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Insulin Degludec

Class: Insulins
Brands: Tresiba

Introduction

Insulin degludec (rDNA origin) is a biosynthetic, long-acting human insulin analog.

Uses for Insulin Degludec

Insulin degludec has the following uses:

Insulin degludec is indicated to improve glycemic control in adults with type 1 or type 2 diabetes mellitus.1

Insulin degludec has the following limitations of use:

Not recommended for treating diabetic ketoacidosis.1

Insulin Degludec Dosage and Administration

General

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

  • 100 units/mL (U-100): 3 mL FlexTouch.1

  • 200 units/mL (U-200): 3 mL FlexTouch.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:

  • Individualize dose based on type of diabetes, metabolic needs, blood glucose monitoring results and glycemic control goal.1

  • Rotate injection sites to reduce the risk of lipodystrophy.1

  • Do not dilute or mix with any other insulin or solution. 1

  • Administer subcutaneously once daily at any time of day.1

  • Do NOT perform dose conversion when using the insulin degludec 100 units/mL or 200 units/mL FlexTouch pens. The insulin degludec 100 units/mL and 200 units/mL FlexTouch pens dose window shows the number of insulin units to be delivered and NO conversion is needed. 1

Cautions for Insulin Degludec

Contraindications

  • During episodes of hypoglycemia.1

  • Hypersensitivity to insulin degludec or one of its excipients.1

Warnings/Precautions

Never Share an Insulin Degludec FlexTouch Pen Between Patients

Insulin degludec FlexTouch disposable prefilled pens should never be shared between patients, even if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens.1

Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen

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. For patients with type 2 diabetes, adjustments in concomitant oral anti-diabetic treatment may be needed. When converting from other insulin therapies to insulin degludec follow dosing recommendations. 1

Hypoglycemia

Hypoglycemia is the most common adverse reaction of insulin, including insulin degludec. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Insulin degludec, or any insulin, should not be used during episodes of hypoglycemia.1

Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers), or in patients who experience recurrent hypoglycemia.1

The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of insulin degludec may vary among different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature.1

Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia.1

Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.1

Hypoglycemia Due to Medication Errors

Accidental mix-ups between basal insulin products and other insulins, particularly rapid-acting insulins, have been reported. To avoid medication errors between insulin degludec and other insulins, instruct patients to always check the insulin label before each injection.1

Do not transfer insulin degludec from the insulin degludec pen to a syringe. The markings on the insulin syringe will not measure the dose correctly and can result in overdosage and severe hypoglycemia.1

Hypersensitivity and Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including insulin degludec. If hypersensitivity reactions occur, discontinue insulin degludec; treat per standard of care and monitor until symptoms and signs resolve. Insulin degludec is contraindicated in patients who have had hypersensitivity reactions to insulin degludec or one of the excipients.1

Hypokalemia

All insulin products, including insulin degludec, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).1

Fluid Retention and Congestive Heart Failure with Concomitant Use of a Peroxisome Proliferator-activated Receptor (PPAR)-Gamma Agonist

Thiazolidinediones (TZDs), which are PPAR-gamma agonists, can cause dose related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with insulin, including insulin degludec and a PPAR-gamma agonist, should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.1

Specific Populations

Pregnancy

Pregnancy Category C.1

There are no well-controlled clinical studies of the use of insulin degludec in pregnant women. Patients should be advised to discuss with their health care provider if they intend to or if they become pregnant. Because animal reproduction studies are not always predictive of human response, insulin degludec should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is essential for patients with diabetes or a history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients.1

Subcutaneous reproduction and teratology studies have been performed with insulin degludec and human insulin (NPH) as a comparator in rats and rabbits. In these studies, insulin was given to female rats before mating throughout pregnancy until weaning, and to rabbits during organogenesis. The effect of insulin degludec was consistent with those observed with human insulin as both caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at an insulin degludec dose of 21 units/kg/day (approximately 5 times the human exposure (AUC) at a human subcutaneous dose of 0.75 units/kg/day) and in rabbits at a dose of 3.3 units/kg/day (approximately 10 times the human exposure (AUC) at a human subcutaneous dose of 0.75 units/kg/day). The effects are probably secondary to maternal hypoglycemia.1

Lactation

It is unknown whether insulin degludec is excreted in human milk. Because many drugs, including human insulin, are excreted in human milk, caution should be exercised when insulin degludec is administered to a nursing mother. Women with diabetes who are lactating may require adjustments in insulin dose, meal plan, or both.1

In rats, insulin degludec was secreted in milk and the concentration in milk was lower than in plasma.1

Pediatric Use

The safety and efficacy of insulin degludec in children and adolescents under the age of 18 have not been established.1

Geriatric Use

In controlled clinical studies a total of 77 (7%) of the 1102 insulin degludec-treated patients with type 1 diabetes were 65 years or older and 9 (1%) were 75 years or older. A total of 670 (25%) of the 2713 insulin degludec-treated patients with type 2 diabetes were 65 years or older and 80 (3%) were 75 years or older. Differences in safety or effectiveness were not suggested in subgroup analyses comparing subjects older than 65 years to younger subjects.1

Nevertheless, greater caution should be exercised when insulin degludec is administered to geriatric patients since greater sensitivity of some older individuals to the effects of insulin degludec cannot be ruled out. The initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be more difficult to recognize in the elderly.1

Renal Impairment

In clinical studies, a total of 75 (7%) of the 1102 insulin degludec-treated patients with type 1 diabetes had an estimated GFR less than 60 mL/min/1.73 m2 and 1 (0.1%) had an estimated GFR less than 30 mL/min/1.73 m2. A total of 250 (9%) of the 2713 insulin degludec-treated patients with type 2 diabetes had an estimated GFR less than 60 mL/min/1.73 m2 and no subjects had an eGFR less than 30 mL/min/1.73 m2. 1

No clinically relevant difference in the pharmacokinetics of insulin degludec was identified in a study comparing healthy subjects and subjects with renal impairment including subjects with end stage renal disease. However, as with all insulin products, glucose monitoring should be intensified and the insulin degludec dosage adjusted on an individual basis in patients with renal impairment.1

Hepatic Impairment

No difference in the pharmacokinetics of insulin degludec was identified in a study comparing healthy subjects and subjects with hepatic impairment (mild, moderate, and severe hepatic impairment). However, as with all insulin products, glucose monitoring should be intensified and the insulin degludec dosage adjusted on an individual basis in patients with hepatic impairment.1

Common Adverse Effects

Adverse reactions commonly associated with insulin degludec are:

  • Hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema and weight gain.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:

  • Drugs that affect glucose metabolism: Adjustment of insulin dosage may be needed; closely monitor blood glucose.1

  • Anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent.1

Actions

Mechanism of Action

The primary activity of insulin, including insulin degludec, is regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin also inhibits lipolysis and proteolysis, and enhances protein synthesis. Insulin degludec forms multi-hexamers when injected into the subcutaneous tissue resulting in a subcutaneous insulin degludec depot. The protracted time action profile of insulin degludec is predominantly due to delayed absorption of insulin degludec from the subcutaneous tissue to the systemic circulation and to a lesser extent due to binding of insulin degludec to circulating albumin.1

Advice to Patients

See FDA-Approved Patient Labeling (Patient Information and Instructions for Use)1

Never Share an Insulin Degludec FlexTouch Pen Between Patients

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

Hyperglycemia or Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia. Inform patients that the ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.1

Advise patients that changes in insulin regimen can predispose to hyper- or hypoglycemia.1

Advise patients that changes in insulin regimen should be made under close medical supervision.1

Medication Errors

Inform patients to always check the insulin label before each injection. Insulin degludec FlexTouch pen is available in concentrations of 100 units/mL or 200 units/mL.1

Inform patients that the dose counter of insulin degludec FlexTouch pen shows the number of units of insulin degludec to be injected. NO dose re-calculation is required.1

Instruct patients that when injecting insulin degludec, they must press and hold down the dose button until the dose counter shows 0 and then keep the needle in the skin and count slowly to 6. When the dose counter returns to 0, the prescribed dose is not completely delivered until 6 seconds later. If the needle is removed earlier, they may see a stream of insulin coming from the needle tip. If so, the full dose will not be delivered (a possible under-dose may occur by as much as 20%), and they should increase the frequency of checking their blood glucose levels and possible additional insulin administration may be necessary. 1

If 0 does not appear in the dose counter after continuously pressing the dose button, the patient may have used a blocked needle. In this case they would not have received any insulin, even though the dose counter has moved from the original dose that was set.1 If the patient did have a blocked or damaged needle, instruct them to change the needle according to the manufacturer's instructions for use and repeat all steps in the instructions for use starting with a new needle and the section “Preparing your insulin degludec FlexTouch pen”. Make sure the patient selects the full dose needed.1

If patients routinely do not hold the needle under the skin as recommended, the patient may need to slightly increase the dialed insulin dose to achieve the patient’s glycemic targets.1

Instruct patients to not re-use needles. A new needle must be attached before each injection. Reuse of needles increases the risk of blocked needles which may cause under-dosing or overdosing.1

Instruct patients to never use a syringe to remove insulin degludec from the FlexTouch disposable insulin prefilled pen.1

Administration

Insulin degludec must only be used if the solution is clear and colorless with no particles visible.1

Patients must be advised that insulin degludec must NOT be diluted or mixed with any other insulin or solution.1

Management of Hypoglycemia and Handling of Special Situations

Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia. Patients must be instructed on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals.1

Refer patients to the insulin degludec Patient Information for additional information about the potential side effects of insulin therapy, including lipodystrophy (and the need to rotate injection sites within the same body region), weight gain, allergic reactions, and hypoglycemia.1

Women of Reproductive Potential

Advise patients to inform their health care professional if they are pregnant or are contemplating pregnancy.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.

Insulin Degludec

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, Solution

100 units/mL

Tresiba

Novo Nordisk

200 units/mL

Tresiba

Novo Nordisk

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. Novo Nordisk. Tresiba (insulin degludec injection) SUBCUTANEOUS prescribing information. 2016 Jun.

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