DRUG INTERACTIONS-

• Drugs that affect glucose metabolism: Adjustment of insulin dosage may 61 be needed; closely monitor blood glucose 

• Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and 63 reserpine): Signs and symptoms of hypoglycemia may be reduced or 64 absent (7). 65 See 17 for 

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 coadministered 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 coadministered 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 coadministered with these drugs.

Drugs That May Blunt Signs and Symptoms of Hypoglycemia Reference ID: 3825141 11 Drugs: beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when TRESIBA is co-administered with these drugs. 423 424 425

27/15    TRESIBA

Name of the Drug-   TRESIBA

Active Ingredient-      Insulin degludec injection

Indication-                  To improve blood sugar (glucose) in adults with diabetic                                                    mellitus                                               

Date                              9/25/2015   

HIGHLIGHTS OF PRESCRIBING INFORMATION

 These highlights do not include all the information needed to use                                       3 TRESIBA safely and effectively.

See full prescribing information for 4 TRESIBA. 5 TRESIBA® (insulin degludec injection), for subcutaneous use 6

Initial U.S. Approval: 2015

INDICATIONS AND USAGE-

 TRESIBA is a long-acting human insulin analog indicated to improve 9 glycemic control in adults with diabetes mellitus (1). 10 Limitations of Use: 11 Not recommended for treating diabetic ketoacidosis.

ADVERSE REACTIONS-

Adverse reactions commonly associated with TRESIBA are:

• hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, 56 pruritus, rash, edema and weight gain

CONTRAINDICATIONS-

 • During episodes of hypoglycemia 

• Hypersensitivity to TRESIBA or one of its excipients 

WARNINGS AND PRECAUTIONS-

• Never share a TRESIBA FlexTouch pen between patients, even if the 31 needle is changed 

• Hyper- or hypoglycemia with changes in insulin regimen: Carry out under 33 close medical supervision and increase frequency of blood glucose 34 monitoring 

Hypoglycemia: May be life-threatening. Increase monitoring with 36 changes to: insulin dosage, co-administered glucose lowering 37 medications, meal pattern, physical activity; and in patients with renal 38 impairment or hepatic impairment or hypoglycemia unawareness (

• Hypoglycemia due to medication errors: Accidental mix-ups between 41 insulin products can occur. Instruct patients to check insulin labels before 42 injection.

DO NOT transfer TRESIBA into a syringe for administration as 43 overdosage and severe hypoglycemia can result 

• Hypersensitivity reactions: Severe, life-threatening, generalized allergy, 45 including anaphylaxis, can occur. Discontinue TRESIBA, monitor and 46 treat if indicated (5.5). 47

• Hypokalemia: May be life-threatening. Monitor potassium levels in 48 patients at risk for hypokalemia and treat if indicated (5.6). 49

• Fluid retention and heart failure with concomitant use of 50 Thiazolidinediones (TZDs): Observe for signs and symptoms of heart 51 failure; consider dosage reduction or discontinuation if heart failure 52 occurs 

-DOSAGE AND ADMINISTRATION-

• Individualize dose based on type of diabetes, metabolic needs, blood 14 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). 16 • 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 U19 200 FlexTouch pens. The TRESIBA U-100 and U-200 FlexTouch pens 20 dose window shows the number of insulin units to be delivered and NO 21 conversion is needed (2.2). 

DOSAGE FORMS AND STRENGTHS--

 TRESIBA is available in the following package sizes: 24 • 100 units/mL (U-100): 3 mL FlexTouch® (3). 25 • 200 units/mL (U-200): 3 mL 

PATIENT COUNSELING INFORMATION-

Approved Patient Labeling (Patient Information and Instructions for Use) 9

Never Share a TRESIBA FlexTouch Pen Between Patients 974 Advise patients that they should never share a TRESIBA FlexTouch, pen device with another 975 person, even if the needle is changed, because doing so carries a risk for transmission of blood976 borne pathogens 

Hyperglycemia or Hypoglycemia 979

Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform 980 patients of the symptoms of hypoglycemia. Inform patients that the ability to concentrate and 981 react may be impaired as a result of hypoglycemia.

This may present a risk in situations where 982 these abilities are especially important, such as driving or operating other machinery.

Advise 983 patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to 984 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 988 [see Warnings and Precautions (5.2)].

 Medication errors 991 Inform patients to always check the insulin label before each injection 

TRESIBA FlexTouch pen is available in concentrations of 100 units/mL or 993 200 units/mL. 994 995 Inform patients that the dose counter of TRESIBA FlexTouch pen shows the number of units of 996 TRESIBA to be injected.

Management of Hypoglycemia and Handling of Special Situations 1030

Patients should be instructed on self-management procedures including glucose monitoring, 1031 proper injection technique, and management of hypoglycemia and hyperglycemia.

Patients must 1032 be instructed on handling of special situations such as intercurrent conditions (illness, stress, or 1033 emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an 1034 increased insulin dose, inadequate food intake, and skipped meals [see Warnings and 1035 Precautions (5.3)]. 1036 1037 Refer patients to the TRESIBA

“Patient Information” for additional information about the 1038 potential side effects of insulin therapy, including lipodystrophy (and the need to rotate injection 1039 sites within the same body region), weight gain, allergic reactions, and hypoglycemia. 1040 1041

Women of Reproductive Potential 1042 Advise patients to inform their health care professional if they are pregnant or are contemplating 1043 pregnancy. Reference ID: 3825141 30 1044 1045 1046 1047 Rx Only 1048 1049 Date of Issue: 1050 Version: 1051

Manufactured by: 1062 Novo Nordisk A/S 1063 DK-2880 Bagsvaerd, Denmark 1064 1065 For information about TRESIBA contact: 1066 Novo Nordisk Inc. 1067 800 Scudders Mill Road 1068 Plainsboro, NJ 08536 1069 1070 1-800-727-6500 1071 1072 www.novonordisk-us.com

CLINICAL PHARMACOLOGY

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.

2. Pharmacodynamics-                                                                                                  The glucose-lowering effect of TRESIBA after 8 days of once-daily dosing was measured in a 546 euglycemic glucose clamp study enrolling 21 patients with type 1 diabetes.

The glucose lowering effect 558 of TRESIBA lasted at least 42 hours after the last of 8 once-daily injections. 559 560 In patients with type 1 diabetes mellitus, the steady-state, within subjects, day-to-day variability 561 in total glucose lowering effect was 20% with

3 Pharmacokinetics 

Absorption- In patients with type 1 diabetes, after 8 days of once daily subcutaneous dosing with 0.4 U/kg of 575 TRESIBA, maximum degludec concentrations of 4472 pmol/L were attained at a median of 9 576 hours (tmax). After the first dose of TRESIBA, median onset of appearance was around one hour. 577 578

Distribution-                                                                                                                    The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of 588 >99% in human plasma. The results of the in vitro protein binding studies demonstrate that there 589 is no clinically relevant interaction between insulin degludec and other protein bound drugs. 590 59

Elimination-                                                                                                                    The half-life after subcutaneous administration is determined primarily by the rate of absorption 593 from the subcutaneous tissue. On average, the half-life at steady state is approximately 25 hours 594 independent of dose.

Degradation of TRESIBA is similar to that of insulin human; all 595 metabolites formed are inactive. The mean apparent clearance of insulin degludec is 0.03 L/kg 596 (2.1 L/h in 70 kg individual) after single subcutaneous dose of 0.4 U/kg. 597 598

Specific Populations 599 600 As with other insulin preparations, TRESIBA should always be titrated according to individual 601 requirements. 602 603

Geriatrics604 Pharmacokinetic and pharmacodynamic response of TRESIBA in 13 younger adult (18-35 605 years) and 14 geriatric (=65 years) subjects with type 1 diabetes following two 6 day periods of 606 once-daily subcutaneous dosing with 0.4 U/kg dose of TRESIBA or insulin glargine.

On 607 average, the pharmacokinetic and pharmacodynamic properties of TRESIBA at steady state were 608 similar in younger adult and geriatric subjects, albeit with greater between subject variability 609 among the geriatric subjects. 610 611

Gender6- The effect of gender on the pharmacokinetics of TRESIBA was examined in an across-trial 613 analysis of the pharmacokinetic and pharmacodynamic studies.

Overall, there were no clinically 614 relevant differences in the pharmacokinetic properties of insulin degludec between female and 615 male subjects. 616 617 Obesity618

Race and Ethnicit-                                                                                                       TRESIBA has been studied in a pharmacokinetic and pharmacodynamic study in Black or 628 African American subjects not of Hispanic or Latino origin (n=18), White subjects of Hispanic 629 or Latino origin (n=22) and White subjects not of Hispanic or Latino origin (n=23) with type 2 630 diabetes mellitus. There were no statistically significant differences between the racial and 631 ethnic groups investigated. 632 633

Pregnancy-                                                                                                                       The effect of pregnancy on the pharmacokinetics and pharmacodynamics of TRESIBA has not 635 been studied [

Renal Impairment6-                                                                                                       TRESIBA pharmacokinetics was studied in 32 subjects (n=4-8/group) with normal or impaired 639 renal function/end-stage renal disease following administration of a single subcutaneous dose 640 (0.4U/kg) of TRESIBA.

Renal function was defined using creatinine clearance (Clcr) as follows: 641 =90 mL/min (normal), 60-89 mL/min (mild), 30-59 mL/min (moderate) and <30 mL/min 642 (severe).

Hemodialysis did not affect clearance of TRESIBA (CL/FIDeg,SD) in subjects with 648 ESRD 

Hepatic Impairment-                                                                                                     TRESIBA has been studied in a pharmacokinetic study in 24 subjects (n=6/group) with normal 652 or impaired hepatic function (mild, moderate, and severe hepatic impairment) following 653 administration of a single subcutaneous dose (0.4U/kg) 

No differences in the pharmacokinetics of TRESIBA were identified between 656 healthy subjects and subjects with hepatic impairment 

USE IN SPECIFIC POPULATIONS

1 Pregnancy 427 Pregnancy Category C 428 429 There are no well-controlled clinical studies of the use of insulin degludec in pregnant women. 430 Patients should be advised to discuss with their health care provider if they intend to or if they 431 become pregnant.

Because animal reproduction studies are not always predictive of human 432 response, insulin degludec should be used during pregnancy only if the potential benefit justifies 433 the potential risk to the fetus. It is essential for patients with diabetes or a history of gestational 434 diabetes to maintain good metabolic control before conception and throughout pregnancy. 435 Insulin requirements may decrease during the first trimester, generally increase during the 436 second and third trimesters, and rapidly decline after delivery.

Careful monitoring of glucose 437 control is essential in these patients. 438 439 Subcutaneous reproduction and teratology studies have been performed with insulin degludec 440 and human insulin (NPH) as a comparator in rats and rabbits. In these studies, insulin was given 441 to female rats before mating throughout pregnancy until weaning, and to rabbits during 442 organogenesis.

The effect of insulin degludec was consistent with those observed with human 443 insulin as both caused pre- and post-implantation losses and visceral/skeletal abnormalities in 444 rats at an insulin degludec dose of 21 U/kg/day (approximately 5 times the human exposure 445 (AUC) at a human subcutaneous dose of 0.75 U/kg/day) and in rabbits at a dose of 3.3 U/kg/day 446 (approximately 10 times the human exposure (AUC) at a human subcutaneous dose of 0.75 447 U/kg/day). The effects are probably secondary to maternal hypoglycemia. 448 449

8.3 Nursing Mothers 450 It is unknown whether insulin degludec is excreted in human milk. Because many drugs, 451 including human insulin, are excreted in human milk, caution should be exercised when insulin 452 degludec is administered to a nursing mother.

Women with diabetes who are lactating may 453 require adjustments in insulin dose, meal plan, or both. 454 455 In rats, insulin degludec was secreted in milk and the concentration in milk was lower than in 456 plasma. 457 458 459

8.4 Pediatric Use 460 The safety and efficacy of TRESIBA in children and adolescents under the age of 18 have not 461 been established. 462 463

8.5 Geriatric Use Reference ID: 3825141 12 464 In controlled clinical studies [see Clinical Studies (14)] a total of 77 (7%) of the 1102 TRESIBA 465 -treated patients with type 1 diabetes were 65 years or older and 9 (1%) were 75 years or older. 466 A total of 670 (25%) of the 2713 TRESIBA-treated patients with type 2 diabetes were 65 years 467 or older and 80 (3%) were 75 years or older.

Differences in safety or effectiveness were not 468 suggested in subgroup analyses comparing subjects older than 65 years to younger subjects. 469 470 Nevertheless, greater caution should be exercised when TRESIBA is administered to geriatric 471 patients since greater sensitivity of some older individuals to the effects of TRESIBA cannot be 472 ruled out.

The initial dosing, dose increments, and maintenance dosage should be conservative to 473 avoid hypoglycemia. Hypoglycemia may be more difficult to recognize in the elderly. 474 475 8.6 Renal Impairment 476 In clinical studies [see Clinical Studies (14)] a total of 75 (7%) of the 1102 TRESIBA-treated 477 patients with type 1 diabetes had an eGFR less than 60 mL/min/1.73 m2 and 1(0.1%) had an 478 eGFR less than 30 mL/min/1.73 m2 . A total of 250 (9%) of the 2713 TRESIBA-treated patients 479 with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m2 and no subjects had an eGFR 480 less than 30 mL/min/1.73 m2 . 481 482

No clinically relevant difference in the pharmacokinetics of TRESIBA was identified in a study 483 comparing healthy subjects and subjects with renal impairment including subjects with end stage 484 renal disease [see Clinical Pharmacology (12.3)]. However, as with all insulin products, glucose 485 monitoring should be intensified and the

TRESIBA dosage adjusted on an individual basis in 486 patients with renal impairment. 487 488

8.7 Hepatic Impairment 489 No difference in the pharmacokinetics of TRESIBA was identified in a study comparing healthy 490 subjects and subjects with hepatic impairment (mild, moderate, and severe hepatic impairment) 491 [see Clinical Pharmacology (12.3)].

However, as with all insulin products, glucose monitoring 492 should be intensified and the TRESIBA dosage adjusted on an individual basis in patients with 493 hepatic impairment. 494 495

 OVERDOSAGE-

496 An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and 497 sometimes prolonged and life-threatening hypoglycemia and hypokalemia [see Warnings and 498 Precautions (5.3,5.6)].

Mild episodes of hypoglycemia usually can be treated with oral glucose. 499 Adjustments in drug dosage, meal patterns, or exercise may be needed.

More severe episodes of 500 hypoglycemia with coma, seizure, or neurologic impairment may be treated with 501 intramuscular/subcutaneous glucagon or concentrated intravenous glucose.

After apparent 502 clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake 503 may be necessary to avoid reoccurrence of hypoglycemia. Hypokalemia must be corrected 504 appropriately. 505 506