Tresiba

TRESIBA is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus.

• •Not recommended for the treatment of diabetic ketoacidosis.

• •See Full Prescribing Information for important administration instructions (
  2.1 Important Administration Instructions

  • •Always check insulin labels before administration
    [see Warnings and Precautions , Adverse Reactions ].
  • •During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions ].
  • •For pediatric patients requiring less than 5 units of TRESIBA each day, use the TRESIBA U-100 vial.
  • •DO NOT administer TRESIBA intravenously or in an insulin infusion pump.
  • •DO NOT dilute or mix TRESIBA with any other insulin or solution.
  • •DO NOT transfer TRESIBA from the TRESIBA FlexTouch pen into a syringe for administration
    [see Warnings and Precautions ].
  • •Use TRESIBA FlexTouch pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose.
  ).
• •Inject TRESIBA subcutaneously into the thigh, upper arm, or abdomen (
  2.1 Important Administration Instructions

  • •Always check insulin labels before administration
    [see Warnings and Precautions , Adverse Reactions ].
  • •During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions ].
  • •For pediatric patients requiring less than 5 units of TRESIBA each day, use the TRESIBA U-100 vial.
  • •DO NOT administer TRESIBA intravenously or in an insulin infusion pump.
  • •DO NOT dilute or mix TRESIBA with any other insulin or solution.
  • •DO NOT transfer TRESIBA from the TRESIBA FlexTouch pen into a syringe for administration
    [see Warnings and Precautions ].
  • •Use TRESIBA FlexTouch pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose.
  ).
• •Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis (
  2.1 Important Administration Instructions

  • •Always check insulin labels before administration
    [see Warnings and Precautions , Adverse Reactions ].
  • •During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions ].
  • •For pediatric patients requiring less than 5 units of TRESIBA each day, use the TRESIBA U-100 vial.
  • •DO NOT administer TRESIBA intravenously or in an insulin infusion pump.
  • •DO NOT dilute or mix TRESIBA with any other insulin or solution.
  • •DO NOT transfer TRESIBA from the TRESIBA FlexTouch pen into a syringe for administration
    [see Warnings and Precautions ].
  • •Use TRESIBA FlexTouch pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose.
  ).
• •For pediatric patients requiring less than 5 units of TRESIBA each day, use a TRESIBA U-100 vial (
  2.1 Important Administration Instructions

  • •Always check insulin labels before administration
    [see Warnings and Precautions , Adverse Reactions ].
  • •During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions ].
  • •For pediatric patients requiring less than 5 units of TRESIBA each day, use the TRESIBA U-100 vial.
  • •DO NOT administer TRESIBA intravenously or in an insulin infusion pump.
  • •DO NOT dilute or mix TRESIBA with any other insulin or solution.
  • •DO NOT transfer TRESIBA from the TRESIBA FlexTouch pen into a syringe for administration
    [see Warnings and Precautions ].
  • •Use TRESIBA FlexTouch pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose.
  ).
• •In adults, inject subcutaneously once daily at any time of day (
  2.2 General Dosing Instructions

  • •TRESIBA is available in 2 concentrations (U-100 and U-200):
    • oTRESIBA 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.
    • oTRESIBA 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 TRESIBA 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 TRESIBA subcutaneously once-daily at any time of day.
  • •In pediatric patients inject TRESIBA subcutaneously once-daily at the same time every day.
  • •Individualize and titrate the dose of TRESIBA 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 ]
    .
  • •For adult patients, instruct patients who miss a dose of TRESIBA 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 TRESIBA injections.
  • •For pediatric patients, instruct patients who miss a dose of TRESIBA to contact their healthcare provider for guidance and to monitor blood glucose levels more frequently until the next scheduled TRESIBA dose.
  • •In patients with type 1 diabetes, TRESIBA must be used concomitantly with short-acting insulin.
  ).
• •In pediatric patients inject subcutaneously once daily at the same time every day (
  2.2 General Dosing Instructions

  • •TRESIBA is available in 2 concentrations (U-100 and U-200):
    • oTRESIBA 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.
    • oTRESIBA 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 TRESIBA 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 TRESIBA subcutaneously once-daily at any time of day.
  • •In pediatric patients inject TRESIBA subcutaneously once-daily at the same time every day.
  • •Individualize and titrate the dose of TRESIBA 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 ]
    .
  • •For adult patients, instruct patients who miss a dose of TRESIBA 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 TRESIBA injections.
  • •For pediatric patients, instruct patients who miss a dose of TRESIBA to contact their healthcare provider for guidance and to monitor blood glucose levels more frequently until the next scheduled TRESIBA dose.
  • •In patients with type 1 diabetes, TRESIBA must be used concomitantly with short-acting insulin.
  ).
• •Individualize dose based on type of diabetes, metabolic needs, blood glucose monitoring results and glycemic control goal (
  2.2 General Dosing Instructions

  • •TRESIBA is available in 2 concentrations (U-100 and U-200):
    • oTRESIBA 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.
    • oTRESIBA 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 TRESIBA 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 TRESIBA subcutaneously once-daily at any time of day.
  • •In pediatric patients inject TRESIBA subcutaneously once-daily at the same time every day.
  • •Individualize and titrate the dose of TRESIBA 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 ]
    .
  • •For adult patients, instruct patients who miss a dose of TRESIBA 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 TRESIBA injections.
  • •For pediatric patients, instruct patients who miss a dose of TRESIBA to contact their healthcare provider for guidance and to monitor blood glucose levels more frequently until the next scheduled TRESIBA dose.
  • •In patients with type 1 diabetes, TRESIBA must be used concomitantly with short-acting insulin.
  ).
• •The recommended days between dose increases are 3 to 4 days (
  2.2 General Dosing Instructions

  • •TRESIBA is available in 2 concentrations (U-100 and U-200):
    • oTRESIBA 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.
    • oTRESIBA 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 TRESIBA 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 TRESIBA subcutaneously once-daily at any time of day.
  • •In pediatric patients inject TRESIBA subcutaneously once-daily at the same time every day.
  • •Individualize and titrate the dose of TRESIBA 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 ]
    .
  • •For adult patients, instruct patients who miss a dose of TRESIBA 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 TRESIBA injections.
  • •For pediatric patients, instruct patients who miss a dose of TRESIBA to contact their healthcare provider for guidance and to monitor blood glucose levels more frequently until the next scheduled TRESIBA dose.
  • •In patients with type 1 diabetes, TRESIBA must be used concomitantly with short-acting insulin.
  ).
• •See Full Prescribing Information for recommended starting dose in insulin naïve patients and patients already on insulin therapy (
  2.3 Starting Dose in Insulin Naïve Patients

  Recommended Starting Dosage in Patients with Type 1 Diabetes Mellitus:

  The recommended starting dose of TRESIBA 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 TRESIBA in insulin naïve patients with type 2 diabetes mellitus is 10 units once daily.
  ,
  2.4 Switching to TRESIBA 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 ].

  Adults with Type 1 or Type 2 Diabetes Mellitus:

  Start TRESIBA 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 TRESIBA at 80% of the total daily long or intermediate-acting insulin unit dose to minimize the risk of hypoglycemia

  [see Warnings and Precautions ].
  ).

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

Available data from one unpublished trial and the published literature with TRESIBA 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 TRESIBA 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 TRESIBA use was observed (

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)

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.

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.

In an open-label clinical trial, 185 pregnant females with type 1 diabetes were treated with either TRESIBA (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

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.

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.

• •
  Never share
  a TRESIBA FlexTouch pen, insulin syringe, or needle between patients, even if the needle is changed (
  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.
  ).
• •
  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 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 ] 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 ].

  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 ].

  ).
• •
  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 Hypoglycemia

  Hypoglycemia is the most common adverse reaction of insulin, including TRESIBA

  [see Adverse Reactions ].

  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 ].

  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 ],

  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 ]

  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 ]

  . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia

  [see Use in Specific Populations ]

  .

  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 and Warnings and Precautions ]

  .
  ,
  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 TRESIBA in subjects with type 1 diabetes or type 2 diabetes was evaluated in nine trials of 6-12 month duration in adults and in one trial of 12-month duration in pediatric patients 1 year of age and older with type 1 diabetes. The cardiovascular safety of TRESIBA 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 ].

  The data in Table 1 reflect the exposure of 1102 adults with type 1 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 34 weeks 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/m². The mean duration of diabetes was 18 years and the mean HbA_1cat 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 m²and 7% of the patients had an eGFR less than 60 mL/min/1.73 m².

  The data in Table 2 reflect the exposure of 2713 adults with type 2 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 36 weeks 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/m². The mean duration of diabetes was 11 years and the mean HbA_1cat 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 m²and 9% had an eGFR less than 60 mL/min/1.73 m².

  Common adverse reactions (excluding hypoglycemia) occurring in TRESIBA treated subjects during clinical trials in adult patients with type 1 diabetes mellitus and adults with type 2 diabetes mellitus are listed in Table 1 and Table 2, respectively. Common adverse reactions were defined as reactions occurring in ≥5% of the population studied. Hypoglycemia is not shown in these tables but discussed in a dedicated subsection below.

  174 pediatric patients 1 year of age and older with type 1 diabetes were exposed to TRESIBA with a mean exposure to TRESIBA of 48 weeks. The mean age was 10 years: 25% were ages 1-5 years, 40% were ages 6-11 years, and 35% were ages 12-17 years. 55% 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/m². The mean duration of diabetes was 3.9 years and the mean HbA_1cat baseline was 8.2%. Common adverse reactions in TRESIBA treated pediatric patients with type 1 diabetes mellitus were similar to the adverse reactions listed in Table 1.

  Table 1: Adverse Reactions Occurring in ≥5% of TRESIBA-Treated Adult Patients with Type 1 Diabetes Mellitus

  Adverse Reaction	TRESIBA (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 TRESIBA-Treated Adult Patients with Type 2 Diabetes Mellitus

  Adverse Reaction	TRESIBA (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 TRESIBA. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for TRESIBA with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.

  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 TRESIBA who experienced at least one episode of hypoglycemia in clinical trials

  [see Clinical Studies ]

  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. 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 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).

  Table 3: Percent (%) of Type 1 Diabetes Patients Experiencing at Least One Episode of Severe Hypoglycemia or Hypoglycemia^§on TRESIBA in Open-Label Adult and Pediatric Clinical Trials

  	Study A Adults + insulin aspart 52 weeks	Study B Adults + insulin aspart 26 weeks	Study C Adults + insulin aspart 26 weeks		Study J Pediatrics + insulin aspart 52 weeks
  	TRESIBA (N=472)	TRESIBA (N=301)	TRESIBA at the same time each day (N=165)	TRESIBA at alternating times (N=164)	TRESIBA (N=174)
  Severe hypoglycemia*
  Percent of patients	12.3%	10.6%	12.7%	10.4%	17.8%
  Hypoglycemia§
  Percent of patients	95.6%	93.0%	99.4%	93.9%	98.3%

  ^*Severe hypoglycemia in pediatric patients: an episode with 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).

  ^§

  Hypoglycemia

  :

  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).

  Table 4: Percent (%) of Patients with Type 2 Diabetes Experiencing at Least One Episode of Severe Hypoglycemia or Hypoglycemia^§on TRESIBA in Open-Label Adult Clinical Trials

  	Study D + 1-2 OADs* insulin naïve 52 weeks	Study E + 1-2 OADs* insulin naïve 26 weeks	Study F ± 1-3 OADs* insulin naïve 26 weeks	Study G T2DM ± 0-3 OADs* 26 weeks		Study H T2DM ± 0-2 OADs* + insulin aspart 52 weeks	Study I T2DM ± 1-2 OADs* insulin naïve 26 weeks
  	TRESIBA (N=766)	TRESIBA (N=228)	TRESIBA (N=284)	TRESIBA (N=226)	TRESIBA (alternating time) (N=230)	TRESIBA (N=753)	TRESIBA (N=226)
  Severe Hypoglycemia
  Percent of patients	0.3%	0	0	0.9%	0.4%	4.5%	0.4%
  Hypoglycemia§
  Percent of patients	46.5%	28.5%	50%	43.8%	50.9%	80.9%	42.5%

  *OAD: oral antidiabetic agent,

  ^§

  Hypoglycemia

  :

  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).

  Hypersensitivity Reactions

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

  Lipodystrophy

  Long-term use of insulin, including TRESIBA, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue) and may affect insulin absorption

  [see Dosage and Administration ]

  . In the clinical program, lipodystrophy, lipohypertrophy, or lipoatrophy was reported in 0.3% of patients treated with TRESIBA.

  Injection Site Reactions

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

  Weight Gain

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

  Peripheral Edema

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

  .
  ).
• •
  Hypersensitivity reactions
  : Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue TRESIBA, monitor and treat if indicated (
  5.5 Hypersensitivity Reactions

  Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including TRESIBA

  [see Adverse Reactions (6.1)]

  . If hypersensitivity reactions occur, discontinue TRESIBA; treat per standard of care and monitor until symptoms and signs resolve. TRESIBA is contraindicated in patients who have had hypersensitivity reactions to insulin degludec or any of the excipients.
  ).
• •
  Hypokalemia:
  May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated (
  5.6 Hypokalemia

  All insulins, including TRESIBA, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).
  ).
• •
  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 Fluid Retention and Congestive Heart Failure with Concomitant Use of a PPAR Gamma Agonist

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