Insulin degludec: Difference between revisions

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{{Drugbox
{{DrugProjectFormSinglePage
| Watchedfields = changed
|authorTag={{SCh}}
| verifiedrevid = 476995027
|genericName=Insulin degludec
| IUPAC_name = B29N(epsilon)-omega-carboxypentadecanoyl-gamma-L-glutamyl desB30 human insulin
|aOrAn=a
|drugClass=long-acting human insulin analog


<!--Clinical data-->
|indication=to improve glycemic control in patients 1 year of age and older with [[diabetes mellitus]].
| Drugs.com = {{Drugs.com|UK|tresiba}}
| tradename = Tresiba
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->
| legal_status = Rx-only
| routes_of_administration = Subcutaneous
| CAS_number = 844439-96-9
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = NA
| PubChemSubstance = 124490467
| KEGG = D09727
| ATC_prefix = A10
| ATC_suffix = AE06


<!--Chemical data-->
|adverseReactions=[[hypoglycemia]], [[allergic reactions]], [[injection site reactions]], [[lipodystrophy]], [[pruritus]], [[rash]], [[edema]] and [[weight gain]].
| C= 274 | H= 411 | N= 65 | O= 81 | S= 6
 
| molecular_weight = 6103.972 g/mol
|fdaLIADAdult=* 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]].
__NOTOC__
* Do not dilute or mix with any other [[insulin]] or solution.
{{SI}}
* Administer subcutaneously once daily at any time of day.
{{CMG}}
* Do NOT perform dose conversion when using the Insulin degludec U-100 or U-200 FlexTouch pens.
== Overview ==
* The Insulin degludec U-100 and U-200 FlexTouch pens dose window shows the number of [[insulin]] units to be delivered and NO conversion is needed.
'''Insulin degludec''' ([[International Nonproprietary Name|INN]]/[[United States Adopted Name|USAN]]) is an ultralong-acting basal [[insulin analogue]] that was developed by [[Novo Nordisk]] under the brand name '''Tresiba'''.<ref name=CHMP2012/>  It is administered via [[subcutaneous injection]] once daily to help control the [[blood sugar]] level of those with [[diabetes]]. It has a duration of action that lasts up to 40 hours (compared to 18 to 26 hours provided by other marketed long-acting insulins such as [[insulin glargine]] and [[insulin detemir]]), making it a once-daily basal insulin,<ref>{{cite pmid|17391154}}</ref><ref>{{cite pmid|25179915}}</ref><ref>European Medicines Agency: [http://ec.europa.eu/health/documents/community-register/2013/20130121124987/anx_124987_en.pdf Tresiba Summary of product characteristics]</ref> that is one that provides a base insulin level, as opposed to the fast and short acting bolus insulins.
 
|contraindications=* During episodes of [[hypoglycemia]].
* [[Hypersensitivity]] to Insulin degludec or one of its excipients.
 
|warnings=====Never share a 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.
 
====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 Insulin degludec follow dosing recommendations.
 
====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).
* 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 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.
* 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 Insulin degludec into a syringe for administration as overdosage and severe [[hypoglycemia]] can result.
 
====Hypersensitivity reactions====
* Severe, life-threatening, generalized [[allergy]], including [[anaphylaxis]], can occur.
* Discontinue Insulin degludec, 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.
 
|clinicalTrials=* 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 Insulin degludec 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 Insulin degludec with a mean exposure duration to Insulin degludec 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 Insulin degludec with a mean exposure duration to Insulin degludec 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 Insulin degludec 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 Insulin degludec with a mean exposure to Insulin degludec 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 Insulin degludec treated pediatric patients with [[type 1 diabetes mellitus]] were similar to the adverse reactions listed in Table 1.
 
[[File:Insulin ADR1.png|400px|thumb|none|This image is provided by the National Library of Medicine]]
 
[[File:Insulin ADR2.png|400px|thumb|none|This image is provided by the National Library of Medicine]]
 
==== Hypoglycemia ====
* [[Hypoglycemia]] is the most commonly observed adverse reaction in patients using [[insulin]], including Insulin degludec.
* 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 Insulin degludec 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 Insulin degludec 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 Insulin degludec 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).
 
[[File:Insulin ADR3.png|400px|thumb|none|This image is provided by the National Library of Medicine]]
 
[[File:Insulin ADR4.png|400px|thumb|none|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 Insulin degludec 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 Insulin degludec.
 
==== Lipodystrophy ====
* Long-term use of insulin, including Insulin degludec, 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 Insulin degludec.
 
==== Injection Site Reactions ====
* Patients taking Insulin degludec 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 Insulin degludec.
 
==== Weight Gain ====
* [[Weight gain]] can occur with insulin therapy, including Insulin degludec, 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 Insulin degludec gained an average of 1.8 kg and patients with [[type 2 diabetes]] treated with Insulin degludec gained an average of 3.0 kg.
 
==== Peripheral Edema ====
* [[Insulin]], including Insulin degludec, 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 Insulin degludec.
 
==== 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 Insulin degludec 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 Insulin degludec 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 Insulin degludec 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.
 
|drugInteractions===== Clinically Significant Drug Interactions with Insulin degludec ====
 
[[File:Insulin DI.png|400px|thumb|none|This image is provided by the National Library of Medicine]]
 
|useInPregnancyFDA===== Risk Summary ====
 
* 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.
* 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]].
 
|useInNursing=* 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 Insulin degludec and any potential adverse effects on the breastfed infant from Insulin degludec or from the underlying maternal condition.
* In lactating rats, insulin degludec was present in milk at a concentration lower than that in plasma.
 
|useInPed=* The safety and effectiveness of Insulin degludec 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 Insulin degludec have not been established in pediatric patients less than 1 year old.
* The use of Insulin degludec 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 Insulin degludec 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 Insulin degludec at a reduced dose to minimize the risk of [[hypoglycemia]].
 
|useInGeri=* 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.
* 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.
 
|useInRenalImpair=* In clinical studies a total of 75 (7%) of the 1102 Insulin degludec-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 Insulin degludec-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 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.
 
|useInHepaticImpair=* 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.
 
|administration===== Important Administration Instructions ====
* Always check insulin labels before administration.
* Inspect visually for particulate matter and discoloration. Only use Insulin degludec if the solution appears clear and colorless.
* Train patients on proper use and injection technique before initiating Insulin degludec. Training reduces the risk of administration errors such as needle sticks and incomplete dosing.
* Inject Insulin degludec subcutaneously 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 Insulin degludec intravenously, intramuscularly or in an insulin infusion pump.
* DO NOT dilute or mix Insulin degludec with any other insulin products or solutions.
* DO NOT transfer Insulin degludec from the Insulin degludec pen into a syringe for administration.
 
|monitoring===== General Dosing Instructions ====
* In adults, inject Insulin degludec subcutaneously once-daily at any time of day.
* In pediatric patients inject Insulin degludec subcutaneously once-daily at the same time every day.
* Individualize and titrate the dose of Insulin degludec based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal.
* The recommended days between dose increases is 3 to 4 days.
* Dose adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., 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.
* For adult patients, instruct patients who miss a dose of Insulin degludec to inject their daily dose during waking hours upon discovering the missed dose. Instruct patients to ensure that at least 8 hours have elapsed between consecutive Insulin degludec injections.
* For pediatric patients, instruct patients who miss a dose of Insulin degludec to contact their healthcare provider for guidance and to monitor blood glucose levels more frequently until the next scheduled Insulin degludec dose.
* DO NOT perform dose conversion when using the Insulin degludec U-100 or U-200 FlexTouch pens.
* The dose window for both the Insulin degludec U-100 and U-200 FlexTouch pens shows the number of insulin units to be delivered and NO conversion is needed.
 
==== Starting Dose in Insulin Naïve Patients ====
 
===== Type 1 Diabetes Mellitus: =====
* The recommended starting dose of Insulin degludec in insulin naïve patients with [[type 1 diabetes]] is approximately one-third to one-half of the total daily insulin dose.
* The remainder of the total daily insulin dose should be administered as a short-acting insulin and divided between each daily meal.
* As a general rule, 0.2 to 0.4 units of insulin per kilogram of body weight can be used to calculate the initial total daily insulin dose in insulin naïve patients with [[type 1 diabetes]].
 
===== Type 2 Diabetes Mellitus: =====
* The recommended starting dose of Insulin degludec in insulin naïve patients with [[type 2 diabetes mellitus]] is 10 units once daily.
 
==== Starting Dose in Patients Already on Insulin Therapy ====
 
===== Adults withType 1 or Type 2 Diabetes Mellitus: =====
* Start Insulin degludec at the same unit dose as the total daily long or intermediate-acting insulin unit dose.
* Pediatric Patients 1 Year of Age and Older with Type 1 or Type 2 [[Diabetes Mellitus]]:
* Start Insulin degludec at 80% of the total daily long or intermediate-acting insulin unit dose to minimize the risk of hypoglycemia.
 
|overdose=* An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening [[hypoglycemia]] and [[hypokalemia]].
* Mild episodes of [[hypoglycemia]] usually can be treated with oral glucose.
* Adjustments in drug dosage, meal patterns, or exercise may be needed.
* More severe episodes of hypoglycemia with [[coma]], [[seizure]], or neurologic impairment may be treated with intramuscular/subcutaneous [[glucagon]] or concentrated intravenous glucose.
* After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid reoccurrence of hypoglycemia.
* [[Hypokalemia]] must be corrected appropriately.
 
|mechAction=* 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.
 
|structure=* Insulin degludec injection is a long-acting basal human insulin analog for subcutaneous injection.
* Insulin degludec is produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification.
* Insulin degludec differs from human insulin in that the amino acid threonine in position B30 has been omitted and a side-chain consisting of glutamic acid and a C16 fatty acid has been attached (chemical name: LysB29(Nε-hexadecandioyl-γ-Glu) des(B30) human insulin).
* Insulin degludec has a molecular formula of C274H411N65O81S6 and a molecular weight of 6103.97.
* It has the following structure:
 
[[File:Insulin degludec structure.png|800px|thumb|none|This image is provided by the National Library of Medicine]]
 
* Insulin degludec is a sterile, aqueous, clear, and colorless solution that contains insulin degludec 100 units/mL (U-100) or 200 units/mL (U-200).
* Inactive ingredients for the 100 units/mL are: glycerol 19.6 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 32.7 mcg/mL and water for injection.
* Inactive ingredients for the 200 units/mL are glycerol 19.6 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 71.9 mcg/mL and water for injection.
* Insulin degludec has a pH of approximately 7.6. Hydrochloric acid or sodium hydroxide may be added to adjust pH.
 
|PD=* The glucose-lowering effect of Insulin degludec after 8 days of once-daily dosing was measured in a euglycemic glucose clamp study enrolling 21 patients with [[type 1 diabetes]].
* Figure 2 shows the pharmacodynamic effect of Insulin degludec over time following 8 once-daily subcutaneous injections of 0.4 U/kg of Insulin degludec in patients with [[type 1 diabetes]].
 
[[File:Insulin PD.png|400px|thumb|none|This image is provided by the National Library of Medicine]]
 
* The mean maximum glucose lowering effect (GIRmax) of a 0.4 units/kg dose of Insulin degludec was 2.0 mg/kg/min, which was observed at a median of 12 hours post-dose.
* The glucose lowering effect of Insulin degludec lasted at least 42 hours after the last of 8 once-daily injections.
* In patients with [[type 1 diabetes mellitus]], the steady-state, within subjects, day-to-day variability in total glucose lowering effect was 20% with Insulin degludec (within-subject coefficient of variation for AUCGIR,τ,SS).
* The total glucose-lowering effect of Insulin degludec over 24 hours measured in a euglycemic clamp study after 8 days of once-daily administration in patients with [[type 1 diabetes]] increases approximately in proportion to the dose for doses between 0.4 units/kg to 0.8 units/kg.
* The total glucose-lowering effect of 0.4 units/kg of Insulin degludec U-100 and 0.4 units/kg of Insulin degludec U-200, administered at the same dose, and assessed over 24 hours in a euglycemic clamp study after 8 days of once-daily injection was comparable.
 
|PK===== Absorption ====
* In patients with [[type 1 diabetes]], after 8 days of once daily [[subcutaneous]] dosing with 0.4 units/kg of Insulin degludec, maximum degludec concentrations of 4472 pmol/L were attained at a median of 9 hours (tmax).
* After the first dose of Insulin degludec, median onset of appearance was around one hour.
* Total insulin degludec concentration (i.e., exposure) increased in a dose proportional manner after subcutaneous administration of 0.4 units/kg to 0.8 units/kg Insulin degludec.
* Total and maximum insulin degludec exposure at steady state are comparable between Insulin degludec U-100 and Insulin degludec U-200 when each is administered at the same units/kg dose.
* Insulin degludec concentration reach steady state levels after 3-4 days of Insulin degludec administration.
 
==== Distribution ====
* The affinity of insulin degludec to serum [[albumin]] corresponds to a plasma protein binding of >99% in human plasma.
* The results of the in vitro protein binding studies demonstrate that there is no clinically relevant interaction between insulin degludec and other protein bound drugs.
 
==== Elimination ====
* The half-life after subcutaneous administration is determined primarily by the rate of absorption from the subcutaneous tissue.
* On average, the half-life at steady state is approximately 25 hours independent of dose.
* Degradation of Insulin degludec is similar to that of insulin human; all metabolites formed are inactive.
* The mean apparent clearance of insulin degludec is 0.03 L/kg (2.1 L/h in 70 kg individual) after single subcutaneous dose of 0.4 units/kg.
 
=== Specific Populations ===
 
==== Pediatrics ====
* Population pharmacokinetic analysis was conducted for Insulin degludec using data from 199 pediatric subjects (1 to <18 years of age) with [[type 1 diabetes]].
* Body weight was a significant covariate affecting the clearance of Insulin degludec.
* After adjusting for body weight, the total exposure of Insulin degludec at steady state was independent of age.
 
==== Geriatrics ====
* Pharmacokinetic and pharmacodynamic response of Insulin degludec was compared in 13 younger adult (18−35 years) and 14 geriatric (≥65 years) subjects with [[type 1 diabetes]] following two 6-day periods of once-daily subcutaneous dosing with 0.4 units/kg dose of Insulin degludec or [[insulin glargine]].
* On average, the pharmacokinetic and pharmacodynamic properties of Insulin degludec at steady-state were similar in younger adult and geriatric subjects, albeit with greater between subject variability among the geriatric subjects.
 
==== Gender ====
* The effect of gender on the pharmacokinetics of Insulin degludec was examined in an across-trial analysis of the pharmacokinetic and pharmacodynamic studies conducted using unit/kg doses of Insulin degludec.
* Overall, there were no clinically relevant differences in the pharmacokinetic properties of insulin degludec between female and male subjects.
 
==== Obesity ====
* The effect of [[BMI]] on the pharmacokinetics of Insulin degludec was explored in a cross-trial analysis of pharmacokinetic and pharmacodynamic studies conducted using unit/kg doses of Insulin degludec.
* For subjects with [[type 1 diabetes]], no relationship between exposure of Insulin degludec and [[BMI]] was observed.
* For subjects with type 1 and type 2 diabetes a trend for decrease in glucose-lowering effect of Insulin degludec with increasing [[BMI]] was observed.
 
==== Race and Ethnicity ====
* Insulin degludec has been studied in a pharmacokinetic and pharmacodynamic study in Black or African American subjects not of Hispanic or Latino origin (n=18), White subjects of Hispanic or Latino origin (n=22) and White subjects not of Hispanic or Latino origin (n=23) with [[type 2 diabetes mellitus]] conducted using unit/kg doses of Insulin degludec.
* There were no statistically significant differences in the pharmacokinetic and pharmacodynamic properties of Insulin degludec between the racial and ethnic groups investigated.
 
==== Pregnancy ====
* The effect of pregnancy on the pharmacokinetics and pharmacodynamics of Insulin degludec has not been studied.
 
==== Renal Impairment ====
* Insulin degludec pharmacokinetics was studied in 32 subjects (n=4-8/group) with normal or impaired renal function/[[end stage renal disease]] following administration of a single subcutaneous dose (0.4 units/kg) of Insulin degludec.
* Renal function was defined using [[creatinine]] clearance (Clcr) as follows: ≥90 mL/min (normal), 60-89 mL/min (mild), 30-59 mL/min (moderate) and <30 mL/min (severe).
* Subjects requiring [[dialysis]] were classified as having [[end stage renal disease]] (ESRD).
* Total (AUCIDeg,0-120h,SD) and peak exposure of Insulin degludec were on average about 10-25% and 13-27% higher, respectively in subjects with mild to severe renal impairment except subjects with ESRD who showed similar exposure as compared to subjects with normal renal function.
* No systematic trend was noted for this increase in exposure across different renal impairment subgroups. [[Hemodialysis]] did not affect clearance of Insulin degludec (CL/FIDeg,SD) in subjects with [[ESRD]].
 
==== Hepatic Impairment ====
* Insulin degludec has been studied in a pharmacokinetic study in 24 subjects (n=6/group) with normal or impaired hepatic function (mild, moderate, and severe hepatic impairment) following administration of a single subcutaneous dose (0.4 units/kg) of Insulin degludec.
* Hepatic function was defined using [[Child-Pugh Score]] ranging from 5 (mild hepatic impairment) to 15 (severe hepatic impairment).
* No differences in the pharmacokinetics of Insulin degludec were identified between healthy subjects and subjects with hepatic impairment.
 
|nonClinToxic===== Carcinogenesis, Mutagenesis, Impairment of Fertility ====
* Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of insulin degludec.
* In a 52-week study including human insulin (NPH insulin) as comparator (6.7 units/kg/day), Sprague-Dawley rats were dosed subcutaneously with insulin degludec at 3.3, 6.7, and 10 units/kg/day, resulting in 5 times the human exposure (AUC) when compared to a human subcutaneous dose of 0.75 units/kg/day. Human insulin was dosed at 6.7 units/kg/day.
* No treatment-related increases in incidences of hyperplasia, benign or malignant tumors were recorded in female mammary glands from rats dosed with insulin degludec and no treatment related changes in the female mammary gland cell proliferation were found using BrdU incorporation.
* Further, no treatment related changes in the occurrence of hyperplastic or neoplastic lesions were seen in other tissues in animals dosed with insulin degludec when compared to vehicle or human insulin.
* Genotoxicity testing of insulin degludec was not performed.
* In a combined fertility and embryo-fetal study in male and female rats, treatment with insulin degludec up to 21 units/kg/day (approximately 5 times the human subcutaneous dose of 0.75 units/kg/day, based on units/body surface area) prior to mating and in female rats during gestation had no effect on mating performance and fertility.
 
|clinicalStudies=* The efficacy of Insulin degludec administered once-daily either at the same time each day or at any time each day in patients with [[type 1 diabetes]] and used in combination with a mealtime [[insulin]] was evaluated in three randomized, open-label, treat-to-target, active-controlled trials in adults and one randomized, open-label, treat-to-target, active-controlled trial in pediatric patients 1 year of age and older.
* The efficacy of Insulin degludec administered once-daily either at the same time each day or at any time each day in adult patients with type 2 diabetes and used in combination with a mealtime insulin or in combination with common oral anti-diabetic agents was evaluated in six randomized, open-label, treat-to-target active-controlled trials.
* Adult patients treated with Insulin degludec achieved levels of glycemic control similar to those achieved with LANTUS ([[insulin glargine]] 100 units/mL) and LEVEMIR ([[insulin detemir]]) and achieved statistically significant improvements compared to [[sitagliptin]].
 
====Type 1 Diabetes – Adult====
* Insulin degludec Administered at the Same Time Each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes in Adult Patients.
 
===== Study A =====
* The efficacy of Insulin degludec was evaluated in a 52-week randomized, open-label, multicenter trial in 629 patients with [[type 1 diabetes mellitus]] (Study A).
* Patients were randomized to Insulin degludec once-daily with the evening meal or [[insulin glargine]] U-100 once-daily according to the approved labeling.
* [[Insulin aspart]] was administered before each meal in both treatment arms.
* The mean age of the trial population was 43 years and mean duration of [[diabetes]] was 18.9 years. 58.5% were male. 93% were White, 1.9% Black or African American. 5.1% were Hispanic. 8.6% of patients had eGFR<60 mL/min/1.73m2.
* The mean [[BMI]] was approximately 26.3 kg/m2.
* At week 52, the difference in [[HbA1c]] reduction from baseline between Insulin degludec and [[insulin glargine]] U-100 was -0.01% with a 95% confidence interval of [-0.14%; 0.11%] and met the pre-specified non-inferiority margin (0.4%).
 
===== Study B =====
* The efficacy of Insulin degludec was evaluated in a 26-week randomized, open-label, multicenter trial in 455 patients with [[type 1 diabetes mellitus]] (Study B).
* Patients were randomized to Insulin degludec or insulin detemir once-daily in the evening.
* After 8 weeks, [[insulin detemir]] could be dosed twice-daily. 67.1% used insulin detemir once daily at end of trial. 32.9% used [[insulin detemir]] twice daily at end of trial.
* [[Insulin aspart]] was administered before each meal in both treatment arms.
* The mean age of the trial population was 41.3 years and mean duration of diabetes was 13.9 years. 51.9% were male. 44.6% were White, 0.4% Black or African American. 4.4% were Hispanic. 4.4% of patients had eGFR<60 mL/min/1.73m2. The mean [[BMI]] was approximately 23.9 kg/m2.
* At week 26, the difference in [[HbA1c]] reduction from baseline between Insulin degludec and [[insulin detemir]] was -0.09% with a 95% confidence interval of [-0.23%; 0.05%] and met the pre-specified non-inferiority margin (0.4%).
 
===== Study C: =====
* Insulin degludec Administered at the Same Time Each Day or at Any Time Each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes in Adult Patients.
* The efficacy of Insulin degludec was evaluated in a 26-week randomized, open-label, multicenter trial in 493 patients with [[type 1 diabetes mellitus]].
* Patients were randomized to Insulin degludec injected once-daily at the same time each day (with the main evening meal), to Insulin degludec injected once daily at any time each day or to [[insulin glargine]] U-100 injected once-daily according to the approved labeling.
* The any time each day Insulin degludec arm was designed to simulate a worst-case scenario injection schedule of alternating short and long, once daily, dosing intervals (i.e., alternating intervals of 8 to 40 hours between doses).
* Insulin degludec in this arm was dosed in the morning on Monday, Wednesday, and Friday and in the evening on Tuesday, Thursday, Saturday, and Sunday.
* [[Insulin aspart]] was administered before each meal in all treatment arms.
* The mean age of the trial population was 43.7 years and mean duration of [[diabetes]] was 18.5 years. 57.6% were male. 97.6% were White, 1.8% Black or African American. 3.4% were Hispanic. 7.4% of patients had eGFR<60 mL/min/1.73m2. The mean [[BMI]] was approximately 26.7 kg/m2.
* At week 26, the difference in [[HbA1c]] reduction from baseline between Insulin degludec administered at alternating times and [[insulin glargine]] U-100 was 0.17% with a 95% confidence interval of [0.04%; 0.30%] and met the pre-specified non-inferiority margin (0.4%).
 
==== Type 1 Diabetes – Pediatric Patients 1 Year of Age and Older ====
* '''Study J''':Insulin degludec Administered at the Same Time Each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes in Pediatric Patients 1 Year of Age and Older.
* The efficacy of Insulin degludec was evaluated in a 26-week, randomized, open label, multicenter trial in 350 patients with [[type 1 diabetes mellitus]] (Study J).
* Patients were randomized to Insulin degludec once-daily or [[insulin detemir]] once or twice-daily.
* Subjects on a twice-daily [[insulin detemir]] regimen were dosed at breakfast and in the evening either with the main evening meal or at bedtime.
* [[Insulin aspart]] was administered before each main meal in both treatment arms.
* At end of trial, 36% used [[insulin detemir]] once daily and 64% used [[insulin detemir]] twice daily.
* The mean age of the trial population was 10 years; 24% were ages 1-5 years; 39% were ages 6-11 years and 36% were ages 12-17 years.
* The mean duration of [[diabetes]] was 4 years. 55.4% were male. 74.6% were White, 2.9% Black or African American. 2.9% were Hispanic. The mean z-score for body weight was 0.31.
* At week 26, the difference in [[HbA1c]] reduction from baseline between Insulin degludec and [[insulin detemir]] was 0.15% with a 95% confidence interval of [-0.03%; 0.33%] and met the pre-specified non-inferiority margin (0.4%).
 
==== Type 2 Diabetes - Adult ====
* '''Study D''': Insulin degludec Administered at the Same Time Each Day as an Add-on to [[Metformin]] with or without a [[DPP-4 Inhibitor]] in Insulin Naïve Adult Patients.
* The efficacy of Insulin degludec was evaluated in a 52-week randomized, open-label, multicenter trial that enrolled 1030 insulin naïve patients with [[type 2 diabetes mellitus]] inadequately controlled on one or more oral antidiabetic agents (OADs).
* Patients were randomized to Insulin degludec once-daily with the evening meal or [[insulin glargine]] U-100 once-daily according to the approved labeling.
* [[Metformin]] alone (82.5%) or in combination with a [[DPP-4 inhibitor]] (17.5%) was used as background therapy in both treatment arms.
* The mean age of the trial population was 59.1 years and mean duration of [[diabetes]] was 9.2 years. 61.9% were male. 88.4% were White, 7.1% Black or African American. 17.2% were Hispanic. 9.6% of patients had eGFR<60 mL/min/1.73m2. The mean [[BMI]] was approximately 31.1 kg/m2.
* At week 52, the difference in [[HbA1c]] reduction from baseline between Insulin degludec and [[insulin glargine]] U-100 was 0.09% with a 95% confidence interval of [-0.04%; 0.22%] and met the pre-specified non-inferiority margin (0.4%);
 
* '''Study E''': Insulin degludec U-200 Administered at the Same Time Each Day as an Add-on to [[Metformin]] with or without a [[DPP-4 Inhibitor]] in Insulin Naïve Adult Patients
* The efficacy of Insulin degludec U-200 was evaluated in a 26-week randomized, open-label, multicenter trial in 457 insulin naïve patients with [[type 2 diabetes mellitus]] inadequately controlled on one or more oral antidiabetic agents (OADs) at baseline.
* Patients were randomized to Insulin degludec U-200 once-daily with the evening meal or [[insulin glargine]] U-100 once-daily according to the approved labeling.
* Both treatment arms were receiving [[metformin]] alone (84%) or in combination with a [[DPP-4 inhibitor]] (16%) as background therapy.
* The mean age of the trial population was 57.5 years and mean duration of [[diabetes]] was 8.2 years. 53.2% were male. 78.3% were White, 13.8% Black or African American. 7.9% were Hispanic. 7.5% of patients had eGFR <60 mL/min/1.73m2. The mean BMI was approximately 32.4 kg/m2.
* At week 26, the difference in [[HbA1c]] reduction from baseline between Insulin degludec U-200 and [[insulin glargine]] U-100 was 0.04% with a 95% confidence interval of [-0.11%; 0.19%] and met the pre-specified non-inferiority margin (0.4%).
 
* '''Study F''': Insulin degludec administered at the Same Time Each Day in Insulin Naïve Adult Patients as an Add-on to One or More of the Following Oral Agents: [[Metformin]], [[Sulfonylurea]], Glinides or [[Alpha-Glucosidase Inhibitors]]
* The efficacy of Insulin degludec was evaluated in a 26-week randomized, open-label, multicenter trial in Asia in 435 insulin naïve patients with [[type 2 diabetes mellitus]] inadequately controlled on one or more oral antidiabetic agents (OADs) at baseline.
* Patients were randomized to Insulin degludec once-daily in the evening or [[insulin glargine]] U-100 once-daily according to the approved labeling.
* Pre-trial oral antidiabetes agents were continued as background therapy except for [[DPP-4 inhibitors]] or [[thiazolidinediones]] in both treatment arms.
* The mean age of the trial population was 58.6 years and mean duration of diabetes was 11.6 years. 53.6% were male. All patients were Asian. 10.9% of patients had eGFR<60 mL/min/1.73m2. The mean [[BMI]] was approximately 25.0 kg/m2.
* At week 26, the difference in [[HbA1c]] reduction from baseline between Insulin degludec and insulin glargine U-100 was 0.11% with a 95% confidence interval of [-0.03%; 0.24%] and met the pre-specified non-inferiority margin (0.4%).
 
* '''Study G''': Insulin degludec Administered at the Same Time Each Day or Any Time Each Day as an Add-on to One and up to Three of the Following Oral Agents: [[Metformin]], [[Sulfonylurea]] or Glinides or [[Pioglitazone]] in Adult Patients
* The efficacy of Insulin degludec was evaluated in a 26-week randomized, open-label, multicenter trial in 687 patients with [[type 2 diabetes mellitus]] inadequately controlled on basal insulin alone, oral antidiabetic agents (OADs) alone or both basal [[insulin]] and OAD.
* Patients were randomized to Insulin degludec injected once-daily at the same time each day (with the main evening meal), to Insulin degludec injected once daily at any time each day or to [[insulin glargine]] U-100 injected once-daily according to the approved labeling.
* The any time each day Insulin degludec arm was designed to simulate a worst-case scenario injection schedule of alternating short and long, once daily, dosing intervals (i.e., alternating intervals of 8 to 40 hours between doses).
* Insulin degludec in this arm was dosed in the morning on Monday, Wednesday, and Friday and in the evening on Tuesday, Thursday, Saturday, and Sunday.  
* Up to three of the following oral antidiabetes agents ([[metformin]], [[sulfonylureas]], glinides or [[thiazolidinediones]]) were administered as background therapy in both treatment arms.
* The mean age of the trial population was 56.4 years and mean duration of diabetes was 10.6 years. 53.9% were male. 66.7% were White, 2.5% Black or African American. 10.6% were Hispanic. 5.8% of patients had eGFR<60 mL/min/1.73m2. The mean BMI was approximately 29.6 kg/m2.
* At week 26, the difference in HbA1c reduction from baseline between Insulin degludec at alternating times and insulin glargine U-100 was 0.04% with a 95% confidence interval of [-0.12%; 0.20%]. This comparison met the pre-specified non-inferiority margin (0.4%).
 
* '''Study H''': Insulin degludec Administered at the Same Time Each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes in Adult Patients
* The efficacy of Insulin degludec was evaluated in a 52-week randomized, open-label, multicenter trial in 992 patients with [[type 2 diabetes mellitus]] inadequately controlled on premix insulin, bolus insulin alone, basal insulin alone, oral antidiabetic agents (OADs) alone or any combination thereof.
* Patients were randomized to Insulin degludec once-daily with the main evening meal or [[insulin glargine]] U-100 once-daily according to the approved labeling.
* Insulin aspart was administered before each meal in both treatment arms.
* Up to two of the following oral antidiabetes agents ([[metformin]] or [[pioglitazone]]) were used as background therapy in both treatment arms.
* The mean age of the trial population was 58.9 years and mean duration of diabetes was 13.5 years. 54.2% were male. 82.9% were White, 9.5% Black or African American. 12.0% were Hispanic. 12.4% of patients had eGFR<60 mL/min/1.73m2. The mean BMI was approximately 32.2 kg/m2.
* At week 52, the difference in HbA1c reduction from baseline between Insulin degludec and insulin glargine U-100 was 0.08% with a 95% confidence interval of [-0.05%; 0.21%] and met the pre-specified non-inferiority margin (0.4%).
 
* '''Study I''': Insulin degludec Administered at Any Time Each Day as an Add-on to One or Two of the Following Oral Agents: [[Metformin]], [[Sulfonylurea]], or [[Pioglitazone]] in Adult Patients.
* The efficacy of Insulin degludec was evaluated in a 26-week randomized, open-label, multicenter trial in 447 patients with type 2 diabetes mellitus inadequately controlled on one or more oral antidiabetic agent (OADs) at baseline.
* Patients were randomized to Insulin degludec once-daily at any time of day or [[sitagliptin]] once-daily according to the approved labeling.
* One or two of the following oral antidiabetes agents ([[metformin]], [[sulfonylurea]] or [[pioglitazone]]) were also administered in both treatment arms.
* The mean age of the trial population was 55.7 years and mean duration of diabetes was 7.7 years. 58.6% were male. 61.3% were White, 7.6% Black or African American. 21.0% were Hispanic. 6% of patients had eGFR<60 mL/min/1.73m2. The mean BMI was approximately 30.4 kg/m2.
* At the end of 26 weeks, Insulin degludec provided greater reduction in mean HbA1c compared to [[sitagliptin]] (p < 0.001).
 
|howSupplied=* Insulin degludec is available as a clear and colorless solution in the following package sizes.
 
[[File:Insulin Supply.png|400px|thumb|none|This image is provided by National Library of Medicine]]
 
|storage=* Unused Insulin degludec should be stored between 36°F to 46°F (2°C to 8°C).
* Do not store in the freezer or directly adjacent to the refrigerator cooling element.
* Do not freeze.
* Do not use Insulin degludec if it has been frozen.
* '''Unopened FlexTouch disposable prefilled pen''':
** Not in-use (unopened) Insulin degludec disposable prefilled pen should be stored in a refrigerator (36°F to 46°F [2°C to 8°C]). Discard after expiration date.
* '''Open (In-Use) FlexTouch disposable prefilled pen''':
** The in-use Insulin degludec FlexTouch pen should be refrigerated (36°F to 46°F [2°C to 8°C]) or be kept at room temperature (below 86°F [30°C]) away from direct heat and light.
** The opened (in-use) Insulin degludec FlexTouch pen may be used for up to 56 days (8 weeks) after being opened, if it is refrigerated or kept at room temperature.
* The storage conditions are summarized in Table 16:
 
[[File:Insulin Storage.png|400px|thumb|none|This image is provided by the National Library of Medicine]]
 
|packLabel=NDC 0169-2660-15
 
List: 266015
 
'''TRESIBA'''®
 
'''FlexTouch'''®
 
('''insulin degludec injection''')
 
'''For Single Patient Use Only'''
 
'''100 units/mL (U-100)'''
 
5×3 mL Prefilled Pens
 
'''For subcutaneous use only'''
 
Rx Only
 
'''Recommended for use with NovoFine®,
NovoFine® Plus or NovoTwist® disposable needles'''.
 
'''Keep in a cold place until first use.'''
 
'''Store at 36°F to 46°F (2°C to 8°C).'''
 
'''Do not freeze'''.
 
'''After first use, store between 36°F to 86°F (2°C to 30°C)'''.
 
'''Protect from light'''.
[[File:Insulin degludec 100.png|400px|thumb|none|This image is provided by National Library of Medicine]]
 
'''NDC 0169-2550-13'''
 
'''List: 255013'''
 
'''TRESIBA'''®
 
'''FlexTouch'''®
 
('''insulin degludec injection''')
 
'''For Single Patient Use Only'''
 
'''200 units/mL (U-200)'''


Insulin degludec is a modified insulin that has one single amino acid deleted in comparison to human insulin, and is conjugated to hexadecanedioic acid via gamma-L-glutamyl spacer at the amino acid [[lysine]] at position B29.
3×3 mL Prefilled Pens


==Pharmacology==
'''For subcutaneous use only'''


===Mechanism of action===
Rx Only
Insulin degludec is an ultra-long acting insulin that, unlike [[insulin glargine]], is active at a physiologic pH.  The addition of hexadecanedioic acid to lysine at the B29 position allows for the formation of multi-hexamers in subcutaneous tissues.<ref name="Degludec review">{{cite journal|last=Nasrallah|first=SN|author2=Reynolds, LR|title=Insulin Degludec, The New Generation Basal Insulin or Just another Basal Insulin?|journal=Clinical medicine insights. Endocrinology and diabetes|year=2012|volume=5|pages=31–7|pmid=22879797|doi=10.4137/CMED.S9494|pmc=3411522}}</ref>  This allows for the formation of a subcutaneous [[Injection (medicine)#Depot injection|depot]] that results in slow insulin release into the systemic circulation.<ref name="Drugs article">{{cite journal|last=Robinson|first=JD|author2=Neumiller, JJ |author3=Campbell, RK |title=Can a New Ultra-Long-Acting Insulin Analogue Improve Patient Care? Investigating the Potential Role of Insulin Degludec.|journal=Drugs|date=Nov 2, 2012|pmid=23145524|doi=10.2165/11642240-000000000-00000|volume=72|issue=18|pages=2319–25}}</ref>


===Pharmacodynamics===
'''Recommended for use with
Insulin degludec has an onset of action of 30–90 minutes (similar to [[insulin glargine]] and [[insulin detemir]]).  There is no peak in activity, due to the slow release into systemic circulation.  The duration of action of insulin degludec is reported as being longer than 24 hours.<ref name="Degludec review" /><ref name=systematicrev>{{cite journal|last=Wang|first=F|author2=Surh, J |author3=Kaur, M |title=Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review.|journal=Diabetes, metabolic syndrome and obesity : targets and therapy|year=2012|volume=5|pages=191–204|pmid=22826637|doi=10.2147/DMSO.S21979|pmc=3402007}}</ref>
NovoFine®, NovoFine® Plus or NovoTwist®
disposable needles'''.


==Effectiveness profile==
'''Keep in a cold place
Studies have shown that patients taking insulin degludec needed to take significantly smaller doses of [[basal rate|basal insulin]] than those taking insulin glargine, while achieving similar blood glucose levels.  Insulin degludec also has the ability to be mixed with other insulins, thereby improving [[glycemic control]]. This cannot be done using current long-acting insulins.<ref name=monograph>{{cite web|url=http://www.medscape.com/druginfo/monograph?cid=med&drugid=20805&drugname=Insulin+Glargine+SubQ&monotype=monograph&secid=3|title=Monograph - Insulin Glargine: Dosage & Administration|work=American Society of Health-System Pharmacists, Inc.|accessdate=2010-11-07}}</ref><ref name=reuters>{{cite news|url=http://www.reuters.com/article/idUSLDE65P0DB20100626|work=[[Reuters]]|author=Ringstrom, Anna|title=Novo says degludec has potential to lower blood sugar|accessdate=2010-11-07|date=2010-06-26}}</ref> A physician involved in the trials was quoted as saying,
until first use'''.
<blockquote>
"This allows the creation of a novel formulation that retains the smooth control of a long-acting basal with rapid-acting mealtime control from [[insulin aspart]]. This 2-component insulin retains the ultralow risk characteristics of degludec with simultaneous mealtime coverage."<ref name=medscape>{{cite news|url=http://www.medscape.com/viewarticle/724316|title=Novel Ultralong-Acting Insulin as Effective as Insulin Glargine|author=Lowry, Fran|work=[[Medscape]]|accessdate=2010-11-07}}</ref> </blockquote>


Insulin degludec has been filed for registration in the United States.<ref name=novo>{{cite web|url=http://www.novonordisk.com/science/pipeline/rd_pipeline.asp?sort=6&phase=000.All&indication=Diabetes|work=[[Novo Nordisk]]|title=R&D Pipeline|accessdate=2012-01-27}}</ref>  Novo Nordisk hopes to begin marketing the insulin analog in 2015 or 2016 after the completion of additional cardiac safety studies requested by the U.S. [[Food and Drug Administration]] (FDA) in February 2013.<ref name=reuters2>{{cite news|url=http://www.reuters.com/article/idUSLDE69Q13H20101027?feedType=RSS&feedName=rbssHealthcareNews|work=Reuters|title=New Novo insulin fails to knock out rival Sanofi|author=Hirschler, Ben|date=2010-10-27|accessdate=2010-11-07}}</ref>
'''Store at 36°F to 46°F (2°C to 8°C)'''.


==Clinical trial data==
'''Do not freeze'''.


===Type 1 diabetes mellitus===
'''After first use, store between 36°F to 86°F (2°C to 30°C)'''.
Insulin degludec was studied as an alternative to insulin glargine as part of a basal-bolus regimen in the BEGIN Basal-Bolus Type 1 trial.  629 patients with [[type 1 diabetes]] were randomized in a 3:1 ratio to either insulin degludec (n=472) or insulin glargine (n=157) in addition to mealtime insulin aspart.  Patients in the degludec treatment arm were switched from their basal insulin to insulin degludec in a 1:1 ratio, with a 20-30% dose reduction in patients receiving multiple basal doses per day.  After 52 weeks, patients treated with insulin degludec produced a similar reduction in [[HbA1c]] (0.40% vs. 0.39%) meeting the criteria for noninferiority.  Adverse events were similar in the two treatment arms; however, rates of nocturnal [[hypoglycemia]] (between midnight and 6am) were 27% lower in patients treated with insulin degludec (3.91 vs. 5.22%,p=0.024). The reduction in the incidence of hypoglycemia was seen as a therapeutic benefit, as hypoglycemia is often a dose limiting toxicity in insulin therapy.<ref>{{cite journal|last=Heller|first=S|coauthors=Buse, J; Fisher, M; Garg, S; Marre, M; Merker, L; Renard, E; Russell-Jones, D; Philotheou, A; Francisco, AM; Pei, H; Bode, B; BEGIN Basal-Bolus Type 1 Trial, Investigators|title=Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.|journal=Lancet|date=Apr 21, 2012|volume=379|issue=9825|pages=1489–97|pmid=22521071|doi=10.1016/S0140-6736(12)60204-9}}</ref>


===Type 2 diabetes mellitus===
'''Protect from light'''.
In the BEGIN Basal-Bolus Type 2 trial, insulin degludec was studied as an alternative to insulin glargine in patients with [[type 2 diabetes mellitus]]. 995 patients were randomized to receive either insulin degludec (n=755) or insulin glargine (n=251), in addition to either mealtime insulin aspart, [[metformin]], and/or [[pioglitazone]].  Patients in this trial had an average HbA1c of 8.3-8.4%, and 49-50% were on a regimen consisting of basal-bolus insulin + oral antidiabetic medications.  After 52 weeks, insulin degludec was found to be noninferior to insulin glargine, providing a similar HbA1c lowering effect (-1.10 vs. -1.18%).  Overall rates of hypoglycemia were significantly lower with insulin degludec (11.09 vs. 13.63%/yr, p=0.0359), including cases of nocturnal hypoglycemia (1.39 vs. 1.84%/yr, p=0.0399).<ref>{{cite journal|last=Garber|first=AJ|coauthors=King, AB; Del Prato, S; Sreenan, S; Balci, MK; Muñoz-Torres, M; Rosenstock, J; Endahl, LA; Francisco, AM; Hollander, P; NN1250-3582 (BEGIN BB T2D) Trial, Investigators|title=Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.|journal=Lancet|date=Apr 21, 2012|volume=379|issue=9825|pages=1498–507|pmid=22521072|doi=10.1016/S0140-6736(12)60205-0}}</ref>


==Side effects==
[[File:Insulin degludec 200.png|400px|thumb|none|This image is provided by National Library of Medicine]]
A significant side effect of insulin therapy is hypoglycemia.  A meta-analysis of clinical trails published in July 2012 found 39-47.9 events of hypoglycemia (defined as blood glucose <56&nbsp;mg/dL) per patient year, with higher rates in the more concentrated degludec formulation. Rates of nocturnal hypoglycemia ranged from 3.7-5.1 events per patient year.<ref name="systematicrev"/>


==References==
|fdaPatientInfo===== Never Share a Insulin degludec FlexTouch Pen Between Patients ====
{{reflist|2|ref=
* 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.


<ref name=CHMP2012>{{Citation |author=[[Committee for Medicinal Products for Human Use|CHMP]] |publication-date=October 18, 2012 |title=Summary of opinion 1 (initial authorisation): Tresiba |type=PDF |work=Pending EC decisions |publisher=[[European Medicines Agency|EMA]] |url=http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002498/WC500134060.pdf |accessdate=November 6, 2012 }}</ref>
==== 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.
* Advise patients that changes in insulin regimen can predispose to hyper- or hypoglycemia.
* Advise patients that changes in insulin regimen should be made under close medical supervision.


==== 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.
* 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.
* 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.
* 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.
* If the patient did have a blocked or damaged needle, instruct them to change the needle as described in Step 15 of the Instructions for Use and repeat all steps in the IFU starting with a new needle and the Section Preparing your Insulin degludec FlexTouch Pen.
* Make sure the patient selects the full dose needed.
* 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.
* 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.
* Instruct Patients to never use a syringe to remove Insulin degludec from the FlexTouch disposable insulin prefilled pen.


==External links==
==== Administration ====
*[http://www.novonordisk.com/science/pipeline/rd_pipeline.asp?showid=4 Novo Nordisk]
* Insulin degludec must only be used if the solution is clear and colorless with no particles visible.
*[http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Insulin+degludec U.S. National Library of Medicine: Drug Information Portal - Insulin degludec]
* Patients must be advised that Insulin degludec must NOT be diluted or mixed with any other insulin or solution.


{{Oral hypoglycemics and insulin analogs}}
==== 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.
* 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.


{{DEFAULTSORT:Insulin degludec}}
==== Women of Reproductive Potential ====
* Advise patients to inform their health care professional if they are pregnant or are contemplating pregnancy.


[[Category:Drug]]
|brandNames=Novo Nordisk®, TRESIBA®, FlexTouch®, LEVEMIR®, NOVOLOG®, NovoFine® and NovoTwist® are registered trademarks of Novo Nordisk A/S.
[[Category:Insulin therapies]]
}}
[[Category:Human proteins]]
[[Category:Recombinant proteins]]
[[Category:Peptide hormones]]

Latest revision as of 01:20, 8 March 2017

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]

Disclaimer

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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 Insulin degludec U-100 or U-200 FlexTouch pens.
  • The Insulin degludec 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

Warnings

Never share a 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.

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 Insulin degludec follow dosing recommendations.

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).
  • 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 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.
  • 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 Insulin degludec into a syringe for administration as overdosage and severe hypoglycemia can result.

Hypersensitivity reactions

  • Severe, life-threatening, generalized allergy, including anaphylaxis, can occur.
  • Discontinue Insulin degludec, 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)

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 Insulin degludec 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 Insulin degludec with a mean exposure duration to Insulin degludec 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 Insulin degludec with a mean exposure duration to Insulin degludec 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 Insulin degludec 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 Insulin degludec with a mean exposure to Insulin degludec 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 Insulin degludec 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 Insulin degludec.
  • 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 Insulin degludec 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 Insulin degludec 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 Insulin degludec 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

Lipodystrophy

  • Long-term use of insulin, including Insulin degludec, 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 Insulin degludec.

Injection Site Reactions

Weight Gain

  • Weight gain can occur with insulin therapy, including Insulin degludec, 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 Insulin degludec gained an average of 1.8 kg and patients with type 2 diabetes treated with Insulin degludec gained an average of 3.0 kg.

Peripheral Edema

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 Insulin degludec 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 Insulin degludec 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 Insulin degludec 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 Insulin degludec

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 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:

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 Insulin degludec and any potential adverse effects on the breastfed infant from Insulin degludec 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 Insulin degludec 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 Insulin degludec have not been established in pediatric patients less than 1 year old.
  • The use of Insulin degludec 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 Insulin degludec 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 Insulin degludec at a reduced dose to minimize the risk of hypoglycemia.

Geriatic 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.
  • 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.

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 a total of 75 (7%) of the 1102 Insulin degludec-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 Insulin degludec-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 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.

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.

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

Important Administration Instructions

  • Always check insulin labels before administration.
  • Inspect visually for particulate matter and discoloration. Only use Insulin degludec if the solution appears clear and colorless.
  • Train patients on proper use and injection technique before initiating Insulin degludec. Training reduces the risk of administration errors such as needle sticks and incomplete dosing.
  • Inject Insulin degludec subcutaneously 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 Insulin degludec intravenously, intramuscularly or in an insulin infusion pump.
  • DO NOT dilute or mix Insulin degludec with any other insulin products or solutions.
  • DO NOT transfer Insulin degludec from the Insulin degludec pen into a syringe for administration.

Monitoring

General Dosing Instructions

  • In adults, inject Insulin degludec subcutaneously once-daily at any time of day.
  • In pediatric patients inject Insulin degludec subcutaneously once-daily at the same time every day.
  • Individualize and titrate the dose of Insulin degludec based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal.
  • The recommended days between dose increases is 3 to 4 days.
  • Dose adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., 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.
  • For adult patients, instruct patients who miss a dose of Insulin degludec to inject their daily dose during waking hours upon discovering the missed dose. Instruct patients to ensure that at least 8 hours have elapsed between consecutive Insulin degludec injections.
  • For pediatric patients, instruct patients who miss a dose of Insulin degludec to contact their healthcare provider for guidance and to monitor blood glucose levels more frequently until the next scheduled Insulin degludec dose.
  • DO NOT perform dose conversion when using the Insulin degludec U-100 or U-200 FlexTouch pens.
  • The dose window for both the Insulin degludec U-100 and U-200 FlexTouch pens shows the number of insulin units to be delivered and NO conversion is needed.

Starting Dose in Insulin Naïve Patients

Type 1 Diabetes Mellitus:
  • The recommended starting dose of Insulin degludec in insulin naïve patients with type 1 diabetes is approximately one-third to one-half of the total daily insulin dose.
  • The remainder of the total daily insulin dose should be administered as a short-acting insulin and divided between each daily meal.
  • As a general rule, 0.2 to 0.4 units of insulin per kilogram of body weight can be used to calculate the initial total daily insulin dose in insulin naïve patients with type 1 diabetes.
Type 2 Diabetes Mellitus:
  • The recommended starting dose of Insulin degludec in insulin naïve patients with type 2 diabetes mellitus is 10 units once daily.

Starting Dose in Patients Already on Insulin Therapy

Adults withType 1 or Type 2 Diabetes Mellitus:
  • Start Insulin degludec at the same unit dose as the total daily long or intermediate-acting insulin unit dose.
  • Pediatric Patients 1 Year of Age and Older with Type 1 or Type 2 Diabetes Mellitus:
  • Start Insulin degludec at 80% of the total daily long or intermediate-acting insulin unit dose to minimize the risk of hypoglycemia.

IV Compatibility

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

Overdosage

  • An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia.
  • Mild episodes of hypoglycemia usually can be treated with oral glucose.
  • Adjustments in drug dosage, meal patterns, or exercise may be needed.
  • More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose.
  • After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid reoccurrence of hypoglycemia.
  • Hypokalemia must be corrected appropriately.

Pharmacology

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

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.

Structure

  • Insulin degludec injection is a long-acting basal human insulin analog for subcutaneous injection.
  • Insulin degludec is produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification.
  • Insulin degludec differs from human insulin in that the amino acid threonine in position B30 has been omitted and a side-chain consisting of glutamic acid and a C16 fatty acid has been attached (chemical name: LysB29(Nε-hexadecandioyl-γ-Glu) des(B30) human insulin).
  • Insulin degludec has a molecular formula of C274H411N65O81S6 and a molecular weight of 6103.97.
  • It has the following structure:
This image is provided by the National Library of Medicine
  • Insulin degludec is a sterile, aqueous, clear, and colorless solution that contains insulin degludec 100 units/mL (U-100) or 200 units/mL (U-200).
  • Inactive ingredients for the 100 units/mL are: glycerol 19.6 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 32.7 mcg/mL and water for injection.
  • Inactive ingredients for the 200 units/mL are glycerol 19.6 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 71.9 mcg/mL and water for injection.
  • Insulin degludec has a pH of approximately 7.6. Hydrochloric acid or sodium hydroxide may be added to adjust pH.

Pharmacodynamics

  • The glucose-lowering effect of Insulin degludec after 8 days of once-daily dosing was measured in a euglycemic glucose clamp study enrolling 21 patients with type 1 diabetes.
  • Figure 2 shows the pharmacodynamic effect of Insulin degludec over time following 8 once-daily subcutaneous injections of 0.4 U/kg of Insulin degludec in patients with type 1 diabetes.
This image is provided by the National Library of Medicine
  • The mean maximum glucose lowering effect (GIRmax) of a 0.4 units/kg dose of Insulin degludec was 2.0 mg/kg/min, which was observed at a median of 12 hours post-dose.
  • The glucose lowering effect of Insulin degludec lasted at least 42 hours after the last of 8 once-daily injections.
  • In patients with type 1 diabetes mellitus, the steady-state, within subjects, day-to-day variability in total glucose lowering effect was 20% with Insulin degludec (within-subject coefficient of variation for AUCGIR,τ,SS).
  • The total glucose-lowering effect of Insulin degludec over 24 hours measured in a euglycemic clamp study after 8 days of once-daily administration in patients with type 1 diabetes increases approximately in proportion to the dose for doses between 0.4 units/kg to 0.8 units/kg.
  • The total glucose-lowering effect of 0.4 units/kg of Insulin degludec U-100 and 0.4 units/kg of Insulin degludec U-200, administered at the same dose, and assessed over 24 hours in a euglycemic clamp study after 8 days of once-daily injection was comparable.

Pharmacokinetics

Absorption

  • In patients with type 1 diabetes, after 8 days of once daily subcutaneous dosing with 0.4 units/kg of Insulin degludec, maximum degludec concentrations of 4472 pmol/L were attained at a median of 9 hours (tmax).
  • After the first dose of Insulin degludec, median onset of appearance was around one hour.
  • Total insulin degludec concentration (i.e., exposure) increased in a dose proportional manner after subcutaneous administration of 0.4 units/kg to 0.8 units/kg Insulin degludec.
  • Total and maximum insulin degludec exposure at steady state are comparable between Insulin degludec U-100 and Insulin degludec U-200 when each is administered at the same units/kg dose.
  • Insulin degludec concentration reach steady state levels after 3-4 days of Insulin degludec administration.

Distribution

  • The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of >99% in human plasma.
  • The results of the in vitro protein binding studies demonstrate that there is no clinically relevant interaction between insulin degludec and other protein bound drugs.

Elimination

  • The half-life after subcutaneous administration is determined primarily by the rate of absorption from the subcutaneous tissue.
  • On average, the half-life at steady state is approximately 25 hours independent of dose.
  • Degradation of Insulin degludec is similar to that of insulin human; all metabolites formed are inactive.
  • The mean apparent clearance of insulin degludec is 0.03 L/kg (2.1 L/h in 70 kg individual) after single subcutaneous dose of 0.4 units/kg.

Specific Populations

Pediatrics

  • Population pharmacokinetic analysis was conducted for Insulin degludec using data from 199 pediatric subjects (1 to <18 years of age) with type 1 diabetes.
  • Body weight was a significant covariate affecting the clearance of Insulin degludec.
  • After adjusting for body weight, the total exposure of Insulin degludec at steady state was independent of age.

Geriatrics

  • Pharmacokinetic and pharmacodynamic response of Insulin degludec was compared in 13 younger adult (18−35 years) and 14 geriatric (≥65 years) subjects with type 1 diabetes following two 6-day periods of once-daily subcutaneous dosing with 0.4 units/kg dose of Insulin degludec or insulin glargine.
  • On average, the pharmacokinetic and pharmacodynamic properties of Insulin degludec at steady-state were similar in younger adult and geriatric subjects, albeit with greater between subject variability among the geriatric subjects.

Gender

  • The effect of gender on the pharmacokinetics of Insulin degludec was examined in an across-trial analysis of the pharmacokinetic and pharmacodynamic studies conducted using unit/kg doses of Insulin degludec.
  • Overall, there were no clinically relevant differences in the pharmacokinetic properties of insulin degludec between female and male subjects.

Obesity

  • The effect of BMI on the pharmacokinetics of Insulin degludec was explored in a cross-trial analysis of pharmacokinetic and pharmacodynamic studies conducted using unit/kg doses of Insulin degludec.
  • For subjects with type 1 diabetes, no relationship between exposure of Insulin degludec and BMI was observed.
  • For subjects with type 1 and type 2 diabetes a trend for decrease in glucose-lowering effect of Insulin degludec with increasing BMI was observed.

Race and Ethnicity

  • Insulin degludec has been studied in a pharmacokinetic and pharmacodynamic study in Black or African American subjects not of Hispanic or Latino origin (n=18), White subjects of Hispanic or Latino origin (n=22) and White subjects not of Hispanic or Latino origin (n=23) with type 2 diabetes mellitus conducted using unit/kg doses of Insulin degludec.
  • There were no statistically significant differences in the pharmacokinetic and pharmacodynamic properties of Insulin degludec between the racial and ethnic groups investigated.

Pregnancy

  • The effect of pregnancy on the pharmacokinetics and pharmacodynamics of Insulin degludec has not been studied.

Renal Impairment

  • Insulin degludec pharmacokinetics was studied in 32 subjects (n=4-8/group) with normal or impaired renal function/end stage renal disease following administration of a single subcutaneous dose (0.4 units/kg) of Insulin degludec.
  • Renal function was defined using creatinine clearance (Clcr) as follows: ≥90 mL/min (normal), 60-89 mL/min (mild), 30-59 mL/min (moderate) and <30 mL/min (severe).
  • Subjects requiring dialysis were classified as having end stage renal disease (ESRD).
  • Total (AUCIDeg,0-120h,SD) and peak exposure of Insulin degludec were on average about 10-25% and 13-27% higher, respectively in subjects with mild to severe renal impairment except subjects with ESRD who showed similar exposure as compared to subjects with normal renal function.
  • No systematic trend was noted for this increase in exposure across different renal impairment subgroups. Hemodialysis did not affect clearance of Insulin degludec (CL/FIDeg,SD) in subjects with ESRD.

Hepatic Impairment

  • Insulin degludec has been studied in a pharmacokinetic study in 24 subjects (n=6/group) with normal or impaired hepatic function (mild, moderate, and severe hepatic impairment) following administration of a single subcutaneous dose (0.4 units/kg) of Insulin degludec.
  • Hepatic function was defined using Child-Pugh Score ranging from 5 (mild hepatic impairment) to 15 (severe hepatic impairment).
  • No differences in the pharmacokinetics of Insulin degludec were identified between healthy subjects and subjects with hepatic impairment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

  • Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of insulin degludec.
  • In a 52-week study including human insulin (NPH insulin) as comparator (6.7 units/kg/day), Sprague-Dawley rats were dosed subcutaneously with insulin degludec at 3.3, 6.7, and 10 units/kg/day, resulting in 5 times the human exposure (AUC) when compared to a human subcutaneous dose of 0.75 units/kg/day. Human insulin was dosed at 6.7 units/kg/day.
  • No treatment-related increases in incidences of hyperplasia, benign or malignant tumors were recorded in female mammary glands from rats dosed with insulin degludec and no treatment related changes in the female mammary gland cell proliferation were found using BrdU incorporation.
  • Further, no treatment related changes in the occurrence of hyperplastic or neoplastic lesions were seen in other tissues in animals dosed with insulin degludec when compared to vehicle or human insulin.
  • Genotoxicity testing of insulin degludec was not performed.
  • In a combined fertility and embryo-fetal study in male and female rats, treatment with insulin degludec up to 21 units/kg/day (approximately 5 times the human subcutaneous dose of 0.75 units/kg/day, based on units/body surface area) prior to mating and in female rats during gestation had no effect on mating performance and fertility.

Clinical Studies

  • The efficacy of Insulin degludec administered once-daily either at the same time each day or at any time each day in patients with type 1 diabetes and used in combination with a mealtime insulin was evaluated in three randomized, open-label, treat-to-target, active-controlled trials in adults and one randomized, open-label, treat-to-target, active-controlled trial in pediatric patients 1 year of age and older.
  • The efficacy of Insulin degludec administered once-daily either at the same time each day or at any time each day in adult patients with type 2 diabetes and used in combination with a mealtime insulin or in combination with common oral anti-diabetic agents was evaluated in six randomized, open-label, treat-to-target active-controlled trials.
  • Adult patients treated with Insulin degludec achieved levels of glycemic control similar to those achieved with LANTUS (insulin glargine 100 units/mL) and LEVEMIR (insulin detemir) and achieved statistically significant improvements compared to sitagliptin.

Type 1 Diabetes – Adult

  • Insulin degludec Administered at the Same Time Each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes in Adult Patients.
Study A
  • The efficacy of Insulin degludec was evaluated in a 52-week randomized, open-label, multicenter trial in 629 patients with type 1 diabetes mellitus (Study A).
  • Patients were randomized to Insulin degludec once-daily with the evening meal or insulin glargine U-100 once-daily according to the approved labeling.
  • Insulin aspart was administered before each meal in both treatment arms.
  • The mean age of the trial population was 43 years and mean duration of diabetes was 18.9 years. 58.5% were male. 93% were White, 1.9% Black or African American. 5.1% were Hispanic. 8.6% of patients had eGFR<60 mL/min/1.73m2.
  • The mean BMI was approximately 26.3 kg/m2.
  • At week 52, the difference in HbA1c reduction from baseline between Insulin degludec and insulin glargine U-100 was -0.01% with a 95% confidence interval of [-0.14%; 0.11%] and met the pre-specified non-inferiority margin (0.4%).
Study B
  • The efficacy of Insulin degludec was evaluated in a 26-week randomized, open-label, multicenter trial in 455 patients with type 1 diabetes mellitus (Study B).
  • Patients were randomized to Insulin degludec or insulin detemir once-daily in the evening.
  • After 8 weeks, insulin detemir could be dosed twice-daily. 67.1% used insulin detemir once daily at end of trial. 32.9% used insulin detemir twice daily at end of trial.
  • Insulin aspart was administered before each meal in both treatment arms.
  • The mean age of the trial population was 41.3 years and mean duration of diabetes was 13.9 years. 51.9% were male. 44.6% were White, 0.4% Black or African American. 4.4% were Hispanic. 4.4% of patients had eGFR<60 mL/min/1.73m2. The mean BMI was approximately 23.9 kg/m2.
  • At week 26, the difference in HbA1c reduction from baseline between Insulin degludec and insulin detemir was -0.09% with a 95% confidence interval of [-0.23%; 0.05%] and met the pre-specified non-inferiority margin (0.4%).
Study C:
  • Insulin degludec Administered at the Same Time Each Day or at Any Time Each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes in Adult Patients.
  • The efficacy of Insulin degludec was evaluated in a 26-week randomized, open-label, multicenter trial in 493 patients with type 1 diabetes mellitus.
  • Patients were randomized to Insulin degludec injected once-daily at the same time each day (with the main evening meal), to Insulin degludec injected once daily at any time each day or to insulin glargine U-100 injected once-daily according to the approved labeling.
  • The any time each day Insulin degludec arm was designed to simulate a worst-case scenario injection schedule of alternating short and long, once daily, dosing intervals (i.e., alternating intervals of 8 to 40 hours between doses).
  • Insulin degludec in this arm was dosed in the morning on Monday, Wednesday, and Friday and in the evening on Tuesday, Thursday, Saturday, and Sunday.
  • Insulin aspart was administered before each meal in all treatment arms.
  • The mean age of the trial population was 43.7 years and mean duration of diabetes was 18.5 years. 57.6% were male. 97.6% were White, 1.8% Black or African American. 3.4% were Hispanic. 7.4% of patients had eGFR<60 mL/min/1.73m2. The mean BMI was approximately 26.7 kg/m2.
  • At week 26, the difference in HbA1c reduction from baseline between Insulin degludec administered at alternating times and insulin glargine U-100 was 0.17% with a 95% confidence interval of [0.04%; 0.30%] and met the pre-specified non-inferiority margin (0.4%).

Type 1 Diabetes – Pediatric Patients 1 Year of Age and Older

  • Study J:Insulin degludec Administered at the Same Time Each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes in Pediatric Patients 1 Year of Age and Older.
  • The efficacy of Insulin degludec was evaluated in a 26-week, randomized, open label, multicenter trial in 350 patients with type 1 diabetes mellitus (Study J).
  • Patients were randomized to Insulin degludec once-daily or insulin detemir once or twice-daily.
  • Subjects on a twice-daily insulin detemir regimen were dosed at breakfast and in the evening either with the main evening meal or at bedtime.
  • Insulin aspart was administered before each main meal in both treatment arms.
  • At end of trial, 36% used insulin detemir once daily and 64% used insulin detemir twice daily.
  • The mean age of the trial population was 10 years; 24% were ages 1-5 years; 39% were ages 6-11 years and 36% were ages 12-17 years.
  • The mean duration of diabetes was 4 years. 55.4% were male. 74.6% were White, 2.9% Black or African American. 2.9% were Hispanic. The mean z-score for body weight was 0.31.
  • At week 26, the difference in HbA1c reduction from baseline between Insulin degludec and insulin detemir was 0.15% with a 95% confidence interval of [-0.03%; 0.33%] and met the pre-specified non-inferiority margin (0.4%).

Type 2 Diabetes - Adult

  • Study D: Insulin degludec Administered at the Same Time Each Day as an Add-on to Metformin with or without a DPP-4 Inhibitor in Insulin Naïve Adult Patients.
  • The efficacy of Insulin degludec was evaluated in a 52-week randomized, open-label, multicenter trial that enrolled 1030 insulin naïve patients with type 2 diabetes mellitus inadequately controlled on one or more oral antidiabetic agents (OADs).
  • Patients were randomized to Insulin degludec once-daily with the evening meal or insulin glargine U-100 once-daily according to the approved labeling.
  • Metformin alone (82.5%) or in combination with a DPP-4 inhibitor (17.5%) was used as background therapy in both treatment arms.
  • The mean age of the trial population was 59.1 years and mean duration of diabetes was 9.2 years. 61.9% were male. 88.4% were White, 7.1% Black or African American. 17.2% were Hispanic. 9.6% of patients had eGFR<60 mL/min/1.73m2. The mean BMI was approximately 31.1 kg/m2.
  • At week 52, the difference in HbA1c reduction from baseline between Insulin degludec and insulin glargine U-100 was 0.09% with a 95% confidence interval of [-0.04%; 0.22%] and met the pre-specified non-inferiority margin (0.4%);
  • Study E: Insulin degludec U-200 Administered at the Same Time Each Day as an Add-on to Metformin with or without a DPP-4 Inhibitor in Insulin Naïve Adult Patients
  • The efficacy of Insulin degludec U-200 was evaluated in a 26-week randomized, open-label, multicenter trial in 457 insulin naïve patients with type 2 diabetes mellitus inadequately controlled on one or more oral antidiabetic agents (OADs) at baseline.
  • Patients were randomized to Insulin degludec U-200 once-daily with the evening meal or insulin glargine U-100 once-daily according to the approved labeling.
  • Both treatment arms were receiving metformin alone (84%) or in combination with a DPP-4 inhibitor (16%) as background therapy.
  • The mean age of the trial population was 57.5 years and mean duration of diabetes was 8.2 years. 53.2% were male. 78.3% were White, 13.8% Black or African American. 7.9% were Hispanic. 7.5% of patients had eGFR <60 mL/min/1.73m2. The mean BMI was approximately 32.4 kg/m2.
  • At week 26, the difference in HbA1c reduction from baseline between Insulin degludec U-200 and insulin glargine U-100 was 0.04% with a 95% confidence interval of [-0.11%; 0.19%] and met the pre-specified non-inferiority margin (0.4%).
  • Study F: Insulin degludec administered at the Same Time Each Day in Insulin Naïve Adult Patients as an Add-on to One or More of the Following Oral Agents: Metformin, Sulfonylurea, Glinides or Alpha-Glucosidase Inhibitors
  • The efficacy of Insulin degludec was evaluated in a 26-week randomized, open-label, multicenter trial in Asia in 435 insulin naïve patients with type 2 diabetes mellitus inadequately controlled on one or more oral antidiabetic agents (OADs) at baseline.
  • Patients were randomized to Insulin degludec once-daily in the evening or insulin glargine U-100 once-daily according to the approved labeling.
  • Pre-trial oral antidiabetes agents were continued as background therapy except for DPP-4 inhibitors or thiazolidinediones in both treatment arms.
  • The mean age of the trial population was 58.6 years and mean duration of diabetes was 11.6 years. 53.6% were male. All patients were Asian. 10.9% of patients had eGFR<60 mL/min/1.73m2. The mean BMI was approximately 25.0 kg/m2.
  • At week 26, the difference in HbA1c reduction from baseline between Insulin degludec and insulin glargine U-100 was 0.11% with a 95% confidence interval of [-0.03%; 0.24%] and met the pre-specified non-inferiority margin (0.4%).
  • Study G: Insulin degludec Administered at the Same Time Each Day or Any Time Each Day as an Add-on to One and up to Three of the Following Oral Agents: Metformin, Sulfonylurea or Glinides or Pioglitazone in Adult Patients
  • The efficacy of Insulin degludec was evaluated in a 26-week randomized, open-label, multicenter trial in 687 patients with type 2 diabetes mellitus inadequately controlled on basal insulin alone, oral antidiabetic agents (OADs) alone or both basal insulin and OAD.
  • Patients were randomized to Insulin degludec injected once-daily at the same time each day (with the main evening meal), to Insulin degludec injected once daily at any time each day or to insulin glargine U-100 injected once-daily according to the approved labeling.
  • The any time each day Insulin degludec arm was designed to simulate a worst-case scenario injection schedule of alternating short and long, once daily, dosing intervals (i.e., alternating intervals of 8 to 40 hours between doses).
  • Insulin degludec in this arm was dosed in the morning on Monday, Wednesday, and Friday and in the evening on Tuesday, Thursday, Saturday, and Sunday.
  • Up to three of the following oral antidiabetes agents (metformin, sulfonylureas, glinides or thiazolidinediones) were administered as background therapy in both treatment arms.
  • The mean age of the trial population was 56.4 years and mean duration of diabetes was 10.6 years. 53.9% were male. 66.7% were White, 2.5% Black or African American. 10.6% were Hispanic. 5.8% of patients had eGFR<60 mL/min/1.73m2. The mean BMI was approximately 29.6 kg/m2.
  • At week 26, the difference in HbA1c reduction from baseline between Insulin degludec at alternating times and insulin glargine U-100 was 0.04% with a 95% confidence interval of [-0.12%; 0.20%]. This comparison met the pre-specified non-inferiority margin (0.4%).
  • Study H: Insulin degludec Administered at the Same Time Each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes in Adult Patients
  • The efficacy of Insulin degludec was evaluated in a 52-week randomized, open-label, multicenter trial in 992 patients with type 2 diabetes mellitus inadequately controlled on premix insulin, bolus insulin alone, basal insulin alone, oral antidiabetic agents (OADs) alone or any combination thereof.
  • Patients were randomized to Insulin degludec once-daily with the main evening meal or insulin glargine U-100 once-daily according to the approved labeling.
  • Insulin aspart was administered before each meal in both treatment arms.
  • Up to two of the following oral antidiabetes agents (metformin or pioglitazone) were used as background therapy in both treatment arms.
  • The mean age of the trial population was 58.9 years and mean duration of diabetes was 13.5 years. 54.2% were male. 82.9% were White, 9.5% Black or African American. 12.0% were Hispanic. 12.4% of patients had eGFR<60 mL/min/1.73m2. The mean BMI was approximately 32.2 kg/m2.
  • At week 52, the difference in HbA1c reduction from baseline between Insulin degludec and insulin glargine U-100 was 0.08% with a 95% confidence interval of [-0.05%; 0.21%] and met the pre-specified non-inferiority margin (0.4%).
  • Study I: Insulin degludec Administered at Any Time Each Day as an Add-on to One or Two of the Following Oral Agents: Metformin, Sulfonylurea, or Pioglitazone in Adult Patients.
  • The efficacy of Insulin degludec was evaluated in a 26-week randomized, open-label, multicenter trial in 447 patients with type 2 diabetes mellitus inadequately controlled on one or more oral antidiabetic agent (OADs) at baseline.
  • Patients were randomized to Insulin degludec once-daily at any time of day or sitagliptin once-daily according to the approved labeling.
  • One or two of the following oral antidiabetes agents (metformin, sulfonylurea or pioglitazone) were also administered in both treatment arms.
  • The mean age of the trial population was 55.7 years and mean duration of diabetes was 7.7 years. 58.6% were male. 61.3% were White, 7.6% Black or African American. 21.0% were Hispanic. 6% of patients had eGFR<60 mL/min/1.73m2. The mean BMI was approximately 30.4 kg/m2.
  • At the end of 26 weeks, Insulin degludec provided greater reduction in mean HbA1c compared to sitagliptin (p < 0.001).

How Supplied

  • Insulin degludec is available as a clear and colorless solution in the following package sizes.
This image is provided by National Library of Medicine

Storage

  • Unused Insulin degludec should be stored between 36°F to 46°F (2°C to 8°C).
  • Do not store in the freezer or directly adjacent to the refrigerator cooling element.
  • Do not freeze.
  • Do not use Insulin degludec if it has been frozen.
  • Unopened FlexTouch disposable prefilled pen:
    • Not in-use (unopened) Insulin degludec disposable prefilled pen should be stored in a refrigerator (36°F to 46°F [2°C to 8°C]). Discard after expiration date.
  • Open (In-Use) FlexTouch disposable prefilled pen:
    • The in-use Insulin degludec FlexTouch pen should be refrigerated (36°F to 46°F [2°C to 8°C]) or be kept at room temperature (below 86°F [30°C]) away from direct heat and light.
    • The opened (in-use) Insulin degludec FlexTouch pen may be used for up to 56 days (8 weeks) after being opened, if it is refrigerated or kept at room temperature.
  • The storage conditions are summarized in Table 16:
This image is provided by the National Library of Medicine

Images

Drug Images

{{#ask: Page Name::Insulin degludec |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

NDC 0169-2660-15

List: 266015

TRESIBA®

FlexTouch®

(insulin degludec injection)

For Single Patient Use Only

100 units/mL (U-100)

5×3 mL Prefilled Pens

For subcutaneous use only

Rx Only

Recommended for use with NovoFine®, NovoFine® Plus or NovoTwist® disposable needles.

Keep in a cold place until first use.

Store at 36°F to 46°F (2°C to 8°C).

Do not freeze.

After first use, store between 36°F to 86°F (2°C to 30°C).

Protect from light.

This image is provided by National Library of Medicine

NDC 0169-2550-13

List: 255013

TRESIBA®

FlexTouch®

(insulin degludec injection)

For Single Patient Use Only

200 units/mL (U-200)

3×3 mL Prefilled Pens

For subcutaneous use only

Rx Only

Recommended for use with NovoFine®, NovoFine® Plus or NovoTwist® disposable needles.

Keep in a cold place until first use.

Store at 36°F to 46°F (2°C to 8°C).

Do not freeze.

After first use, store between 36°F to 86°F (2°C to 30°C).

Protect from light.

This image is provided by National Library of Medicine

{{#ask: Label Page::Insulin degludec |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

Never Share a 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.

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.
  • Advise patients that changes in insulin regimen can predispose to hyper- or hypoglycemia.
  • Advise patients that changes in insulin regimen should be made under close medical supervision.

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.
  • 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.
  • 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.
  • 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.
  • If the patient did have a blocked or damaged needle, instruct them to change the needle as described in Step 15 of the Instructions for Use and repeat all steps in the IFU starting with a new needle and the Section Preparing your Insulin degludec FlexTouch Pen.
  • Make sure the patient selects the full dose needed.
  • 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.
  • 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.
  • Instruct Patients to never use a syringe to remove Insulin degludec from the FlexTouch disposable insulin prefilled pen.

Administration

  • Insulin degludec must only be used if the solution is clear and colorless with no particles visible.
  • Patients must be advised that Insulin degludec must NOT be diluted or mixed with any other insulin or solution.

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.
  • 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.

Women of Reproductive Potential

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

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

Novo Nordisk®, TRESIBA®, FlexTouch®, LEVEMIR®, NOVOLOG®, NovoFine® and NovoTwist® are registered trademarks of Novo Nordisk A/S.

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.

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