Insulin degludec: uses, appearance and warnings

TRESIBA 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. TRESIBA 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.

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 ).

16.1 How Supplied TRESIBA (insulin degludec) injection is available as a clear and colorless solution as follows: Table 17: Presentations of TRESIBA TRESIBA 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 0169-2660-15 80 Units 1 Unit 5 pens/pack U-100 multiple-dose Vial 10 mL 100 units/mL 1,000 Units 0169-2662-11 _ _ 1 vial/pack U-200 single-patient-use FlexTouch Pen 3 mL 200 units/mL 600 Units 0169-2550-13 160 Units 2 Unit 3 pens/pack Additional Information about TRESIBA FlexTouch: • TRESIBA U-100 FlexTouch pen dials in 1 unit increments. • TRESIBA 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 TRESIBA vials in the original carton to protect from light. Store unused TRESIBA 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 TRESIBA if it has been frozen. The storage conditions are summarized in Table 18: Table 18: Storage Conditions for TRESIBA 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 TRESIBA U-100 FlexTouch Until expiration date 56 days (8 weeks) 56 days (8 weeks) 56 days (8 weeks) 10 mL multiple-dose TRESIBA U-100 Vial Until expiration date 56 days (8 weeks) 56 days (8 weeks) 56 days (8 weeks) 3 mL single-patient-use TRESIBA U-200 FlexTouch Until expiration date 56 days (8 weeks) 56 days (8 weeks) 56 days (8 weeks)

TRESIBA 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 TRESIBA [see Warnings and Precautions ( 5.5 )] . • During episodes of hypoglycemia ( 4 ). • Hypersensitivity to insulin degludec or any of the excipients in TRESIBA ( 4 ).

• Never share a TRESIBA 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 TRESIBA from the TRESIBA 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 TRESIBA, 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 a TRESIBA FlexTouch Pen, Needle, or Insulin Syringe Between Patients TRESIBA FlexTouch disposable prefilled pens should never be shared between patients, even if the needle is changed. Patients using TRESIBA 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 TRESIBA [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). TRESIBA, 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 TRESIBA 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 TRESIBA 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 TRESIBA 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 TRESIBA from the TRESIBA FlexTouch disposable insulin prefilled pen [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.3 )] . 5.5 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including TRESIBA [see Adverse Reactions (6.1)] . …

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 TRESIBA are: • hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema and weight gain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. …

Table 5 includes clinically significant drug interactions with TRESIBA. Table 5: Clinically Significant Drug Interactions with TRESIBA 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 TRESIBA is co-administered with these drugs. …