Insulin Degludec
Injection, Solution · Subcutaneous
Uses
Insulin Degludec is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus. Limitations of Use
• Not recommended for the treatment of diabetic ketoacidosis. Insulin Degludec is a long-acting human insulin analog indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus ( 1 ). Limitations of Use:
• Not recommended for the treatment of diabetic ketoacidosis.
Dosage and administration
• See Full Prescribing Information for important administration instructions ( 2.1 ).
• Inject Insulin Degludec subcutaneously into the thigh, upper arm, or abdomen ( 2.1 ).
• Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis ( 2.1 ).
• For pediatric patients requiring less than 5 units of Insulin Degludec each day, use an Insulin Degludec U-100 vial ( 2.1 ).
• In adults, inject subcutaneously once daily at any time of day ( 2.2 ).
• In pediatric patients inject subcutaneously once daily at the same time every day ( 2.2 ).
• Individualize dose based on type of diabetes, metabolic needs, blood glucose monitoring results and glycemic control goal ( 2.2 ).
• The recommended days between dose increases are 3 to 4 days ( 2.2 ).
• See Full Prescribing Information for recommended starting dose in insulin naïve patients and patients already on insulin therapy ( 2.3 , 2.4 ). 2.1 Important Administration Instructions
• Always check insulin labels before administration. This product is Tresiba (insulin degludec) [see Warnings and Precautions ( 5.4 ) ] .
• Inspect visually for particulate matter and discoloration. Only use Insulin Degludec if the solution appears clear and colorless.
• 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 and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6.1 , 6.3 )].
• During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )] .
• For pediatric patients requiring less than 5 units of Insulin Degludec each day, use the Insulin Degludec U-100 vial.
• DO NOT administer Insulin Degludec intravenously or in an insulin infusion pump.
• DO NOT dilute or mix Insulin Degludec with any other insulin or solution.
• DO NOT transfer Insulin Degludec from the Insulin Degludec FlexTouch pen into a syringe for administration [see Warnings and Precautions ( 5.4 )].
• Use Insulin Degludec FlexTouch pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose. 2.2 General Dosing Instructions
• Insulin Degludec is available in 2 concentrations (U-100 and U-200): o Insulin Degludec U-100 is available, as a single-patient use FlexTouch pen and multiple-dose vial. ▪ The FlexTouch pen delivers doses in 1 unit increments and can deliver up to 80 units in a single injection. o Insulin Degludec U-200 is available as a single-patient-use FlexTouch pen. ▪ The FlexTouch pen delivers doses in 2 unit increments and can deliver up to 160 units in a single injection.
• DO NOT perform dose conversion when using the Insulin Degludec U-100 or U-200 FlexTouch pens. The dose window shows the number of insulin units to be delivered and no conversion is needed.
• 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 are 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 [see Warnings and Precautions ( 5.3 )] .
• 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.
• In patients with type 1 diabetes, Insulin Degludec must be used concomitantly with short-acting insulin. 2.3 Starting Dose in Insulin Naïve Patients Recommended Starting Dosage in Patients with 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. Recommended Starting Dosage in Patients with 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. 2.4 Switching to Insulin Degludec from Other Insulin Therapies Dosage adjustments are recommended to lower the risk of hypoglycemia when switching patients to Insulin Degludec from another insulin therapy [see Warnings and Precautions ( 5.3 )]. Adults with Type 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 [see Warnings and Precautions ( 5.2 )].
Dosage forms and strengths
Injection: Available as a clear and colorless solution:
• 100 units/mL (U-100): 3 mL single-patient-use FlexTouch prefilled pen
• 100 units/mL (U-100): 10 mL multiple-dose vial
• 200 units/mL (U-200): 3 mL single-patient-use FlexTouch prefilled pen Injection: Available as:
• 100 units/mL (U-100): 3 mL single-patient-use FlexTouch ® prefilled pen ( 3 ).
• 100 units/mL (U-100): 10 mL multiple-dose vial ( 3 ).
• 200 units/mL (U-200): 3 mL single-patient-use FlexTouch ® prefilled pen ( 3 ).
Contraindications
Insulin Degludec is contraindicated:
• During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] .
• In patients with hypersensitivity to insulin degludec or any of the excipients in Insulin Degludec [see Warnings and Precautions ( 5.5 )] .
• During episodes of hypoglycemia ( 4 ).
• Hypersensitivity to insulin degludec or any of the excipients in Insulin Degludec ( 4 ).
Warnings and precautions
• Never share an Insulin Degludec FlexTouch pen, insulin syringe, or needle between patients, even if the needle is changed ( 5.1 ).
• Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to a patient’s insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring ( 5.2 ).
• Hypoglycemia : May be life-threatening. Increase monitoring with changes to: insulin dosage, concomitant drugs, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness ( 5.3 , 5.4 , 6.1 ).
• 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 from the Insulin Degludec pen into a syringe for administration as overdosage and severe hypoglycemia can result ( 5.4 ).
• Hypersensitivity reactions : Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue Insulin Degludec, monitor and treat if indicated ( 5.5 ).
• Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated ( 5.6 ).
• 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 ( 5.7 ). 5.1 Never Share an Insulin Degludec FlexTouch Pen, Needle, or Insulin Syringe Between Patients Insulin Degludec FlexTouch disposable prefilled pens should never be shared between patients, even if the needle is changed. Patients using Insulin Degludec vials should never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions ( 5.3 )] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions ( 6.1 , 6.3 )] . Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, adjustments in concomitant anti-diabetic treatment may be needed [see Dosage and Administration ( 2.4 )] . 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction of insulin, including Insulin Degludec [see Adverse Reactions (6.1)]. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Insulin Degludec, or any insulin, should not be used during episodes of hypoglycemia [see Contraindications ( 4 )]. Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, using drugs that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions ( 7 )], or who experience recurrent hypoglycemia. The long-acting effect of Insulin Degludec may delay recovery from hypoglycemia compared to shorter-acting insulins. 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 [see Clinical Pharmacology ( 12.2 )] and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins, the glucose lowering effect time course of Insulin Degludec may vary among different patients or at different times in the same patients 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 concomitant drugs [see Drug Interactions ( 7 )] . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations ( 8.6 , 8.7 )] . 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. 5.4 Hypoglycemia Due to Medication Errors Accidental mix-ups between insulin products, have been reported. To avoid medication errors between Insulin Degludec and other insulins, instruct patients to always check the insulin label before each injection. To avoid dosing errors and potential overdose, never use a syringe to remove Insulin Degludec from the Insulin Degludec FlexTouch disposable insulin prefilled pen [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.3 )] .
Side effects
The following adverse reactions are also discussed elsewhere:
• Hypoglycemia [see Warnings and Precautions ( 5.3 )]
• Hypoglycemia due to Medication errors [see Warnings and Precautions ( 5.4 )]
• Hypersensitivity reactions [see Warnings and Precautions ( 5.5 )]
• Hypokalemia [see Warnings and Precautions ( 5.6 )] Adverse reactions commonly associated with Insulin Degludec are:
• hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema and weight gain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Pharma, Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 cardiovascular safety of Insulin Degludec was evaluated in one double-blinded, event-driven trial of 2-year median duration in patients with type 2 diabetes at high risk of cardiovascular events [see Clinical Studies (14)]. 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 in three open-label trials; Study A, B and C [see Clinical Studies (14.1)] . 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/m 2 . The mean duration of diabetes was 18 years and the mean HbA 1c 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 m 2 and 7% of the patients had an eGFR less than 60 mL/min/1.73 m 2 . 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 in six open-label trials; Study D, E, F, G, H and I [see Clinical Studies (14.3)] . 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/m 2 . The mean duration of diabetes was 11 years and the mean HbA 1c 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 m 2 and 9% had an eGFR less than 60 mL/min/1.73 m 2 . 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% were male, 78% were White, 3% were Black or African American and 4% were Hispanic. The mean body mass index (BMI) was 18.7 kg/m 2 . The mean duration of diabetes was 3.9 years and the mean HbA 1c 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. Table 1: Adverse Reactions Occurring in ≥5% of Insulin Degludec-Treated Adult Patients with Type 1 Diabetes Mellitus Adverse Reaction Insulin Degludec (N=1,102) Nasopharyngitis 23.9 % Upper respiratory tract infection 11.9 % Headache 11.8 % Sinusitis 5.1 % Gastroenteritis 5.1 % Table 2: Adverse Reactions Occurring in ≥5% of Insulin Degludec-Treated Adult Patients with Type 2 Diabetes Mellitus Adverse Reaction Insulin Degludec (N=2,713) Nasopharyngitis 12.9 % Headache 8.8 % Upper respiratory tract infection 8.4 % Diarrhea 6.3 % Hypoglycemia Hypoglycemia was the most commonly observed adverse reaction in patients treated with Insulin Degludec. The rates of reported hypoglycemia depended 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. In the open-label adult clinical trials of patients with type 1 and type 2 diabetes, and in the open-label pediatric clinical trial of patients with type 1 diabetes, percentages of adult and pediatric patients with type 1 diabetes randomized to Insulin Degludec who experienced at least one episode of hypoglycemia in clinical trials [see Clinical Studies ( 14 )] and adults with type 2 diabetes are shown in Tables 3 and 4, respectively. Severe hypoglycemia in the open-label trials with adult patients was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
Drug interactions
Table 5 includes clinically significant drug interactions with Insulin Degludec. Table 5: Clinically Significant Drug Interactions with Insulin Degludec Drugs That May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors. Intervention: Dosage reductions and increased frequency of glucose monitoring may be required when Insulin Degludec is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of Insulin Degludec Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dosage increases and increased frequency of glucose monitoring may be required when Insulin Degludec is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Degludec Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dosage adjustment and increased frequency of glucose monitoring may be required when Insulin Degludec is co-administered with these drugs. Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when Insulin Degludec is co-administered with these drugs.
• Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed. ( 7 )
• Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. ( 5.3 , 7 )
Use in specific populations
8.1 Pregnancy Risk Summary Available data from one unpublished trial and the published literature with Insulin Degludec use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In a randomized, parallel-group, open-label actively controlled clinical trial that included 91 pregnant women with type 1 diabetes who were administered Insulin Degludec once daily and insulin aspart, beginning in gestational weeks 8 to 13 or prior to conception, no clear evidence of maternal or fetal risk associated with Insulin Degludec use was observed ( see Data ). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). 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) (see Data) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a peri-conceptional HbA 1c >7 and has been reported to be as high as 20 to 25% in women with a peri-conceptional HbA 1c >10. The estimated background risk of miscarriage for the indicated population is unknown. Clinical Considerations Disease-Associated Maternal and/or Embryo/fetal Risk Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Human Data In an open-label clinical trial, 185 pregnant females with type 1 diabetes were treated with either Insulin Degludec (once daily) or insulin detemir (once or twice daily); both groups received insulin aspart 2 to 4 times daily with meals. There were no significant drug-associated differences in pregnancy outcomes or the health of the fetus and newborn between the two groups. In this study, the proportion of subjects with severe hypoglycemia and hypoglycemia was similar between the two treatment arms; for the definitions of severe hypoglycemia and hypoglycemia [see Adverse Reactions (6.1)]. Poor glucose control during pregnancy in both groups and small sample size were limitations of the study. In about two thirds of infants, insulin degludec was detected in the infant cord blood at levels above the lower level of quantification of the assay. 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 embryo-fetal 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. 8.2 Lactation Risk Summary 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 [ see Data ]. 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. Data In lactating rats, insulin degludec was present in milk at a concentration lower than that in plasma. 8.4 Pediatric Use The safety and effectiveness of Insulin Degludec to improve glycemic control in pediatric patients 1 year of age or older with diabetes mellitus have been established. The use of Insulin Degludec for this indication is supported by evidence from an adequate and well-controlled trial and a pharmacokinetic study (trials included pediatric patients 1 year of age and older with type 1 diabetes mellitus) [ see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 )]. 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 trials in adults with type 2 diabetes mellitus [see Clinical Studies ( 14.3 )] . 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 [see Dosage and Administration ( 2.4 )]. The safety and effectiveness of Insulin Degludec have not been established in pediatric patients less than 1-year-old. 8.5 Geriatric Use In controlled clinical trials [see Clinical Studies ( 14 )] 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.
Pregnancy
8.1 Pregnancy Risk Summary Available data from one unpublished trial and the published literature with Insulin Degludec use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In a randomized, parallel-group, open-label actively controlled clinical trial that included 91 pregnant women with type 1 diabetes who were administered Insulin Degludec once daily and insulin aspart, beginning in gestational weeks 8 to 13 or prior to conception, no clear evidence of maternal or fetal risk associated with Insulin Degludec use was observed ( see Data ). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). 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) (see Data) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a peri-conceptional HbA 1c >7 and has been reported to be as high as 20 to 25% in women with a peri-conceptional HbA 1c >10. The estimated background risk of miscarriage for the indicated population is unknown. Clinical Considerations Disease-Associated Maternal and/or Embryo/fetal Risk Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Human Data In an open-label clinical trial, 185 pregnant females with type 1 diabetes were treated with either Insulin Degludec (once daily) or insulin detemir (once or twice daily); both groups received insulin aspart 2 to 4 times daily with meals. There were no significant drug-associated differences in pregnancy outcomes or the health of the fetus and newborn between the two groups. In this study, the proportion of subjects with severe hypoglycemia and hypoglycemia was similar between the two treatment arms; for the definitions of severe hypoglycemia and hypoglycemia [see Adverse Reactions (6.1)]. Poor glucose control during pregnancy in both groups and small sample size were limitations of the study. In about two thirds of infants, insulin degludec was detected in the infant cord blood at levels above the lower level of quantification of the assay. 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 embryo-fetal 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.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of Insulin Degludec to improve glycemic control in pediatric patients 1 year of age or older with diabetes mellitus have been established. The use of Insulin Degludec for this indication is supported by evidence from an adequate and well-controlled trial and a pharmacokinetic study (trials included pediatric patients 1 year of age and older with type 1 diabetes mellitus) [ see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 )]. 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 trials in adults with type 2 diabetes mellitus [see Clinical Studies ( 14.3 )] . 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 [see Dosage and Administration ( 2.4 )]. The safety and effectiveness of Insulin Degludec have not been established in pediatric patients less than 1-year-old.
Geriatric use
8.5 Geriatric Use In controlled clinical trials [see Clinical Studies ( 14 )] 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. In the safety outcomes trial (DEVOTE), a total of 1983 (52%) of the 3818 Insulin Degludec-treated patients with type 2 diabetes were 65 years or older and 381 (10%) were 75 years or older. Differences in safety or effectiveness were not observed in these subgroup analyses. 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 geriatric patients.
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 [see Warnings and Precautions ( 5.3 , 5.6 )] . Mild episodes of hypoglycemia usually can be treated with oral glucose. Lowering the insulin dosage, and adjustments in meal patterns or exercise may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with a glucagon for emergency use 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.
Description
Insulin degludec is a long-acting basal human insulin analog for subcutaneous injection 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 C 274 H 411 N 65 O 81 S 6 and a molecular weight of 6.104 kDa. It has the following structure: Figure 1: Structural Formula of Insulin Degludec Insulin Degludec injection is a sterile, aqueous, clear, and colorless solution available as 100 units/mL (U-100) or 200 units/mL (U-200) for subcutaneous use. For the 100 units/mL solution, each mL contains 100 units of insulin degludec and glycerin (19.6 mg), metacresol (1.72 mg), phenol (1.5 mg), zinc (32.7 mcg), and Water for Injection, USP. For the 200 units/mL solution, each mL contains 200 units of insulin degludec and glycerin (19.6 mg), metacresol (1.72 mg), phenol (1.5 mg), zinc (71.9 mcg), and Water for Injection, USP. Insulin Degludec has a pH of approximately 7.6. Hydrochloric acid or sodium hydroxide may be added to adjust pH. Figure 1: Structural Formula of Tresiba
Mechanism of action
12.1 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.
How supplied
16.1 How Supplied Insulin Degludec injection is available as a clear and colorless solution as follows: Table 17: Presentations of Insulin Degludec Insulin Degludec Presentation Total volume Concentration Total units available in presentation NDC number Max dose per injection Dose increment Package Size U-100 single-patient-use FlexTouch Pen 3 mL 100 units/mL 300 Units 73070-403-15 80 Units 1 Unit 5 pens/pack U-100 multiple-dose Vial 10 mL 100 units/mL 1,000 Units 73070-400-11 _ _ 1 vial/pack U-200 single-patient-use FlexTouch Pen 3 mL 200 units/mL 600 Units 73070-503-15 160 Units 2 Unit 3 pens/pack Additional Information about Insulin Degludec FlexTouch:
• Insulin Degludec U-100 FlexTouch pen dials in 1 unit increments.
• Insulin Degludec U-200 FlexTouch pen dials in 2 unit increments. 16.2 Recommended Storage Dispense in the original sealed carton with the enclosed Instructions for Use. Store Insulin Degludec vials in the original carton to protect from light. Store unused Insulin Degludec in a refrigerator (36ºF to 46ºF [2ºC to 8ºC]). 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. The storage conditions are summarized in Table 18: Table 18: Storage Conditions for Insulin Degludec Not in-use (unopened) In-use (opened) Refrigerated (36°F to 46°F [2°C to 8°C]) Room Temperature (up to 86°F [30°C]) Room Temperature (up to 86°F [30°C]) Refrigerated (36°F to 46°F [2°C to 8°C]) 3 mL single-patient-use Insulin Degludec U-100 FlexTouch Until expiration date 56 days (8 weeks) 56 days (8 weeks) 56 days (8 weeks) 10 mL multiple-dose Insulin Degludec U-100 Vial Until expiration date 56 days (8 weeks) 56 days (8 weeks) 56 days (8 weeks) 3 mL single-patient-use Insulin Degludec U-200 FlexTouch Until expiration date 56 days (8 weeks) 56 days (8 weeks) 56 days (8 weeks)
Patient information
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use). There are separate Instructions for Use for the Vials and FlexTouch Pens. Never Share an Insulin Degludec FlexTouch Pen, Needle, or Insulin Syringe Between Patients Advise patients that they should never share an Insulin Degludec FlexTouch pen device with another person, even if the needle is changed. Advise patients using Insulin Degludec vials not to share needles or insulin syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and Precautions ( 5.1 )]. Hyperglycemia or Hypoglycemia Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia (e.g., impaired ability to concentrate and react). 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 [see Warnings and Precautions ( 5.3 )]. Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions ( 5.2 )]. Hypoglycemia Due to Medication Errors Inform patients to always check the insulin label before each injection to reduce the risk of a medication error [see Warnings and Precautions ( 5.4 )]. 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 [see Dosage and Administration ( 2.2 )]. Instruct patients to never use a syringe to remove Insulin Degludec from the FlexTouch disposable insulin prefilled pen. Hypersensitivity Reactions Advise patients that hypersensitivity reactions have occurred with Insulin Degludec. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions ( 5.5 )]. Version: 1 Novo Nordisk ® , FlexTouch ® , LEVEMIR ® , NOVOLOG ® , and NovoFine ® are registered trademarks of Novo Nordisk A/S. © 2022 Novo Nordisk PATENT Information: http://novonordisk-us.com/products/product-patents.html Manufactured by: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 U.S. License Number 1261 For information about Insulin Degludec contact: Novo Nordisk Pharma, Inc. 1-800-727-6500
Label text from the FDA structured product label by Novo Nordisk Pharma, Inc. (revised Jul 1, 2022). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Insulin Degludec in 5 products
Insulin Degludec NDC products (5)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 50090-7175 | Insulin Degludec 200 U/mL Injection, Solution | A-S Medication Solutions | BLA |
| 50090-7176 | Insulin Degludec 100 U/mL Injection, Solution | A-S Medication Solutions | BLA |
| 73070-400 | Insulin Degludec 100 U/mL Injection, Solution | Novo Nordisk Pharma, Inc. | BLA |
| 73070-403 | Insulin Degludec 100 U/mL Injection, Solution | Novo Nordisk Pharma, Inc. | BLA |
| 73070-503 | Insulin Degludec 200 U/mL Injection, Solution | Novo Nordisk Pharma, Inc. | BLA |
Frequently asked questions
What is Insulin Degludec used for?
Insulin Degludec is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus. Limitations of Use • Not recommended for the treatment of diabetic ketoacidosis. Insulin Degludec is a long-acting human insulin analog indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus ( 1 ). Limitations of Use: • Not recommended for…
What are the side effects of Insulin Degludec?
The following adverse reactions are also discussed elsewhere: • Hypoglycemia [see Warnings and Precautions ( 5.3 )] • Hypoglycemia due to Medication errors [see Warnings and Precautions ( 5.4 )] • Hypersensitivity reactions [see Warnings and Precautions ( 5.5 )] • Hypokalemia [see Warnings and Precautions ( 5.6 )] Adverse reactions commonly associated with Insulin Degludec are: • hypoglycemia,… See the full label for the complete list.
Who makes Insulin Degludec?
Insulin Degludec is listed by 2 labelers in the FDA NDC directory, including A-S Medication Solutions, Novo Nordisk Pharma, Inc..