insulin degludec (Rx)

>10%

Nasopharyngitis (12.9-23.9%)

Severe hypoglycemic episode (0.3-12.3%)

Upper respiratory tract infection (8.4-11.9%)

Headache (8.8-11.8%)

1-10%

Diarrhea (6.3%)

Sinusitis (5.1%)

Gastroenteritis (5.1%)

Injection site reactions (3.8%)

Peripheral edema (0.9-3%)

<1%

Lipodystrophy

Postmarketing Reports

Localized cutaneous amyloidosis at the injection

Contraindications

During episodes of hypoglycemia

Documented hypersensitivity

Cautions

Do not share, even if the needle is changed; sharing poses a risk for transmission of blood-borne pathogens

Changes in insulin, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia or hyperglycemia; these changes should be made cautiously and only under medical supervision, and the frequency of blood glucose monitoring should be increased

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur

All insulin products cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia; monitor potassium levels in patients at risk for hypokalemia including patients using potassium-lowering medications or those taking medications sensitive to serum potassium concentrations; treat if indicated

To avoid dosing errors and potential overdose, never use a syringe to remove drug from pen injector into a syringe

Thiazolidinediones, which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists can cause dose-related fluid retention, particularly when used in combination with insulin; this may lead to or exacerbate heart failure

Hyperglycemia or hypoglycemia with changes in insulin regimen

• Hypoglycemia is the most common adverse effect and can happen suddenly; severe hypoglycemia can cause seizures, may be life-threatening, or cause death
• Hypoglycemia can impair concentration ability and reaction time and place an individual and others at risk in situations where these abilities are important (eg, driving or operating other machinery)
• Risk increases with intensity of glycemic control and is related to the duration of action of the insulin
• Other factors that may increase the risk of hypoglycemia include changes in meal pattern (eg, macronutrient content or timing of meals), changes in level of physical activity, or changes to coadministered medication
• Renal or hepatic impairment may increase hypoglycemia risk
• In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended
• Accidental mix-ups between basal insulin products and other insulins, particularly rapid-insulins, have been reported
• Do not transfer insulin degludec from the prefilled pen to a syringe; the markings on the insulin syringe will not measure the dose correctly and can result in overdosage and severe hypoglycemia
• 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 interactions overview

• Thiazolidinediones are peroxisome proliferator-activated receptor (PPAR)-gamma agonists and can cause dose-related fluid retention, particularly when used in combination with insulin; fluid retention may lead to or exacerbate heart failure; monitor for signs and symptoms of heart failure, treat accordingly, and consider discontinuing thiazolidinediones
• Coadministration with these drugs (eg, antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs [eg, octreotide], sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors) may increase the risk of hypoglycemia
• Coadministration with these drugs (eg, atypical antipsychotics [eg, olanzapine and clozapine], corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens [eg, oral contraceptives], protease inhibitors, somatropin, sympathomimetic agents [eg, albuterol, epinephrine, terbutaline], and thyroid hormones) may decrease the risk of hypoglycemia
• Concomitant use of alcohol, beta-blockers, clonidine, and lithium salts with insulin degludec may increase or decrease blood glucose lowering effect of insulin glargine
• Pentamidine may cause hypoglycemia, which may sometimes be followed with hyperglycemia
• Coadministration with beta-blockers, clonidine, guanethidine, or reserpine may blunt signs and symptoms of hypoglycemia

Pregnancy

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

There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy

Animal studies

• The effect of insulin degludec was consistent with those observed with human insulin as both caused preimplantation and postimplantation losses and visceral/skeletal abnormalities in rats at an insulin degludec dose of 21 U/kg/day (~5 times the human exposure [AUC] at a human SC dose of 0.75 U/kg/day) and in rabbits at a dose of 3.3 U/kg/day (~10 times the AUC at a human SC dose of 0.75 U/kg/day)
• The effects are probably secondary to maternal hypoglycemia

Lactation

There are no data on the presence of insulin degludec in human milk, the effects on the breastfed infant, or the effects on milk production

Insulin degludec is present in rat 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

Once-daily basal insulin analogue

Insulin and its analogues lower 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: 9 hr

Peak plasma concentration: 4472 pmol/L

Steady state: 3-4 days

Distribution

Protein bound: >99% to albumin

Metabolism

Metabolites: Inactive

Elimination

Half-life: ~25 hr

Clearance: 0.03 L/kg

Preparation

Inspect visually for particulate matter and discoloration; only use if the solution appears clear and colorless

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

Do not transfer drug from the insulin degludec pen into a syringe for administration

SC Administration

Inject SC once daily at any time of day

Inject SC into the thigh, upper arm, or abdomen

Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy

Do not administer IV, IM, or in an insulin infusion pump

Individualize and titrate the dose based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal

Recommended days between dose increases is 3-4 days

Dose adjustments may be needed with changes in physical activity, changes in meal patterns (ie, macronutrient content or timing of food intake), changes in renal or hepatic function, or during acute illness to minimize the risk of hypoglycemia or hyperglycemia

Instruct patients who miss a dose to inject their daily dose during waking hours upon discovering the missed dose

Instruct patients to ensure that at least 8 hr have elapsed between consecutive insulin degludec injections

DO NOT perform dose conversion when using the insulin degludec U-100 or U-200 FlexTouch pens; the dose window for both the U-100 and U-200 FlexTouch pens shows the number of insulin units to be delivered and NO conversion is needed

Storage

Unopened (not in-use) prefilled pen

• Refrigerate at 36-46°F (2-8°C)
• Do not store in the freezer or directly adjacent to the refrigerator cooling element
• Do not freeze
• Do not use if it has been frozen

Open (in-use) prefilled pen

• Refrigerate at 36-46°F (2-8°C) or store at room temperature (<86°F [30°C]) for up to 56 days (8 wk)
• Do not freeze
• Keep away from direct heat and light