Lixisenatide

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Pen-injector Kit, Subcutaneous:

Adlyxin Starter Pack: 10 mcg/0.2 mL & 20 mcg/0.2 mL (6 mL) [contains metacresol]

Solution Pen-injector, Subcutaneous:

Adlyxin: 20 mcg/0.2 mL (3 mL) [contains metacresol]

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

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

Use in Specific Populations

Special Populations: Renal Function Impairment

Compared to healthy subjects (CrCl ≥90 mL/minute), lixisenatide C_max 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

Dosage and Administration

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.

Missed dose: If dose is missed, administer within one hour of next meal.

Dosing: Geriatric

Refer to adult dosing.

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. 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

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

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

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

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

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

Insulins: Glucagon-Like Peptide-1 Agonists may enhance the hypoglycemic effect of Insulins. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Consider therapy modification

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

Monoamine Oxidase 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

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

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

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones 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

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. 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

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Consider therapy modification

Sulfonylureas: Glucagon-Like Peptide-1 Agonists may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. 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%, postmarketing, and/or case reports: Acute renal injury, hypersensitivity reaction, pancreatitis (acute, chronic, and edematous), renal insufficiency

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:

• Bariatric surgery: ­

- Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy, and closely monitor the patient for the duration of therapy; acute and chronic kidney failure exacerbation may occur. A majority of cases occurred in patients with nausea, vomiting, diarrhea, and/or dehydration. Nausea is common and fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2013). ­

- Excessive glucagon-like peptide-1 exposure: Closely monitor for efficacy and assess for signs and symptoms of pancreatitis if therapy is initiated after surgery; gastric bypass and sleeve gastrectomy (but not gastric band) significantly increase endogenous postprandial glucagon-like peptide-1 (GLP-1) concentrations (Korner 2009; Peterli 2012). Administration of exogenous GLP-1 agonists may be redundant to surgery effects.

• 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 A_1c (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 2019]), renal function, signs/symptoms of pancreatitis; signs/symptoms of adverse GI effects (diarrhea, nausea, vomiting); signs/symptoms of hypersensitivity

Pregnancy

Pregnancy Considerations

Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia (ACOG 201 2018). To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA_1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2020; Blumer 2013).

Agents other than lixisenatide are currently recommended to treat diabetes mellitus in pregnancy (ADA 2020).

Patient Education

What is this drug used for?

• It is used to lower blood sugar in patients with high blood sugar (diabetes).

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Diarrhea
• Headache

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Severe dizziness
• Passing out
• Fast heartbeat
• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.