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Lixisenatide

Class: Incretin Mimetics
Brands: Adlyxin

Introduction

Lixisenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist (incretin mimetic), is an antidiabetic agent.

Uses for Lixisenatide

Lixisenatide has the following uses:

Lixisenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.1

Lixisenatide has the following limitations of use:

Has not been studied in patients with chronic pancreatitis or a history of unexplained pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.1

Not for treatment of type 1 diabetes or diabetic ketoacidosis.1

Has not been studied in combination with short acting insulin.1

Has not been studied in patients with gastroparesis and is not recommended in patients with gastroparesis.1

Lixisenatide Dosage and Administration

General

Lixisenatide is available in the following dosage form(s) and strength(s):

  • Injection: 50 mcg/mL in 3 mL in green prefilled pen (for 14 pre-set doses; 10 mcg per dose).1

  • Injection: 100 mcg/mL in 3 mL in burgundy prefilled pen (for 14 pre-set doses; 20 mcg per dose).1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Initiate at 10 mcg once daily for 14 days. On day 15, increase dosage to 20 mcg once daily. 1

  • Administer once daily within one hour before the first meal of the day. 1

  • Inject subcutaneously in the abdomen, thigh or upper arm.1

Cautions for Lixisenatide

Contraindications

Hypersensitivity to lixisenatide or any product components. Hypersensitivity reactions including anaphylaxis have occurred with lixisenatide. 1

Warnings/Precautions

Anaphylaxis and Serious Hypersensitivity Reactions

In clinical trials of lixisenatide, there have been cases of anaphylaxis determined to be related to lixisenatide (frequency of 0.1% or 10 cases per 10,000 patient-years). Other serious hypersensitivity reactions including angioedema also occurred.1

Inform and closely monitor patients with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist for allergic reactions, because it is unknown whether such patients will be predisposed to anaphylaxis with lixisenatide. Lixisenatide is contraindicated in patients with known hypersensitivity to lixisenatide. If a hypersensitivity reaction occurs, the patient should discontinue lixisenatide and promptly seek medical attention. 1

Pancreatitis

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been reported postmarketing in patients treated with GLP-1 receptor agonists. In clinical trials of lixisenatide, there were 21 cases of pancreatitis among lixisenatide-treated patients and 14 cases in comparator-treated patients (incidence rate of 21 vs. 17 per 10,000 patient-years). Lixisenatide cases were reported as acute pancreatitis (n=3), pancreatitis (n=12), chronic pancreatitis (n=5), and edematous pancreatitis (n=1). Some patients had risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. 1

After initiation of lixisenatide, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue lixisenatide and initiate appropriate management. If pancreatitis is confirmed, do not restart lixisenatide. Consider antidiabetic therapies other than lixisenatide in patients with a history of pancreatitis.1

Never Share Lixisenatide Pen Between Patients

Lixisenatide pens should never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.1

Hypoglycemia with Concomitant Use of Sulfonylureas or Basal Insulin

Patients receiving lixisenatide in combination with basal insulin or a sulfonylurea have an increased risk of hypoglycemia. In patients receiving sulfonylurea with or without metformin, 14.5% patients on lixisenatide reported symptomatic hypoglycemia compared to 10.6% for those on placebo. In patients receiving basal insulin with or without metformin, 28.3% of patients on lixisenatide reported symptomatic hypoglycemia compared to 23.0% for those on placebo. In patients receiving basal insulin with sulfonylurea, 47.2% of patients on lixisenatide reported symptomatic hypoglycemia compared to 21.6% for those on placebo. Reduction in the dose of sulfonylurea or basal insulin may be necessary.1

Acute Kidney Injury

Acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis, has been reported postmarketing in patients treated with GLP-1 receptor agonists. Some of these events were reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. 1

Monitor renal function when initiating or escalating doses of lixisenatide in patients with renal impairment and in patients reporting severe gastrointestinal reactions. Lixisenatide is not recommended in patients with end stage renal disease.1

Immunogenicity

Patients may develop antibodies to lixisenatide following treatment with lixisenatide. A pooled analysis of studies of lixisenatide-treated patients showed that 70% were antibody positive at week 24. In the subset of patients (2.4 %) with the highest antibody concentrations (>100 nmol/L), an attenuated glycemic response was observed. A higher incidence of allergic reactions and injection site reactions occurred in antibody positive patients.1

If there is worsening glycemic control or failure to achieve targeted glycemic control, significant injection site reactions or allergic reactions, alternative antidiabetic therapy should be considered.1

Macrovascular Outcomes

Clinical studies have not shown macrovascular risk reduction with lixisenatide or any other antidiabetic drug.1

Specific Populations

Pregnancy

Risk Summary: The limited available data with lixisenatide in pregnant women are not sufficient to inform a drug-associated risk of major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.1 Based on animal reproduction studies, there may be risks to the fetus from exposure to lixisenatide during pregnancy. Lixisenatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.1 Lixisenatide administered to pregnant rats and rabbits during organogenesis was associated with visceral closure and skeletal defects at systemic exposures that decreased maternal food intake and weight gain during gestation, and that are 1-time and 6-times higher than the 20 mcg/day clinical dose, respectively, based on plasma AUC. 1 The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20–25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.1

Disease-associated Maternal and/or Embryo/fetal Risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.1

Animal Data

In pregnant rats receiving twice daily subcutaneous doses of 2.5, 35, or 500 mcg/kg during organogenesis (gestation day 6 to 17), fetuses were present with visceral closure defects (e.g., microphthalmia, bilateral anophthalmia, diaphragmatic hernia) and stunted growth. Impaired ossification associated with skeletal malformations (e.g., bent limbs, scapula, clavicle, and pelvis) were observed at ≥5 mcg/kg/day, resulting in systemic exposure that is 1-time the 20 mcg/day clinical dose, based on plasma AUC. Decreases in maternal body weight, food consumption, and motor activity were observed concurrent with the adverse fetal findings, which confounds the interpretation of relevance of these malformations to the human risk assessment. Placental transfer of lixisenatide to developing rat fetuses is low with a concentration ratio in fetal/maternal plasma of 0.1%.1

In pregnant rabbits receiving twice daily subcutaneous doses of 2.5, 25, 250 mcg/kg during organogenesis (gestation day 6 to 18), fetuses were present with multiple visceral and skeletal malformations, including closure defects, at ≥5 mcg/kg/day or systemic exposures that are 6-times the 20 mcg/day clinical dose, based on plasma AUC. Decreases in maternal body weight, food consumption, and motor activity were observed concurrent with the fetal findings, which confounds the interpretation of relevance of these malformations to the human risk assessment. Placental transfer of lixisenatide to developing rabbit fetuses is low with a concentration ratio in fetal/maternal plasma of ≤0.3%. In a second study in pregnant rabbits, no drug-related malformations were observed from twice daily subcutaneous doses of 0.15, 1.0, and 2.5 mcg/kg administered during organogenesis, resulting in systemic exposures up to 9-times the clinical exposure at 20 mcg/day, based on plasma AUC.1

In pregnant rats given twice daily subcutaneous doses of 2, 20, or 200 mcg/kg from gestation day 6 through lactation, decreases in maternal body weight, food consumption, motor activity were observed at all doses. Skeletal malformations and increased pup mortality were observed at 400 mcg/kg/day, which is approximately 200-times the 20 mcg/day clinical dose, based on mcg/m2.1

Lactation

There is no information regarding the presence of lixisenatide in human milk, the effects on the breastfed infant, or the effects on milk production. However, lixisenatide is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for lixisenatide and any potential adverse effects on the breastfed infant from lixisenatide or from the underlying maternal condition.1

A study in lactating rats showed low (9.4%) transfer of lixisenatide and its metabolites into milk and negligible (0.01%) levels of unchanged lixisenatide peptide in the gastric contents of weaning offspring.1

Pediatric Use

Safety and effectiveness of lixisenatide have not been established in pediatric patients below 18 years of age. 1

Geriatric Use

In phase 2 and 3 controlled clinical studies of lixisenatide, a total of 1837 (25%) of the patients exposed to the study medication were 65 years of age and over and 288 (4%) were 75 years of age and over. No overall differences were observed in safety or effectiveness between these patients and younger patients, but individual sensitivity cannot be ruled out. 1

Renal Impairment

In patients with mild renal impairment (eGFR: 60–89 mL/min/1.73 m2), no dose adjustment is required but close monitoring for lixisenatide related adverse reactions and for changes in renal function is recommended because a higher incidence of hypoglycemia, nausea and vomiting was observed in these patients.1

In a cardiovascular outcome study, 655 (22%) lixisenatide treated patients had moderate renal impairment (eGFR: 30 to less than 60 mL/min/1.73 m2). No dosing adjustment is recommended in patients with moderate renal impairment, but close monitoring for lixisenatide related adverse gastrointestinal reactions and for changes in renal function is recommended because these may lead to dehydration and acute renal failure and worsening of chronic renal failure in these patients.1

Clinical experience in patients with severe renal impairment is limited as there were only 5 patients with severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) exposed to lixisenatide in all controlled studies. Lixisenatide exposure was higher in these patients. Patients with severe renal impairment exposed to lixisenatide should be closely monitored for occurrence of gastrointestinal adverse reactions and for changes in renal function.1

There is no therapeutic experience in patients with end stage renal disease (eGFR <15 mL/min/1.73 m2), and it is not recommended to use lixisenatide in this population.1

Patients with Gastroparesis

Lixisenatide slows gastric emptying. Patients with preexisting gastroparesis were excluded from clinical trials of lixisenatide. Lixisenatide should not be initiated in patients with severe gastroparesis.1

Common Adverse Effects

The most common adverse reactions (≥5%) in patients treated with lixisenatide are nausea, vomiting, headache, diarrhea, dizziness, and hypoglycemia.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Lixisenatide delays gastric emptying which may impact absorption of concomitantly administered oral medications. Oral medications that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, or medications for which a delay in effect is undesirable, such as acetaminophen, should be administered 1 hour before lixisenatide. 1

  • Oral contraceptives should be taken at least 1 hour before lixisenatide administration or 11 hours after the dose of lixisenatide.1

Actions

Lixisenatide is a GLP-1 receptor agonist. Lixisenatide increases glucose-dependent insulin release, decreases glucagon secretion, and slows gastric emptying. 1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).1

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions, including anaphylaxis, have been reported in clinical trials of lixisenatide and during postmarketing use of GLP-1 receptor agonists. If symptoms of hypersensitivity reactions occur, inform patients that they must stop taking lixisenatide and seek medical advice promptly.1

Risk of Pancreatitis

Inform patients that persistent severe abdominal pain that may radiate to the back and which may or may not be accompanied by vomiting is the hallmark symptom of acute pancreatitis. Instruct patients to promptly discontinue lixisenatide and contact their physician if persistent severe abdominal pain occurs.1

Never Share Lixisenatide Pen Between Patients

Advise patients that they should never share their lixisenatide pen with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens.1

Risk of Hypoglycemia

Inform patients that the risk of hypoglycemia is increased when lixisenatide is used in combination with a sulfonylurea or basal insulin.1

Dehydration and Renal Failure

Advise patients treated with lixisenatide of the potential risk of dehydration due to gastrointestinal adverse reactions and to take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function, which in some cases may require dialysis.1

Use in Pregnancy

Advise patients to inform their physicians if they are pregnant or intend to become pregnant.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Lixisenatide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use only

100 mcg/mL (3 mL)

Adlyxin Maintenance Pack (contains 2 prefilled, single-patient use pens [for 14 doses; 20 mcg/dose])

Sanofi-Aventis U.S. LLC

Starter Pack

50 mcg/mL (3 mL) and 100 mcg/mL (3 mL)

Adlyxin Starter Pack (contains 2 prefilled, single-patient use pens [for 14 doses; 10 or 20 mcg/dose])

Sanofi-Aventis U.S. LLC

AHFS Drug Information. © Copyright 2016, Selected Revisions September 14, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Sanofi-Aventis U.S. LLC. ADLYXIN (Lixisenatide) prescribing information. 2016 July.

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