insulin glargine/lixisenatide (Rx)

>10%

Documented symptomatic hypoglycemia (25.6-40%)

1-10%

Nausea (10%)

Nasopharyngitis (7%)

Diarrhea (7%)

Upper respiratory tract infection (5.5%)

Headache (5.4%)

Severe symptomatic hypoglycemia (1.1%)

Injection site reactions (1.7%)

<1%

Anaphylaxis

Frequency Not Defined

Lipodystrophy

Peripheral edema

Weight gain

Immunogenicity

Localized cutaneous amyloidosis at the injection site

Contraindications

During episodes of hypoglycemia

Hypersensitivity to either of the active drugs or any excipients

Cautions

Anaphylaxis reported (see Contraindications)

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, reported postmarketing

Do not share insulin pens between patients

Caution when changing dosage regimens; increase frequency of blood glucose monitoring to detect hypoglycemia or hyperglycemia

Do not exceed maximum dose or use with other GLP-1 agonists or basal insulins

Hypoglycemia is the most common adverse effect of insulin; self-monitoring of blood glucose is essential to prevent and manage hypoglycemia

Acute kidney injury reported postmarketing, some of which required hemodialysis

Increased risk for hypokalemia; insulin shifts potassium from the extracellular to intracellular space

Increased risk of fluid retention and CHF with coadministration of peroxisome proliferator-activated receptor (PPAR)-gamma agonists (eg, thiazolidinediones)

No clinical studies have established conclusive evidence of macrovascular risk reduction with any antidiabetic drugs

Hyperglycemia or hypoglycemia with changes in insulin regimen

• Changes in insulin, insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia or hyperglycemia
• Changes should be made cautiously and only under close medical supervision and frequency of blood glucose monitoring should be increased
• Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis reported to result in hyperglycemia; a sudden change in the injection site (to unaffected area) has been reported to result in hypoglycemia
• Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring
• Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change injection site to unaffected areas and closely monitor for hypoglycemia
• For patients with type 2 diabetes, dosage adjustments in concomitant oral antidiabetic treatment may be needed

Drug interaction overview

• Drugs that may increase hypoglycemia risk

  • May require dose reduction and increased glucose monitoring frequency if coadministered with drugs that cause hypoglycemia
  • Examples include antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (eg, octreotide), and sulfonamide antibiotics

• Drug that may decrease blood glucose-lowering effect of lixisenatide/insulin glargine

  • May require dose increase and increased glucose monitoring frequency if coadministered with drugs that increase blood glucose
  • Examples include atypical antipsychotics (eg, olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (eg, in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (eg, albuterol, epinephrine, terbutaline), and thyroid hormones

• Drugs that may increase or decrease the blood glucose-lowering effects of lixisenatide/insulin glargine

  • Dose adjustment in increased blood glucose monitoring may be required
  • Examples include alcohol, beta-blockers, clonidine, and lithium salts; pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia

• Drugs that may blunt signs and symptoms of hypoglycemia

  • Increase frequency of blood glucose monitoring
  • Examples include beta-blockers, clonidine, guanethidine, and reserpine

Pregnancy

Based on animal reproduction studies, there may be risks to the fetus from exposure to lixisenatide during pregnancy

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus

There are no available data with use in pregnant women to inform a drug-associated risk for major birth defects or miscarriage

There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy

Lactation

Unknown if distributed in human breast milk

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Lixisenatide: Incretin mimetic; analogue of human glucagonlike peptide-1 (GLP-1); acts as GLP-1 receptor agonist to augment glucose-dependent insulin secretion, decreases glucagon secretion, and slows gastric emptying

Insulin glargine: Basal insulin analog; insulin lowers blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production; insulin inhibits lipolysis and proteolysis and enhances protein synthesis; targets include skeletal muscle, liver, and adipose tissue

Absorption

Peak plasma time (lixisenatide): 2.5-3 hr

Distribution

Protein bound (lixisenatide): 55%

Metabolism

Insulin glargine: Partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form 2 active metabolites with in vitro activity similar to that of human insulin

Lixisenatide: Presumed to be eliminated through glomerular filtration and proteolytic degradation

Elimination

Half-life (lixisenatide): 3 hr

Clearance (lixisenatide): 35 L/hr

SC Administration

The pen delivers 15-60 units of insulin glargine with each injection

Administer SC once daily within 1 hr prior to the first meal of the day

Inject SC in thigh, upper arm, or abdomen

Rotate injection site within the same region from 1 injection to the next to reduce lipodystrophy risk

Do not administer IV, IM, or by infusion pump

Do not dilute or mix with any other insulin products or solutions

Do not split the dose

Missed doses

• Resume the once-daily regimen as prescribed with the next scheduled dose
• Do not administer an extra dose or increase the dose to make up for the missed dos

Storage

Prior to first use

• Refrigerate between 36-46°F (2-8°C)
• Do not freeze; discard if it has been frozen
• Protect from light

After first use

• Store at room temperature below 86°F (30°C)
• Replace the pen cap after each use to protect from light
• Discard pen 14 days after first use
• Always remove the needle after each injection and store the pen without a needle attached; this prevents contamination and/or infection, or leakage of the pen, and ensures accurate dosing
• Always use a new needle for each injection to prevent contamination