preservative.

• Mannitol as a tonicity-adjusting agent.

• Buffering solution of glacial acetic acid and sodium acetate trihydrate in water for injection at pH 4.5.

Clinical Pharmacology:

Incretins like glucagon-like peptide-1 (GLP-1) increase glucose-dependent insulin secretion and exert other antihyperglycemic effects after they are released from the gut into circulation. Exenatide is a GLP-1 receptor agonist that increases glucose-dependent insulin secretion by pancreatic beta cells, suppresses excessive glucagon secretion, and decreases gastric emptying.

Exenatide's amino acid sequence shares some similarities with that of human GLP-1. Exenatide has been documented to bind and activate the human GLP-1 receptor. This increases both glucose-dependent synthesis and insulin secretion from pancreatic beta cells through mechanisms involving cyclic AMP and other intracellular signaling pathways. Exenatide stimulates insulin release from pancreatic beta cells in high glucose levels.

Mechanism of Action:

• Glucose-Dependent Insulin Secretion: Exenatide immediately affects pancreatic beta-cell responsiveness to glucose, allowing insulin release in high glucose concentrations. As blood glucose concentrations fall and attain euglycemia, insulin secretion decreases. Exenatide seems not to affect the normal glucagon response to hypoglycemia.

• First-Phase Insulin Response: An early beta-cell defect seen in patients with type 2 diabetes is due to the loss of the first-phase insulin response. Exenatide at therapeutic plasma concentrations restored first-phase insulin response to an intravenous infusion of glucose bolus in type 2 diabetes patients.

• Glucagon Secretion: During hyperglycemia, Exenatide moderates glucagon secretion and reduces serum glucagon concentrations in patients with type 2 diabetes. Reduced glucagon concentrations result in lower hepatic glucose output and lower insulin demand.

• Gastric Emptying: Exenatide slows gastric emptying, lowering the rate at which glucose from meals enters the circulation.

• Food Intake: Exenatide administration has been shown to decrease food intake in animals and humans.

Pharmacodynamics: The brain's normal response to glucose is regulated when patients take Exenatide. In response to glucose, more insulin and less glucagon are released. Even in cases of hypoglycemia, a normal amount of glucagon is released. Exenatide also slows gastric emptying, resulting in a more prolonged glucose release into the systemic circulation. These effects work together to prevent hyperglycemia and hypoglycemia.

Pharmacokinetics:

• Absorption: Exenatide reaches a peak plasma concentration in 2.1 hours and has a bioavailability of one since it is administered subcutaneously.

• Distribution: The mean volume of distribution of Exenatide after a single subcutaneous administration is 28.3 Liters.

• Metabolism and Elimination: Exenatide is primarily eliminated by glomerular filtration, with subsequent proteolytic degradation, according to nonclinical studies. Exenatide's apparent clearance in humans is 9.1 L/h, and its half-life is 2.4 hours. The pharmacokinetic characteristics of Exenatide are dose-independent, and concentrations are detectable in most people for about ten hours after administration.

Specific Populations:

• Pregnancy: Exenatide causes cleft palate, irregular skeletal ossification, and increased neonatal deaths in animal studies. Hence, it should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

• Nursing Mothers: No data on whether it is excreted in human milk is available. However, Exenatide is observed in lactating mice milk at low concentrations (less than or equal to 2.5 percent of the concentration in maternal plasma following subcutaneous dosage). When administering Exenatide to a nursing woman, exercise caution.

• Renal Impairment: Exenatide is not advised to use in patients with renal diseases or severe renal dysfunction (creatinine clearance less than 30 mL/min) and should be administered cautiously in patients who have received a kidney transplant. Exenatide dosage does not need to be adjusted in patients with mild renal impairment.

• Hepatic Impairment: No pharmacokinetic analysis exists in patients with acute or chronic hepatic impairment because the kidney mainly clears Exenatide, hepatic dysfunction is not expected to influence Exenatide blood concentrations.

• Age: A population pharmacokinetic study of patients aged ranging from 22 to 73 years indicates that age does not affect the pharmacokinetic properties of Exenatide because elderly individuals are more likely to have reduced renal function, dose selection in the elderly should be done with caution.

• Gender: A population pharmacokinetic evaluation of male and female patients indicates that gender does not affect Exenatide distribution and elimination.

• Race: A population pharmacokinetic examination of samples from Caucasian, Hispanic, Asian, and Black patients indicates that race does not affect Exenatide pharmacokinetics.

• Body Mass Index: No effect on the pharmacokinetics of Exenatide.

What if an Exenatide Overdose Occurs?

Overdose results in severe nausea, vomiting, and rapidly declining blood glucose concentrations (severe hypoglycemia). In situations of an overdose, the doctor should start supportive treatment based on the patient's clinical signs and symptoms.