Dulaglutide

Uses

Dulaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used:

• As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
• To reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors.

Dulaglutide is also used to associated treatment for these conditions: Cardiovascular Events, Type 2 Diabetes Mellitus

How Dulaglutide works

Dulaglutide activates the GLP-1 receptor found in pancreatic beta cells, increasing intracellular cyclic AMP (cAMP) in beta cells, leading to insulin release and subsequent reduction of blood glucose concentrations. Additionally, dulaglutide decreases glucagon secretion and slows gastric emptying.

Dosage

Dulaglutide dosage

The recommended initiating dose of Dulaglutide is 0.75 mg once weekly. The dose may be increased to 1.5 mg once weekly for additional glycemic control. The maximum recommended dose is 1.5 mg once weekly. Administer Dulaglutide once weekly, any time of day, with or without food. Dulaglutide should be injected subcutaneously in the abdomen, thigh, or upper arm.

If a dose is missed, instruct patients to administer as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose. If less than 3 days remain before the next scheduled dose, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule. The day of weekly administration can be changed if necessary as long as the last dose was administered 3 or more days before.

Side Effects

The most common adverse reactions, reported in ≥5% of patients treated with Dulaglutide are: nausea, diarrhea, vomiting, abdominal pain, and decreased appetite

Toxicity

LD50 information for dulaglutide is not readily available in the literature. Cases of overdose with dulaglutide have resulted in gastrointestinal disturbance. Appropriate supportive treatment is recommended to manage signs and symptoms. Additionally, hypoglycemia has been observed after an overdose with dulaglutide; frequent plasma glucose monitoring should be performed.

Precaution

Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed. Consider other antidiabetic therapies in patients with history of pancreatitis.
Hypoglycemia: When Dulaglutide is used with an insulin secretagogue (e.g., a sulfonylurea) or insulin, consider lowering the dose of the sulfonylurea or insulin to reduce the risk of hypoglycemia.
Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) have occurred. Discontinue Dulaglutide and promptly seek medical advice.
Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions.
Severe Gastrointestinal Disease: Use may be associated with gastrointestinal adverse reactions, sometimes severe. Has not been studied in patients with severe gastrointestinal disease and is not recommended in these patients.
Diabetic Retinopathy Complications: Have been reported in a cardiovascular outcomes trial. Monitor patients with a history of diabetic retinopathy.

Interaction

Dulaglutide slows gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with Dulaglutide. Drug levels of oral medications with a narrow therapeutic index should be adequately monitored when concomitantly administered with Dulaglutide. In clinical pharmacology studies, Dulaglutide did not affect the absorption of the tested, orally administered medications to a clinically relevant degree.

Food Interaction

• Take with or without food.

[Moderate] MONITOR: Glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists delay gastric emptying, which may impact the absorption of concomitantly administered oral medications.

Mild to moderate decreases in plasma concentrations of coadministered drugs have been demonstrated in pharmacokinetic studies for some GLP-1 receptor agonists (e.g., exenatide, lixisenatide), but not others.

The impact of dual GLP-1 and GIP receptor agonist tirzepatide on gastric emptying was reported to be greatest after a single dose of 5 mg but diminished after subsequent doses.

According to the prescribing information, liraglutide did not affect the absorption of several orally administered drugs to any clinically significant extent, including acetaminophen, atorvastatin, digoxin, griseofulvin, lisinopril, and an oral contraceptive containing ethinyl estradiol-levonorgestrel.

Likewise, no clinically relevant effect on absorption was observed for concomitantly administered oral drugs studied with albiglutide (digoxin, ethinyl estradiol-norethindrone, simvastatin, warfarin), dulaglutide (acetaminophen, atorvastatin, digoxin, ethinyl estradiol-norelgestromin, lisinopril, metformin, metoprolol, sitagliptin, warfarin), or semaglutide (atorvastatin, digoxin, ethinyl estradiol-levonorgestrel, metformin, warfarin).

In addition, coadministration of acetaminophen after a first dose of tirzepatide 5 mg reduced the acetaminophen peak plasma concentration (Cmax) by 50% and delayed its median time to peak plasma concentration (Tmax) by 1 hour, but no significant impact on Cmax and Tmax was observed after coadministration at week 4, and the overall exposure of acetaminophen was unaffected.

Nevertheless, potential clinical impact on other oral medications cannot be ruled out, particularly those with a narrow therapeutic index or low bioavailability, those that depend on threshold concentrations for efficacy (e.g., antibiotics), and those that require rapid gastrointestinal absorption (e.g., hypnotics, analgesics).
br> MANAGEMENT: Pharmacologic response to concomitantly administered oral medications should be monitored more closely following the initiation or discontinuation of treatment with a GLP-1 receptor agonist or a dual GLP-1 and GIP receptor agonist.

Dulaglutide Alcohol interaction

[Moderate] GENERALLY AVOID:

Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes.

Hypoglycemia most frequently occurs during acute consumption of alcohol.

Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise.

The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia.

Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion.

By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia.

[Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes.

A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis.

Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan.

Alcohol should not be consumed on an empty stomach or following exercise.

Dulaglutide Drug Interaction

Moderate: fluticasone / vilanterol, insulin glargine, levothyroxineMinor: sitagliptinUnknown: aspirin, aspirin, aspirin, duloxetine, cholecalciferol, glucose, diltiazem, omega-3 polyunsaturated fatty acids, empagliflozin, metoprolol, metoprolol, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, cetirizine

Dulaglutide Disease Interaction

Major: gastroparesis, pancreatitis, thyroid carcinomaModerate: renal dysfunction

Volume of Distribution

The apparent volume of distribution of dulaglutide was 3.09 L in a pharmacokinetic study; the apparent population mean peripheral volume of distribution was approximately 6 L.

Elimination Route

Dulaglutide is slowly absorbed after subcutaneous injection. In a pharmacokinetic study of 20 healthy adults, Cmax occurred within 24-48 hours after dosing. The average absolute bioavailability of dulaglutide after subcutaneous injections of single 0.75 mg and 1.5 mg doses was 65% and 47%, respectively.

Half Life

In a pharmacokinetic study of 20 healthy adults, the average half-life of dulaglutide administered at various doses was approximately 3.75 days (89.9 hours). This extended half-life allows for once-weekly dosing. Prescribing information indicates a half-life of approximately 5 days.

Clearance

The apparent population mean clearance of dulaglutide was 0.142 L/h in a pharmacokinetic study.

Elimination Route

Elimination of dulaglutide is expected to occur through degradation to individual amino acids.

Pregnancy & Breastfeeding use

Dulaglutide should be used during pregnancy only if the potential benefit justifies the potential risk to fetus. There are no data on the presence of dulaglutide in human milk, the effects on the breastfed infant, or the effects on milk production. The presence of dulaglutide in milk of treated lactating animals was not determined. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Dulaglutide and any potential adverse effects on the breastfed infant from Dulaglutide or from the underlying maternal condition.

Contraindication

Dulaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2. Dulaglutide is contraindicated in patients with a prior serious hypersensitivity reaction to Dulaglutide or any of the product components.

Acute Overdose

Overdoses have been reported in clinical studies. Effects associated with these overdoses were primarily mild or moderate gastrointestinal events (e.g., nausea, vomiting) and non-severe hypoglycemia. In the event of overdose, appropriate supportive care (including frequent plasma glucose monitoring) should be initiated according to the patient’s clinical signs and symptoms.

Storage Condition

Store Dulaglutide in the refrigerator at 2°C to 8°C. Do not use Dulaglutide beyond the expiration date. If needed, each single-dose pen can be kept at room temperature, not to exceed 30°C for a total of 14 days. Do not freeze Dulaglutide.

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