2015年9月25日，美国食品和药品监管局(FDA)批准Tresiba (德谷胰岛素[Insulin degludec] 注射液)和Ryzodeg 70/30 (德谷胰岛素/门冬胰岛素注射液)在有糖尿病成年中改善血糖(葡萄糖)控制。
根据美国疾病控制和预防中心，在美国约21百万人已被诊断有糖尿病。随时间，糖尿病增加严重健康并发症的风险，包括心脏病，失明，神经和肾损伤。改善血糖控制可减低这些长期并发症的有些的风险。
FDA的药品评价和研究中心中代谢和内分泌产品部主任Jean-Marc Guettier，M.D.说："长效胰岛素在有晚期疾病有1型糖尿病患者和有 2型糖尿病患者治疗中起必不可少的作用，"  “FDA仍承诺直至为糖尿病治疗的创新治疗的发展。”
Tresiba是已一种长效胰岛素类似物适用在有1型和2型糖尿病成年中以改善血糖控制。 Tresiba的给药应根据患者的需要个体化。Tresiba是在天任何时间每天1次皮下给药。
批准日期: 2015年9月25日；公司: 诺和诺德
TRESIBA®(德谷胰岛素[insulin degludec]注射液)，为皮下使用
美国初次批准: 2015
适应证和用途
TRESIBA是一种长效人胰岛素类似物适用于改善血糖控制有糖尿病成年。
使用限制:
建议不为治疗糖尿病酮症酸中毒。
剂量和给药方法
⑴ 根据糖尿病类型，代谢需要，血糖监视结果和血糖控制目的个体化剂量。
⑵ 轮转注射部位减低脂肪代谢障碍的风险。
⑶ 不要与任何其他胰岛素或溶液稀释或混合。
⑷ 每日一次皮下注射，在一天中的任何时间。
⑸ 当使用TRESIBA U-100或U-200 FlexTouch笔不要进行剂量转换。TRESIBA U-100和U-200 FlexTouch笔剂量窗显示将被输送胰岛素单位数和无需转换。
剂型和规格
可得到TRESIBA以下包装大小:
⑴ 100 units/mL(U-100): 3 mL FlexTouch®.
⑵ 200 units/mL(U-200): 3 mL FlexTouch®.
包装规格：
100单位/3毫升/预充笔 5预充笔/盒
200单位/3毫升/预充笔 3预充笔/盒

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TRESIBA safely and effectively. See full prescribing information for TRESIBA.
TRESIBA® (insulin degludec injection), for subcutaneous use
Initial U.S. Approval: 2015
INDICATIONS AND USAGE
TRESIBA is a long-acting human insulin analog indicated to improve glycemic control in adults with diabetes mellitus (1).
Limitations of Use:
Not recommended for treating diabetic ketoacidosis.
DOSAGE AND ADMINISTRATION
• Individualize dose based on type of diabetes, metabolic needs, blood glucose monitoring results and glycemic control goal ( 2.1, 2.2, 2.3, 2.4).
• Rotate injection sites to reduce the risk of lipodystrophy ( 2.1).
• Do not dilute or mix with any other insulin or solution ( 2.1).
• Administer subcutaneously once daily at any time of day ( 2.2).
• Do NOT perform dose conversion when using the TRESIBA U-100 or U-200 FlexTouch pens. The TRESIBA U-100 and U-200 FlexTouch pens dose window shows the number of insulin units to be delivered and NO conversion is needed ( 2.2).
DOSAGE FORMS AND STRENGTHS
TRESIBA is available in the following package sizes:
• 100 units/mL (U-100): 3 mL FlexTouch ® ( 3).
• 200 units/mL (U-200): 3 mL FlexTouch ® ( 3).
CONTRAINDICATIONS
• During episodes of hypoglycemia ( 4).
• Hypersensitivity to TRESIBA or one of its excipients ( 4).
WARNINGS AND PRECAUTIONS
• Never share a TRESIBA FlexTouch pen between patients, even if the needle is changed ( 5.1).
• Hyper- or hypoglycemia with changes in insulin regimen: Carry out under close medical supervision and increase frequency of blood glucose monitoring ( 5.2).
• Hypoglycemia: May be life-threatening. Increase monitoring with changes to: insulin dosage, co-administered glucose lowering medications, 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 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).
ADVERSE REACTIONS
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.
DRUG INTERACTIONS
• Drugs that affect glucose metabolism: Adjustment of insulin dosage may be needed; closely monitor blood glucose ( 7).
• Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent ( 7).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 9/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
TRESIBA is indicated to improve glycemic control in adults with diabetes mellitus.
Limitations of Use
TRESIBA is not recommended for the treatment of diabetic ketoacidosis.
2 DOSAGE AND ADMINISTRATION
2.1 Important Administration Instructions
• Always check insulin labels before administration [see Warnings and Precautions (5.4) ].
• Inspect visually for particulate matter and discoloration. Only use TRESIBA if the solution appears clear and colorless.
• Train patients on proper use and injection technique before initiating TRESIBA. Training reduces the risk of administration errors such as needle sticks and incomplete dosing.
• Inject TRESIBA 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 [see Adverse Reactions (6.1)].
• DO NOT administer TRESIBA intravenously, intramuscularly or in an insulin infusion pump.
• DO NOT dilute or mix TRESIBA with any other insulin products or solutions.
• DO NOT transfer TRESIBA from the TRESIBA pen into a syringe for administration [see Warnings and Precautions (5.4)].
2.2 General Dosing Instructions
• Inject TRESIBA subcutaneously once-daily at any time of 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 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 [see Warnings and Precautions (5.3)].
• 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.
• DO NOT perform dose conversion when using the TRESIBA U-100 or U-200 FlexTouch pens. The dose window for both the TRESIBA U-100 and U-200 FlexTouch pens shows the number of insulin units to be delivered and NO conversion is needed.
2.3 Starting Dose in Insulin Naïve Patients
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.
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 Starting Dose in Patients Already on Insulin Therapy
Type 1 and Type 2 Diabetes Mellitus:
Start TRESIBA at the same unit dose as the total daily long or intermediate-acting insulin unit dose.
3 DOSAGE FORMS AND STRENGTHS
TRESIBA is available as a clear, and colorless solution for injection in:
• 100 units/mL (U-100): 3 mL FlexTouch disposable prefilled pen
• 200 units/mL (U-200): 3 mL FlexTouch disposable prefilled pen 
4 CONTRAINDICATIONS(What is this?)
TRESIBA is contraindicated:
• During episodes of hypoglycemia [see Warnings and Precautions (5.3)].
• In patients with hypersensitivity to TRESIBA or one of its excipients [see Warnings and Precautions (5.5)].
5 WARNINGS AND PRECAUTIONS
5.1 Never Share a TRESIBA FlexTouch Pen Between Patients
TRESIBA FlexTouch disposable prefilled pens should never be shared between patients, even if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens.
5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen
Changes in insulin, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia or hyperglycemia. These changes should be made cautiously and only under medical supervision and the frequency of blood glucose monitoring should be increased. For patients with type 2 diabetes, adjustments in concomitant oral anti-diabetic treatment may be needed. When converting from other insulin therapies to TRESIBA follow dosing recommendations [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 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 [see Contraindications (4)].
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) [see Drug Interactions (7)], 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 [see Clinical Pharmacology (12.2)] and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of TRESIBA may vary among different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature.
Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication [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 basal insulin products and other insulins, particularly rapid-acting insulins, have been reported. To avoid medication errors between TRESIBA and other insulins, instruct patients to always check the insulin label before each injection.
Do not transfer TRESIBA from the TRESIBA pen to a syringe. The markings on the insulin syringe will not measure the dose correctly and can result in overdosage and severe hypoglycemia [see Dosage and Administration(2.1) and Warnings and Precautions (5.3)].
5.5 Hypersensitivity and Allergic Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including TRESIBA. 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 one of the excipients [see Contraindications (4)].
5.6 Hypokalemia
All insulin products, 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).
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, particularly 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.
6 ADVERSE REACTIONS
The following adverse reactions are also discussed elsewhere:
• Hypoglycemia [see Warnings and Precautions ( 5.3 )]
• Hypersensitivity and allergic reactions [see Warnings and Precautions (5.5)]
• Hypokalemia [see Warnings and Precautions (5.6)]
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 was evaluated in nine treat to target trials of 6-12 months duration, conducted in subjects with type 1 diabetes or type 2 diabetes [see Clinical Studies (14)].
The data in Table 1 reflect the exposure of 1102 patients with type 1 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 34 weeks. The mean age was 43 years and 1% were older than 75 years. Fifty-seven percent were male, 81% were White, 2% were Black or African American and 4% were Hispanic. The mean body mass index (BMI) was 26 kg/m2. The mean duration of diabetes was 18 years and the mean HbA1c at baseline was 7.8%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported in 11%, 16%, 7% and 0.5% respectively. The mean eGFR at baseline was 87 mL/min/1.73 m2 and 7% of the patients had an eGFR less than 60 mL/min/1.73 m2.
The data in Table 2 reflect the exposure of 2713 patients with type 2 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 36 weeks. The mean age was 58 years and 3% were older than 75 years. Fifty-eight percent were male, 71% were White, 7% were Black or African American and 13% were Hispanic. The mean BMI was 30 kg/m2. The mean duration of diabetes was 11 years and the mean HbA1c at baseline was 8.3%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported for 14%, 10%, 6% and 0.6% of participants respectively. At baseline, the mean eGFR was 83 mL/min/1.73 m2 and 9% had an eGFR less than 60 mL/min/1.73 m2.
Common adverse reactions (excluding hypoglycemia)occurring in TRESIBA treated subjects during clinical trials in patients with type 1 diabetes mellitus and 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.
Table 1: Adverse Reactions Occurring in ≥5% of TRESIBA-Treated Patients with Type 1 Diabetes Mellitus

Adverse Reaction	TRESIBA (n=1102)
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 Patients with Type 2 Diabetes Mellitus

Adverse Reaction	TRESIBA (n=2713)
Nasopharyngitis	12.9 %
Headache	8.8 %
Upper respiratory tract infection	8.4 %
Diarrhea	6.3 %

Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including TRESIBA [see Warnings and Precautions (5.3)]. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for TRESIBA with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.
The percent of participants randomized to TRESIBA who experienced at least one episode of hypoglycemia in adult clinical trials [see Clinical Studies (14)] of patients with type 1 and type 2 diabetes respectively, are shown in Table 3 and 4. No clinically important differences in risk of hypoglycemia between TRESIBA and comparators was observed in clinical trials.
Severe hypoglycemia was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. 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).
Table 3: Percent (%) of Type 1 Diabetes Patients Experiencing at Least One Episode of Severe Hypoglycemia or Novo Nordisk Hypoglycemia§ on TRESIBA in Adult Clinical Trials

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

Novo Nordisk 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 Novo Nordisk Hypoglycemia§ on TRESIBA in Adult Clinical Trials

Study D + 1-2 OADs* insulin naïve 52 weeks	Study E + 1-2 OAD*s 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 26 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%
Novo Nordisk Hypoglycemia§
Percent of patients	46.5%	28.5%	50%	43.8%	50.9%	80.9%	42.5%

*OAD: oral antidiabetic agent, §Novo Nordisk 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).
Allergic Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including TRESIBA and may be life threatening [see Warnings and Precautions (5.5)]. Hypersensitivity (manifested with swelling of tongue and lips, diarrhea, nausea, tiredness, and itching) and urticaria were reported in 0.9% of patients treated with TRESIBA.
Lipodystrophy
Long-term use of insulin, including TRESIBA, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue) and may affect insulin absorption. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy [see Dosage and Administration (2.1)]. In the clinical program, lipodystrophy, lipohypertrophy, or lipoatrophy was reported in 0.3% of patients treated with TRESIBA.
Injection Site Reactions
Patients taking TRESIBA may experience injection site reactions, including injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass. In the clinical program, injection site reactions occurred in 3.8% of patients treated with TRESIBA.
Weight Gain
Weight gain can occur with insulin therapy, including TRESIBA, and has been attributed to the anabolic effects of insulin. In the clinical program after 52 weeks of treatment, patients with type 1 diabetes treated with TRESIBA gained an average of 1.8 kg and patients with type 2 diabetes treated with TRESIBA gained an average of 3.0 kg.
Peripheral Edema
Insulin, including TRESIBA, may cause sodium retention and edema. In the clinical program, peripheral edema occurred in 0.9% of patients with type 1 diabetes mellitus and 3.0% of patients with type 2 diabetes mellitus treated with TRESIBA.
6.2 Immunogenicity
As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to TRESIBA with the incidence of antibodies in other studies or to other products, may be misleading.
In studies of type 1 diabetes patients, 95.9% of patients who received TRESIBA once daily were positive for anti-insulin antibodies (AIA) at least once during the studies, including 89.7% that were positive at baseline. In studies of type 2 diabetes patients, 31.5% of patients who received TRESIBA once daily were positive for AIA at least once during the studies, including 14.5% that were positive at baseline. The antibody incidence rates for type 2 diabetes may be underreported due to potential assay interference by endogenous insulin in samples in these patients. The presence of antibodies that affect clinical efficacy may necessitate dose adjustments to correct for tendencies toward hyper or hypoglycemia.
The incidence of anti-insulin degludec antibodies has not been established.
7 DRUG INTERACTIONS
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, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics, GLP-1 receptor agonists, DDP-4 inhibitors, SGLT-2 inhibitors.
Intervention:	Dose reductions and increased frequency of glucose monitoring may be required when TRESIBA is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of TRESIBA
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:	Dose increases and increased frequency of glucose monitoring may be required when TRESIBA is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of TRESIBA
Drugs:	Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when TRESIBA 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 TRESIBA is co-administered with these drugs.

8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no well-controlled clinical studies of the use of insulin degludec in pregnant women. Patients should be advised to discuss with their health care provider if they intend to or if they become pregnant. Because animal reproduction studies are not always predictive of human response, insulin degludec should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is essential for patients with diabetes or a history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients.
Subcutaneous reproduction and teratology studies have been performed with insulin degludec and human insulin (NPH) as a comparator in rats and rabbits. In these studies, insulin was given to female rats before mating throughout pregnancy until weaning, and to rabbits during organogenesis. The effect of insulin degludec was consistent with those observed with human insulin as both caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at an insulin degludec dose of 21 U/kg/day (approximately 5 times the human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day) and in rabbits at a dose of 3.3 U/kg/day (approximately 10 times the human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day). The effects are probably secondary to maternal hypoglycemia.
8.3 Nursing Mothers
It is unknown whether insulin degludec is excreted in human milk. Because many drugs, including human insulin, are excreted in human milk, caution should be exercised when insulin degludec is administered to a nursing mother. Women with diabetes who are lactating may require adjustments in insulin dose, meal plan, or both.
In rats, insulin degludec was secreted in milk and the concentration in milk was lower than in plasma.
8.4 Pediatric Use
The safety and efficacy of TRESIBA in children and adolescents under the age of 18 have not been established.
8.5 Geriatric Use
In controlled clinical studies [see Clinical Studies (14)] a total of 77 (7%) of the 1102 TRESIBA -treated patients with type 1 diabetes were 65 years or older and 9 (1%) were 75 years or older. A total of 670 (25%) of the 2713 TRESIBA-treated patients with type 2 diabetes were 65 years or older and 80 (3%) were 75 years or older. Differences in safety or effectiveness were not suggested in subgroup analyses comparing subjects older than 65 years to younger subjects.
Nevertheless, greater caution should be exercised when TRESIBA is administered to geriatric patients since greater sensitivity of some older individuals to the effects of TRESIBA cannot be ruled out. The initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be more difficult to recognize in the elderly.
8.6 Renal Impairment
In clinical studies [see Clinical Studies (14)] a total of 75 (7%) of the 1102 TRESIBA-treated patients with type 1 diabetes had an eGFR less than 60 mL/min/1.73 m2 and 1 (0.1%) had an eGFR less than 30 mL/min/1.73 m2. A total of 250 (9%) of the 2713 TRESIBA-treated patients with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m2 and no subjects had an eGFR less than 30 mL/min/1.73 m2.
No clinically relevant difference in the pharmacokinetics of TRESIBA was identified in a study comparing healthy subjects and subjects with renal impairment including subjects with end stage renal disease [see Clinical Pharmacology (12.3)]. However, as with all insulin products, glucose monitoring should be intensified and the TRESIBA dosage adjusted on an individual basis in patients with renal impairment.
8.7 Hepatic Impairment
No difference in the pharmacokinetics of TRESIBA was identified in a study comparing healthy subjects and subjects with hepatic impairment (mild, moderate, and severe hepatic impairment) [see Clinical Pharmacology (12.3)]. However, as with all insulin products, glucose monitoring should be intensified and the TRESIBA dosage adjusted on an individual basis in patients with hepatic impairment.
10 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. 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.
11 DESCRIPTION
TRESIBA (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:

Figure 1: Structural Formula of TRESIBA
TRESIBA 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.
TRESIBA has a pH of approximately 7.6. Hydrochloric acid or sodium hydroxide may be added to adjust pH. 
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The primary activity of insulin, including TRESIBA, 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. TRESIBA forms multi-hexamers when injected into the subcutaneous tissue resulting in a subcutaneous insulin degludec depot. The protracted time action profile of TRESIBA 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.
12.2 Pharmacodynamics
The glucose-lowering effect of TRESIBA 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 TRESIBA over time following 8 once-daily subcutaneous injections of 0.4 U/kg of TRESIBA in patients with type 1 diabetes.

Figure 2: Mean GIR profile for 0.4 U/kg dose of TRESIBA (steady state) in patients with Type 1 diabetes mellitus
The mean maximum glucose lowering effect (GIRmax) of a 0.4 U/kg dose of TRESIBA was 2.0 mg/kg/min, which was observed at a median of 12 hours post-dose. The glucose lowering effect of TRESIBA 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 TRESIBA (within-subject coefficient of variation for AUCGIR,τ,SS).
The total glucose-lowering effect of TRESIBA 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 U/kg to 0.8 U/kg.
The total glucose-lowering effect of 0.4 U/kg of TRESIBA U-100 and 0.4 U/kg of TRESIBA 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.
12.3 Pharmacokinetics
Absorption
In patients with type 1 diabetes, after 8 days of once daily subcutaneous dosing with 0.4 U/kg of TRESIBA,maximum degludec concentrations of 4472 pmol/L were attained at a median of 9 hours (tmax). After the first dose of TRESIBA, 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 U/kg to 0.8 U/kg TRESIBA. Total and maximum insulin degludec exposure at steady state are comparable between TRESIBA U-100 and TRESIBA U-200 when each is administered at the same U/kg dose.
Insulin degludec concentration reach steady state levels after 3-4 days of TRESIBA administration [see Dosage and Administration (2.2)].
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 TRESIBA 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 U/kg.
Specific Populations
As with other insulin preparations, TRESIBA should always be titrated according to individual requirements.
Geriatrics-
Pharmacokinetic and pharmacodynamic response of TRESIBA 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 U/kg dose of TRESIBA or insulin glargine. On average, the pharmacokinetic and pharmacodynamic properties of TRESIBA 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 TRESIBA was examined in an across-trial analysis of the pharmacokinetic and pharmacodynamic studies. 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 TRESIBA was explored in a cross-trial analysis of pharmacokinetic and pharmacodynamic studies. For subjects with type 1 diabetes, no relationship between exposure of TRESIBA and BMI was observed. For subjects with type 1 and type 2 diabetes a trend for decrease in glucose-lowering effect of TRESIBA with increasing BMI was observed.
Race and Ethnicity-
TRESIBA 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. There were no statistically significant differences between the racial and ethnic groups investigated.
Pregnancy-
The effect of pregnancy on the pharmacokinetics and pharmacodynamics of TRESIBA has not been studied [see Use in Specific Populations (8.1)].
Renal Impairment-
TRESIBA 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 U/kg) of TRESIBA. 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 TRESIBA 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 TRESIBA (CL/FIDeg,SD) in subjects with ESRD[see Use in Specific Populations (8.6)].
Hepatic Impairment-
TRESIBA 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 U/kg) of TRESIBA. Hepatic function was defined using Child-Pugh Scores ranging from 5 (mild hepatic impairment) to 15 (severe hepatic impairment). No differences in the pharmacokinetics of TRESIBA were identified between healthy subjects and subjects with hepatic impairment [see Use in Specific Populations (8.7)].
13 NONCLINICAL TOXICOLOGY
13.1 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 U/kg/day), Sprague-Dawley rats were dosed subcutaneously with insulin degludec at 3.3, 6.7, and 10 U/kg/day, resulting in 5 times the human exposure (AUC) when compared to a human subcutaneous dose of 0.75 U/kg/day. Human insulin was dosed at 6.7 U/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 U/kg/day (approximately 5 times the human subcutaneous dose of 0.75 U/kg/day, based on U/body surface area) prior to mating and in female rats during gestation had no effect on mating performance and fertility.
14 CLINICAL STUDIES
The efficacy of TRESIBA 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. The efficacy of TRESIBA administered once-daily either at the same time each day or at any time each day in 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.
Patients treated with TRESIBA achieved levels of glycemic control similar to those achieved with LANTUS (insulin glargine 100 U/mL) and LEVEMIR (insulin detemir) and achieved statistically significant improvements compared to sitagliptin.
14.1 Type 1 Diabetes – Adult
TRESIBA Administered at the Same Time each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes
Study A
The efficacy of TRESIBA 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 TRESIBA 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 TRESIBA 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%). See Table 6, Study A.
Study B
The efficacy of TRESIBA 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 TRESIBA 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 TRESIBA 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%). See Table 6, Study B.
TABLE 6: Results at Week 52 in a Trial Comparing TRESIBA to Insulin glargine U-100 (Study A) and Week 26 in a Trial Comparing TRESIBA to Insulin detemir (Study B) in Patients with Type 1 Diabetes Mellitus receiving Insulin aspart at Mealtimes

Study A		Study B
	TRESIBA + Insulin aspart	Insulin glargine U-100 + Insulin aspart	TRESIBA + Insulin aspart	Insulin detemir + Insulin aspart
N	472	157	302	153
HbA1c (%)
Baseline	7.7	7.7	8.0	8.0
End of trial	7.3	7.3	7.3	7.3
Adjusted mean change from baseline*	-0.36	-0.34	-0.71	-0.61
Estimated treatment difference [95%CI] TRESIBA - Insulin glargine U-100	-0.01 [-0.14;0.11]		-0.09 [-0.23;0.05]
Proportion Achieving HbA1c < 7% at Trial End	39.8%	42.7%	41.1%	37.3%
FPG (mg/dL)
Baseline	165	174	178	171
End of trial	141	149	131	161
Adjusted mean change from baseline	-27.6	-21.6	-43.3	-13.5
Daily basal insulin dose
Baseline mean	28 U	26 U	22 U	22 U
Mean dose at end of study	29 U1	31 U1	25 U2	29 U2
Daily bolus insulin dose
Baseline mean	29 U	29 U	28 U	31 U
Mean dose at end of study	32 U1	35 U1	36 U2	41 U2

1At Week 52
2At Week 26
*The change from baseline to end of treatment visit in HbA 1c was analysed using ANOVA with treatment, region, sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA 1c as covariates.
In Study A, there were 14.8% of subjects in the TRESIBA and 11.5% Insulin glargine arms for whom data was missing at the time of the HbA 1c measurement.
In Study B, there were 6.3% of subjects in the TRESIBA and 9.8% Insulin detemir arms for whom data was missing at the time of the HbA 1c measurement.
Study C: TRESIBA Administered at the Same Time each Day or at Any Time each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes
The efficacy of TRESIBA was evaluated in a 26-week randomized, open-label, multicenter trial in 493 patients with type 1 diabetes mellitus. Patients were randomized to TRESIBA injected once-daily at the same time each day (with the main evening meal), to TRESIBA 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 TRESIBA 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). TRESIBA 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 both 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 TRESIBA 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%). See Table 7.
Table 7: Results at Week 26 in a Trial Comparing TRESIBA Dosed Once Daily at the Same and at Alternating Times Each Day to Insulin glargine U-100 in Patients with Type 1 Diabetes Mellitus receiving Insulin aspart at mealtimes

TRESIBA at the same time each day + Insulin aspart	TRESIBA at alternating times + Insulin aspart	Insulin glargine U-100 + Insulin aspart
N	165	164	164
HbA1c (%)
Baseline	7.7	7.7	7.7
End of trial	7.3	7.3	7.1
Adjusted mean change from baseline*	-0.41	-0.40	-0.57
Estimated treatment difference [95%CI] TRESIBA alternating - Insulin glargine U-100		0.17 [0.04;0.30]
Proportion Achieving HbA1c < 7% at Trial End	37.0%	37.2%	40.9%
FPG (mg/dL)
Baseline	179	173	175
End of trial	133	149	151
Adjusted mean change from baseline	-41.8	-24.7	-23.9
Daily basal insulin dose
Baseline mean	28 U	29 U	29 U
Mean dose at end of study	32 U	36 U	35 U
Daily bolus insulin dose
Baseline mean	29 U	33 U	32 U
Mean dose at end of study	27 U	30 U	35 U

*The change from baseline to end of treatment visit in HbA1c was analysed using ANOVA with treatment, region, sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA1c as covariates.
In Study C, there were 15.8% and 15.9% of subjects in the TRESIBA (same time and alternating times respectively) and 7.9% Insulin glargine arms for whom data was missing at the time of the HbA1c measurement.
14.2 Type 2 Diabetes – Adult
Study D: TRESIBA Administered at the Same Time each Day as an Add-on to Metformin with or without a DPP-4 inhibitor in Insulin Naïve Patients
The efficacy of TRESIBA 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 TRESIBA 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 TRESIBA 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%); See Table 8.
Table 8: Results at Week 52 in a Trial Comparing TRESIBA to Insulin glargine U-100 in Patients with Type 2 Diabetes Mellitus on OAD(s)*

TRESIBA + OAD(s)*		Insulin glargine U-100 + OAD(s)*
N	773		257
HbA1c (%)
Baseline	8.2		8.2
End of trial	7.1		7.0
Adjusted mean change from baseline**	-1.06		-1.15
Estimated treatment difference [95%CI] TRESIBA - Insulin glargine U-100	0.09 [-0.04;0.22]
Proportion Achieving HbA1c < 7% at Trial End	51.7%	54.1%
FPG (mg/dL)
Baseline	174		174
End of trial	106		115
Adjusted mean change from baseline	-68.0		-60.2
Daily insulin dose
Baseline mean (starting dose)	10 U		10 U
Mean dose after 52 weeks	56 U		58 U

OAD: oral antidiabetic agent
**The change from baseline to end of treatment visit in HbA1c was analysed using ANOVA with treatment, region, sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA1c as covariates.
In Study D, there were 20.6% of subjects in the TRESIBA and 22.2% Insulin glargine arms for whom data was missing at the time of the HbA1c measurement.
Study E: TRESIBA 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 Patients
The efficacy of TRESIBA 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 TRESIBA 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 TRESIBA 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%). See Table 9.
Table 9: Results at Week 26 in a Trial Comparing TRESIBA U-200 to Insulin glargine U-100 in Patients with Type 2 Diabetes Mellitus on OAD(s)*

TRESIBA U-200 + Met ± DPP-4		Insulin glargine U-100 + Met ± DPP-4
N	228		229
HbA1c (%)
Baseline	8.3		8.2
End of trial	7.0		6.9
Adjusted mean change from baseline**	-1.18		-1.22
Estimated treatment difference [95%CI] TRESIBA - Insulin glargine U-100	0.04 [-0.11;0.19]
Proportion Achieving HbA1c < 7% at Trial End	52.2%	55.9%
FPG (mg/dL)
Baseline	172		174
End of trial	106		113
Adjusted mean change from baseline	-71.1		-63.5
Daily insulin dose
Baseline mean	10 U		10 U
Mean dose after 26 weeks	59 U		62 U

*OAD: oral antidiabetic agent
**The change from baseline to end of treatment visit in HbA1c was analysed using ANOVA with treatment, region, sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA1c as covariates.
In Study E, there were 12.3% of subjects in the TRESIBA and 12.7% Insulin glargine arms for whom data was missing at the time of the HbA1c measurement.
Study F: TRESIBA Administered at the Same Time each Day in Insulin Naïve Patients as an Add-on to One or More of the Following Oral Agents: Metformin, Sulfonylurea, Glinides or Alpha-Glucosidase inhibitors
The efficacy of TRESIBA 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 TRESIBA 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 TRESIBA 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%). See Table 10.
Table 10: Results at Week 26 in a Trial Comparing TRESIBA to Insulin glargine U-100 in Patients with Type 2 Diabetes Mellitus on OAD(s)*

TRESIBA + OAD(s)*	Insulin glargine U-100 + OAD(s)*
N	289	146
HbA1c (%)
Baseline	8.4	8.5
End of trial	7.2	7.1
Adjusted mean change from baseline**	-1.42	-1.52
Estimated treatment difference [95%CI] TRESIBA - Insulin glargine U-100	0.11 [-0.03 ; 0.24]
Proportion Achieving HbA1c < 7% at Trial End	40.8%	48.6%
FPG (mg/dL)
Baseline	152	156
End of trial	100	102
Adjusted mean change from baseline	-54.6	-53.0
Daily insulin dose
Baseline mean (starting dose)	9 U	9 U
Mean dose after 26 weeks	19 U	24 U

*OAD: oral antidiabetic agent
**The change from baseline to end of treatment visit in HbA1c was analysed using ANOVA with treatment, region, sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA1c as covariates.
In Study F, there were 10% of subjects in the TRESIBA and 6.8% Insulin glargine arms for whom data was missing at the time of the HbA1c measurement.
Study G: TRESIBA 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
The efficacy of TRESIBA 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 TRESIBA injected once-daily at the same time each day (with the main evening meal), to TRESIBA 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 TRESIBA 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). TRESIBA 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 TRESIBA 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%). See Table 11.
Table 11: Results at Week 26 in a Trial Comparing TRESIBA at same and alternating times to Insulin glargine U-100 in Patients with Type 2 Diabetes Mellitus on OAD(s)*

TRESIBA at the same time each day ± OAD(s)*	TRESIBA at alternating times ± OAD(s)*	Insulin glargine U-100 ± OAD(s)*
N	228	229	230
HbA1c (%)
Baseline	8.4	8.5	8.4
End of trial	7.3	7.2	7.1
Adjusted mean change from baseline**	-1.03	-1.17	-1.21
Estimated treatment difference [95%CI] TRESIBA alternating- Insulin glargine U-100		0.04 [-0.12;0.20]
Estimated treatment difference TRESIBA alternating – TRESIBA same	-0.13
Proportion Achieving HbA1c < 7% at Trial End	40.8%	38.9%	43.9%
FPG (mg/dL)
Baseline	158	162	163
End of trial	105	105	112
Adjusted mean change from baseline	-54.2	-55.0	-47.5
Daily insulin dose
Baseline mean	21 U	19 U	19 U
Mean dose after 26 weeks	45 U	46 U	44 U

*OAD: oral antidiabetic agent
**The change from baseline to end of treatment visit in HbA1c was analysed using ANOVA with treatment, region, sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA1c as covariates.
In Study G, there were 11.4% subjects for TRESIBA (both same time and alternating times) and 11.7% Insulin glargine arms for whom data was missing at the time of the HbA1c measurement.
Study H: TRESIBA Administered at the Same Time each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes
The efficacy of TRESIBA 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 TRESIBA 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 TRESIBA 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%). See Table 12.
Table 12: Results at Week 52 in a Trial Comparing TRESIBA to Insulin glargine U-100 in Patients with Type 2 Diabetes Mellitus receiving Insulin aspart at mealtimes and OADs*

TRESIBA + Insulin aspart ± OAD(s)*	Insulin glargine U-100 + Insulin aspart ± OAD(s)*
N	744	248
HbA1c (%)
Baseline	8.3	8.4
End of trial	7.1	7.1
Adjusted mean change from baseline**	-1.10	-1.18
Estimated treatment difference [95%CI] TRESIBA - Insulin glargine U-100	0.08 [-0.05;0.21]
Proportion Achieving HbA1c < 7% at Trial End	49.5%	50.0%
FPG (mg/dL)
Baseline	166	166
End of trial	122	127
Adjusted mean change from baseline	-40.6	-35.3
Daily basal insulin dose
Baseline mean	42 U	41 U
Mean dose after 52 weeks	74 U	67 U
Daily bolus insulin dose
Baseline mean	33 U	33 U
Mean dose after 52 weeks	70 U	73 U

*OAD: oral antidiabetic agent
**The change from baseline to end of treatment visit in HbA1c was analysed using ANOVA with treatment, region, sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA1c as covariates.
In Study H, there were 16.1% of subjects in the TRESIBA and 14.5% Insulin glargine arms for whom data was missing at the time of the HbA1c measurement.
Study I: TRESIBA Administered at Any Time each Day as an Add-on to One or Two of the Following Oral Agents: Metformin, Sulfonylurea, or Pioglitazone
The efficacy of TRESIBA 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 TRESIBA 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, TRESIBA provided greater reduction in mean HbA1c compared to sitagliptin (p < 0.001). See Table 13.
Table 13: Results at Week 26 in a Trial Comparing TRESIBA to Sitagliptin in Patients with Type 2 Diabetes Mellitus on OADs*

TRESIBA + OAD(s)*	Sitagliptin + OAD(s)*
N	225	222
HbA1c (%)
Baseline	8.8	9.0
End of trial	7.2	7.7
Adjusted mean change from baseline**	-1.52	-1.09
Estimated treatment difference [95%CI] TRESIBA - Sitagliptin	-0.43 [-0.61;-0.24]1
Proportion Achieving HbA1c < 7% at Trial End	40.9%	27.9%
FPG (mg/dL)
Baseline	170	179
End of trial	112	154
Adjusted mean change from baseline	-61.4	-22.3
Daily insulin dose
Baseline mean	10 U	N/A
Mean dose after 26 weeks	43 U	N/A

*OAD: oral antidiabetic agent
**The change from baseline to end of treatment visit in HbA1c was analysed using
with treatment, region, sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA1c as covariates.
In Study I, there were 20.9% of subjects in the TRESIBA and 22.5% Sitagliptin arms for whom data was missing at the time of the HbA1c measurement.
1p <0.001; 1-sided p-value evaluated at 2.5% level for superiority
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How SuppliedTRESIBA is available as a clear and colorless solution in the following package sizes (see Table 14).
Table 14 Presentations of TRESIBA

TRESIBA	Total volume	Concentration	Total units available in presentation	NDC number	Max dose per injection	Dose increment	Package Size
U-100 FlexTouch	3 mL	100 units/mL	300 Units	0169-2660-15	80 Units	1 Unit	5 pens/pack
U-200 FlexTouch	3 mL	200 units/mL	600 Units	0169-2550-13	160 Units	2 Unit	3 pens

16.2 Recommended Storage
Unused TRESIBA should be stored between 36°F to 46°F (2°C and 8°C). 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.
Unopened FlexTouch disposable prefilled pen:
Not in-use (unopened) TRESIBA disposable prefilled pen should be stored in a refrigerator (36°F - 46°F [2°C - 8°C]). Discard after expiration date.
Open (In-Use) FlexTouch disposable prefilled pen:
The in-use TRESIBA FlexTouch pen should NOT be refrigerated but should be kept at room temperature (below 86°F [30°C]) away from direct heat and light. The opened (in-use) TRESIBA FlexTouch pen may be used for up to 56 days (8 weeks) after being opened, if it is kept at room temperature.
The storage conditions are summarized in Table 15:
Table 15: Storage Conditions for TRESIBA FlexTouch

Not in-use (unopened) Refrigerated (36°F - 46°F [2°C - 8°C])	Not in-use (unopened) Room Temperature (below 86°F [30°C])	In-use (opened) Room Temperature (below 86°F [30°C])
3 mL TRESIBA U-100 FlexTouch	Until expiration date	56 days (8 weeks)	56 days (8 weeks) (Do not refrigerate)
3 mL TRESIBA U-200 FlexTouch	Until expiration date	56 days (8 weeks)	56 days (8 weeks) (Do not refrigerate)

17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information and Instructions for Use)
Never Share a TRESIBA FlexTouch Pen Between Patients
Advise patients that they should never share a TRESIBA FlexTouch, pen device with another person, even if the needle is changed, because doing so carries 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. 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 [see Warnings and Precautions (5.2)].
Medication errors
Inform patients to always check the insulin label before each injection [see Warnings and Precautions (5.4)]. TRESIBA FlexTouch pen is available in concentrations of 100 units/mL or 200 units/mL.
Inform patients that the dose counter of TRESIBA FlexTouch pen shows the number of units of
TRESIBA to be injected. NO dose re-calculation is required [see Dosage and Administration (2.2)].
Instruct patients that when injecting TRESIBA, 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 TRESIBA 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 TRESIBA from the FlexTouch disposable insulin prefilled pen.
Administration
TRESIBA must only be used if the solution is clear and colorless with no particles visible.
Patients must be advised that TRESIBA must NOT be diluted or mixed with any other insulin or solution [see Dosage and Administration (2.1)].
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 [see Warnings and Precautions (5.3)].
Refer patients to the TRESIBA “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.