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Lixisenatide

Pronunciation

(lix i SEN a tide)

Index Terms

  • AVE0010
  • ZP10A peptide

Brand Names: U.S.

  • Adlyxin

Pharmacologic Category

  • Antidiabetic Agent, Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist

Pharmacology

Lixisenatide is a selective glucagon-like peptide-1 (GLP-1) receptor agonist. Acting on the same receptor as the endogenous hormone incretin, lixisenatide increases glucose-dependent insulin secretion, decreases inappropriate glucagon secretion, and slows gastric emptying.

Distribution

Vz/F: ~100 L

Metabolism

Presumed to undergo proteolytic degradation

Excretion

Urine

Time to Peak

1 to 3.5 hours

Half-Life Elimination

~3 hours

Special Populations: Renal Function Impairment

Compared to healthy subjects (CrCl ≥90 mL/minute), lixisenatide Cmax and AUC were increased by 60% and 34% in mild renal impairment (CrCl 60 to 89 mL/minute), by 42% and 69% in moderate renal impairment (CrCl 30 to 59 mL/minute), and by 83% and 124% in severe renal impairment (CrCl 15 to 29 mL/minute) respectively.

Use: Labeled Indications

Diabetes mellitus, type 2: Treatment of type 2 diabetes mellitus (noninsulin dependent, NIDDM) to improve glycemic control in adult patients as an adjunct to diet and exercise

Contraindications

Hypersensitivity to lixisenatide or any component of the formulation

Dosing: Adult

Diabetes mellitus, type 2: SubQ: Initial: 10 mcg once daily for 14 days; on day 15 increase to 20 mcg once daily. Maintenance dose: 20 mcg once daily.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

eGFR ≥30 to 89 mL/minute/1.73 m2: No dosage adjustment necessary; monitor closely for increased adverse GI effects (eg, diarrhea, nausea, vomiting) which may lead to dehydration and worsening of renal function.

eGFR 15 to 29 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer’s labeling (limited data); exposure is increased in these patients. Monitor closely for increased adverse GI effects (eg, diarrhea, nausea, vomiting) which may lead to dehydration and worsening of renal function.

eGFR <15 mL/minute/1.73 m2: Use is not recommended (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, dosage adjustment not likely as hepatic impairment is not expected to affect lixisenatide pharmacokinetics.

Administration

Subcutaneous: Administer subcutaneously in the abdomen, thigh, or upper arm. Rotate injection sites for each dose; do not use the same site for each injection. Administer within one hour before the first meal of the day, preferably the same meal each day. If dose is missed, administer within one hour of next meal. Solution should appear clear and colorless; do not use if particulate matter or coloration is seen.

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy (ADA 2016b).

Storage

Prior to initial use, store under refrigeration at 2°C to 8°C (36°F to 46°F); after initial use, may store at <30°C (<86°F). Do not freeze. Protect from light (keep in original package). Pen should be discarded 14 days after initial use.

Drug Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Contraceptives (Estrogens): Lixisenatide may decrease the serum concentration of Contraceptives (Estrogens). Management: Administer oral contraceptives 1 hour before or at least 11 hours after administration of lixisenatide. Consider therapy modification

Contraceptives (Progestins): Lixisenatide may decrease the serum concentration of Contraceptives (Progestins). Management: Administer oral contraceptives 1 hour before or at least 11 hours after administration of lixisenatide. Consider therapy modification

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulin: GLP-1 Agonists may enhance the hypoglycemic effect of Insulin. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Consider therapy modification

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sulfonylureas: GLP-1 Agonists may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Adverse Reactions

>10%:

Gastrointestinal: Gastrointestinal symptoms (40%; most were mild to moderate and within the first 3 weeks of starting treatment), nausea (25%)

Immunologic: Antibody development (70%: 2% had high antibody concentrations [>100 nmol/L] and experienced an attenuated glycemic response)

1% to 10%:

Central nervous system: Headache (9%), dizziness (7%)

Gastrointestinal: Vomiting (10%), diarrhea (8%), constipation (3%), dyspepsia (3%), abdominal distension (2%), upper abdominal pain (2%)

Local: Injection site reaction (4%; including pain, pruritus, and erythema)

<1% (Limited to important or life-threatening): Acute renal injury, exacerbation of renal failure, hypersensitivity reaction, pancreatitis (acute, chronic, and edematous)

Warnings/Precautions

Concerns related to adverse effects:

• Anti-lixisenatide antibodies: Use may be associated with the development of anti-lixisenatide antibodies. In clinical trials, high titers were observed in 2.4% of patients and were associated with an attenuated glycemic response. Allergic reactions and injection site reactions were more frequent in antibody positive patients; consider alternative antidiabetic therapy in patients not achieving targeted glycemic control or with worsening glycemic control and/or significant allergic or injection site reactions.

• Hypersensitivity: Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported; discontinue use if hypersensitivity reactions occur and treat promptly as indicated. It is not known if patients with a history of hypersensitivity to other GLP-1 agonists are at increased risk for hypersensitivity reactions with lixisenatide; patients with prior serious reactions to similar agents should be monitored closely.

• Pancreatitis: Cases of acute pancreatitis (including hemorrhagic and necrotizing with some fatalities) have been reported; monitor for signs and symptoms of pancreatitis (eg, persistent severe abdominal pain which may radiate to the back, and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue use. Do not resume unless an alternative etiology of pancreatitis is confirmed. Consider alternative antidiabetic therapy in patients with a history of pancreatitis.

Disease-related concerns:

• Gastroparesis: Lixisenatide slows gastric emptying and is not recommended for use in patients with gastroparesis (has not been studied); do not initiate therapy in patients with severe gastroparesis.

• Renal impairment: Use with caution in patients with mild renal impairment (eGFR ≥60 to 89 mL/minute/1.73 m2) or moderate renal impairment (≥30 to <60 mL/minute/1.73 m2); may be at increased risk of adverse effects (eg, diarrhea, nausea, vomiting) which may lead to dehydration, acute kidney injury and worsening of chronic renal failure. There is limited experience with severe impairment (eGFR 15 to <30 mL/minute/1.73 m2); lixisenatide exposure may be increased in these patients. Monitor all patients with renal impairment closely for decreasing renal function. Use is not recommended in patients with end-stage renal disease (eGFR <15 mL/minute/1.73 m2) (has not been studied).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Multiple dose injection pens: According to the Centers for Disease Control and Prevention (CDC), pen-shaped injection devices should never be used for more than one person (even when the needle is changed) because of the risk of infection. The injection device should be clearly labeled with individual patient information to ensure that the correct pen is used (CDC 2012).

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus (insulin-dependent, IDDM).

Monitoring Parameters

Serum glucose, hemoglobin A1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016a]), renal function, signs/symptoms of pancreatitis; signs/symptoms of adverse GI effects (diarrhea, nausea, vomiting); signs/symptoms of hypersensitivity

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 60 2005; ADA 2016a; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 137 2013; ADA 2016a; Blumer 2013; Kitzmiller 2008). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (ADA 2016a; Kitzmiller 2008). Other agents are currently recommended to treat diabetes in pregnant women (ACOG 137 2013; Blumer 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, headache, or dizziness. Have patient report immediately to prescriber signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), or signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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