Insulin degludec

Insulin degludec
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shivani Chaparala M.B.B.S [2]

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Overview

Insulin degludec is a long-acting human insulin analog that is FDA approved for the {{{indicationType}}} of to improve glycemic control in patients 1 year of age and older with diabetes mellitus.. Common adverse reactions include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema and weight gain..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• Individualize dose based on type of diabetes, metabolic needs, blood glucose monitoring results and glycemic control goal.
• Rotate injection sites to reduce the risk of lipodystrophy.
• Do not dilute or mix with any other insulin or solution.
• Administer subcutaneously once daily at any time of day.
• Do NOT perform dose conversion when using the TRESIBA U-100 or U-200 FlexTouch pens.
• The TRESIBA U-100 and U-200 FlexTouch pens dose window shows the number of insulin units to be delivered and NO conversion is needed.

Off-Label Use and Dosage (Adult)

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Insulin degludec FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Contraindications

• During episodes of hypoglycemia.
• Hypersensitivity to TRESIBA or one of its excipients.

Warnings

Never share a TRESIBA FlexTouch pen between patients

• TRESIBA 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.

Hyper- 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 TRESIBA follow dosing recommendations.

Hypoglycemia

• Hypoglycemia is the most common adverse reaction of insulin, including TRESIBA.
• 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).
• TRESIBA, or any insulin, should not be used during episodes of hypoglycemia.
• 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.

Risk Factors for Hypoglycemia:

• 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 TRESIBA 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.
• 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.

Risk Mitigation Strategies for Hypoglycemia:

• 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.

Hypoglycemia due to medication errors

• Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. DO NOT transfer TRESIBA into a syringe for administration as overdosage and severe hypoglycemia can result.

Hypersensitivity reactions

• Severe, life-threatening, generalized allergy, including anaphylaxis, can occur.
• Discontinue TRESIBA, monitor and treat if indicated.

Hypokalemia

• May be life-threatening.
• Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death.
• Monitor potassium levels in patients at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations) and treat if indicated.

Fluid retention and heart failure with concomitant use of Thiazolidinediones (TZDs)

• Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs.

Adverse Reactions

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• The safety of TRESIBA in subjects with type 1 diabetes or type 2 diabetes was evaluated in nine trials of 6-12 month duration in adults and in one trial of 12-month duration in pediatric patients 1 year of age and older with type 1 diabetes.
• The data in Table 1 reflect the exposure of 1102 adults with type 1 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 34 weeks.
• The mean age was 43 years and 1% were older than 75 years.
• Fifty-seven percent were male, 81% were White, 2% were Black or African American and 4% were Hispanic. * The mean body mass index (BMI) was 26 kg/m2.
• The mean duration of diabetes was 18 years and the mean HbA1c at baseline was 7.8%.
• A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported in 11%, 16%, 7% and 0.5% respectively.
• The mean eGFR at baseline was 87 mL/min/1.73 m2 and 7% of the patients had an eGFR less than 60 mL/min/1.73 m2.
• The data in Table 2 reflect the exposure of 2713 adults with type 2 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 36 weeks.
• The mean age was 58 years and 3% were older than 75 years.
• Fifty-eight percent were male, 71% were White, 7% were Black or African American and 13% were Hispanic.
• The mean BMI was 30 kg/m2.
• The mean duration of diabetes was 11 years and the mean HbA1c at baseline was 8.3%.
• A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported for 14%, 10%, 6% and 0.6% of participants respectively.
• At baseline, the mean eGFR was 83 mL/min/1.73 m2 and 9% had an eGFR less than 60 mL/min/1.73 m2.
• Common adverse reactions (excluding hypoglycemia) occurring in TRESIBA treated subjects during clinical trials in adult patients with type 1 diabetes mellitus and adults with type 2 diabetes mellitus are listed in Table 1 and Table 2, respectively.
• Common adverse reactions were defined as reactions occurring in ≥5% of the population studied.
• Hypoglycemia is not shown in these tables but discussed in a dedicated subsection below.
• 174 pediatric patients 1 year of age and older with type 1 diabetes were exposed to TRESIBA with a mean exposure to TRESIBA of 48 weeks.
• The mean age was 10 years: 25% were ages 1-5 years, 40% were ages 6-11 years, and 35% were ages 12-17 years.
• 55.2% were male, 78.2% were White, 2.9% were Black or African American and 4% were Hispanic.
• The mean body mass index (BMI) was 18.7 kg/m2.
• The mean duration of diabetes was 3.9 years and the mean HbA1c at baseline was 8.2%.
• Common adverse reactions in TRESIBA treated pediatric patients with type 1 diabetes mellitus were similar to the adverse reactions listed in Table 1.

This image is provided by the National Library of Medicine

This image is provided by the National Library of Medicine

Hypoglycemia

• Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including TRESIBA.
• The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors.
• For these reasons, comparing rates of hypoglycemia in clinical trials for TRESIBA with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.
• The percentage of adult and pediatric patients with type 1 diabetes randomized to TRESIBA who experienced at least one episode of hypoglycemia in clinical trials and adults with type 2 diabetes are shown in Tables 3 and 4, respectively.
• No clinically important differences in risk of hypoglycemia between TRESIBA and long-acting insulin comparators were observed in clinical trials conducted in adult patients.
• Severe hypoglycemia in trials with adult patients was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
• Severe hypoglycemia in the pediatric trial was defined as an altered mental status where the child could not assist in his own care, was semiconscious or unconscious, or in a coma ± convulsions and may require parenteral therapy (glucagon or intravenous glucose).
• A Novo Nordisk hypoglycemia episode was defined as a severe hypoglycemia episode or an episode where a laboratory or a self-measured glucose calibrated to plasma was less than 56 mg/dL or where a whole blood glucose was less than 50 mg/dL (i.e., with or without the presence of hypoglycemic symptoms).

This image is provided by the National Library of Medicine

This image is provided by the National Library of Medicine

Allergic Reactions

• Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including TRESIBA and may be life threatening.
• Hypersensitivity (manifested with swelling of tongue and lips, diarrhea, nausea, tiredness, and itching) and urticaria were reported in 0.9% of patients treated with TRESIBA.

Lipodystrophy

• Long-term use of insulin, including TRESIBA, can cause lipodystrophy at the site of repeated insulin injections.
• Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue) and may affect insulin absorption.
• Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy.
• In the clinical program, lipodystrophy, lipohypertrophy, or lipoatrophy was reported in 0.3% of patients treated with TRESIBA.

Injection Site Reactions

• Patients taking TRESIBA may experience injection site reactions, including injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass. * In the clinical program, injection site reactions occurred in 3.8% of patients treated with TRESIBA.

Weight Gain

• Weight gain can occur with insulin therapy, including TRESIBA, and has been attributed to the anabolic effects of insulin.
• In the clinical program after 52 weeks of treatment, patients with type 1 diabetes treated with TRESIBA gained an average of 1.8 kg and patients with type 2 diabetes treated with TRESIBA gained an average of 3.0 kg.

Peripheral Edema

• Insulin, including TRESIBA, may cause sodium retention and edema.
• In the clinical program, peripheral edema occurred in 0.9% of patients with type 1 diabetes mellitus and 3.0% of patients with type 2 diabetes mellitus treated with TRESIBA.

Immunogenicity

• As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form.
• The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease.
• For these reasons, comparison of the incidence of antibodies to TRESIBA with the incidence of antibodies in other studies or to other products, may be misleading.
• In studies of adult type 1 diabetes patients, 95.9% of patients who received TRESIBA once daily were positive for anti-insulin antibodies (AIA) at least once during the studies, including 89.7% that were positive at baseline.
• In studies of type 2 diabetes patients, 31.5% of patients who received TRESIBA once daily were positive for AIA at least once during the studies, including 14.5% that were positive at baseline.
• The antibody incidence rates for type 2 diabetes may be underreported due to potential assay interference by endogenous insulin in samples in these patients.
• The presence of antibodies that affect clinical efficacy may necessitate dose adjustments to correct for tendencies toward hyper or hypoglycemia.
• The incidence of anti-insulin degludec antibodies has not been established.

Postmarketing Experience

There is limited information regarding Insulin degludec Postmarketing Experience in the drug label.

Drug Interactions

Clinically Significant Drug Interactions with TRESIBA

This image is provided by the National Library of Medicine

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

Risk Summary

• There are no available data with TRESIBA or 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.
• Rats and rabbits were exposed to insulin degludec in animal reproduction studies during organogenesis.
• Pre-and post-implantation losses and visceral/skeletal abnormalities were observed in rats at doses 5 times (rat) and at 10 times (rabbit) the human exposure at a dose of 0.75 U/kg/day.
• These effects were similar to those observed in rats administered human insulin (NPH).
• The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10.
• The estimated background risk of miscarriage for the indicated population is unknown.
• In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk:

• Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications.
• Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Animal Data

• Insulin degludec was investigated in studies covering fertility, embryo-fetal development and pre- and post-natal development in rats and during the period of embryofetal development in rabbits.
• Human insulin (NPH insulin) was included as comparator.
• In these studies insulin degludec caused pre- and post-implantation losses and visceral/skeletal abnormalities when given subcutaneously at up to 21 U/kg/day in rats and 3.3 U/kg/day in rabbits, resulting in 5 times (rat) and 10 times (rabbit) the human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day.
• Overall, the effects of insulin degludec were similar to those observed with human insulin, which were probably secondary to maternal hypoglycemia.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Insulin degludec in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Insulin degludec during labor and delivery.

Nursing Mothers

• 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.
• The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRESIBA and any potential adverse effects on the breastfed infant from TRESIBA or from the underlying maternal condition.
• In lactating rats, insulin degludec was present in milk at a concentration lower than that in plasma.

Pediatric Use

• The safety and effectiveness of TRESIBA to improve glycemic control in type 1 and type 2 diabetes mellitus have been established in pediatric patients 1 year of age and older.
• The safety and effectiveness of TRESIBA have not been established in pediatric patients less than 1 year old.
• The use of TRESIBA in pediatric patients 1 year of age and older with type 1 and type 2 diabetes mellitus is supported by evidence from an adequate and well-controlled study and a pharmacokinetic study (studies included pediatric patients 1 year of age and older with type 1 diabetes mellitus).
• The use of TRESIBA in pediatric patients 1 year of age and older with type 2 diabetes mellitus is also supported by evidence from adequate and well-controlled studies in adults with type 2 diabetes mellitus.
• In pediatric patients 1 year of age and older already on insulin therapy, start TRESIBA at a reduced dose to minimize the risk of hypoglycemia.

Geriatic Use

• In controlled clinical studies [see Clinical Studies (14)] a total of 77 (7%) of the 1102 TRESIBA -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 TRESIBA-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.
• Nevertheless, greater caution should be exercised when TRESIBA is administered to geriatric patients since greater sensitivity of some older individuals to the effects of TRESIBA 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.

Gender

There is no FDA guidance on the use of Insulin degludec with respect to specific gender populations.

Race

There is no FDA guidance on the use of Insulin degludec with respect to specific racial populations.

Renal Impairment

• In clinical studies [see Clinical Studies (14)] a total of 75 (7%) of the 1102 TRESIBA-treated patients with type 1 diabetes had an eGFR less than 60 mL/min/1.73 m2 and 1 (0.1%) had an eGFR less than 30 mL/min/1.73 m2.
• A total of 250 (9%) of the 2713 TRESIBA-treated patients with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m2 and no subjects had an eGFR less than 30 mL/min/1.73 m2.
• No clinically relevant difference in the pharmacokinetics of TRESIBA 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 TRESIBA dosage adjusted on an individual basis in patients with renal impairment.

Hepatic Impairment

• No difference in the pharmacokinetics of TRESIBA 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 TRESIBA dosage adjusted on an individual basis in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Insulin degludec in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Insulin degludec in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Insulin degludec Administration in the drug label.

Monitoring

There is limited information regarding Insulin degludec Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Insulin degludec and IV administrations.

Overdosage

There is limited information regarding Insulin degludec overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Insulin degludec Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Insulin degludec Mechanism of Action in the drug label.

Structure

There is limited information regarding Insulin degludec Structure in the drug label.

Pharmacodynamics

There is limited information regarding Insulin degludec Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Insulin degludec Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Insulin degludec Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Insulin degludec Clinical Studies in the drug label.

How Supplied

There is limited information regarding Insulin degludec How Supplied in the drug label.

Storage

There is limited information regarding Insulin degludec Storage in the drug label.

Images

Drug Images

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Patient Counseling Information

There is limited information regarding Insulin degludec Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Insulin degludec interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Insulin degludec Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Insulin degludec Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.