FDA label 06fffc23-62e9-48d8-aab2-0fdf46cda4b7

5 WARNINGS AND PRECAUTIONS • Never share a RYZODEG 70/30 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 RYZODEG 70/30 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 RYZODEG 70/30, monitor and treat if indicated ( 5.5 ). • Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated ( 5.6 ). • Fluid retention and heart failure with concomitant use of Thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs ( 5.7 ). 5.1 Never Share a RYZODEG 70/30 FlexTouch Pen Between Patients RYZODEG 70/30 FlexTouch disposable prefilled pen 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 RYZODEG 70/30 follow dosing recommendations [see Dosage and Administration ( 2.4 , 2.5 )]. 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction of insulin, including RYZODEG 70/30 [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). RYZODEG 70/30, 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 RYZODEG 70/30 may vary in 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 insulin products have been reported. To avoid medication errors between RYZODEG 70/30 and other insulins, instruct patients to always check the insulin label before each injection. Do not transfer RYZODEG 70/30 from the RYZODEG 70/30 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 RYZODEG 70/30. If hypersensitivity reactions occur, discontinue RYZODEG 70/30; treat per standard of care and monitor until symptoms and signs resolve. RYZODEG 70/30 is contraindicated in patients who have had hypersensitivity reactions to insulin degludec, insulin aspart, or one of the excipients [see Contraindications ( 4 )]. 5.6 Hypokalemia All insulin products, including RYZODEG 70/30, 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 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 RYZODEG 70/30 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 )] Adverse reactions commonly associated with RYZODEG 70/30 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 . 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 RYZODEG 70/30 in subjects with type 1 diabetes or type 2 diabetes was evaluated in five trials of 6-12 month duration in adults and in one trial of 16 week duration in pediatric patients 1 year of age and older with type 1 diabetes [see Clinical Studies ( 14 )] . The data in Table 1 reflect the exposure of 362 adults with type 1 diabetes to RYZODEG 70/30, with a mean exposure duration to RYZODEG 70/30 of 43 weeks. The mean age was 41 years and 1% were older than 75 years. Fifty-two percent were male, 91% were White, 3% were Black or African American and 3% were Hispanic. The mean body mass index (BMI) was 26 kg/m 2 . The mean duration of diabetes was 17 years and the mean HbA 1c at baseline was 8.3%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported in 19%, 25%, 6% and 4% respectively. The mean eGFR at baseline was 88 mL/min/1.73 m 2 and 6% of patients had an eGFR less than 60 mL/min/1.73 m 2 . The data in Table 2 reflect the exposure of 998 adults with type 2 diabetes to RYZODEG 70/30 with a mean exposure duration to RYZODEG 70/30 of 24 weeks. The mean age was 58 years and 3% were older than 75 years. Fifty-four percent were male, 44% were White, 4% were Black or African American and 6% were Hispanic. The mean BMI was 29 kg/m 2 . The mean duration of diabetes was 12 years and the mean HbA 1c at baseline was 8.5%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported for 15%, 21%, 10% and 1% respectively. At baseline, the mean eGFR was 84 mL/min/1.73 m 2 and 11% of patients had an eGFR less than 60 mL/min/1.73 m 2 . Common adverse reactions (excluding hypoglycemia) occurring in RYZODEG 70/30-treated subjects during clinical trials in adult patients with type 1 diabetes mellitus and adults with type 2 diabetes mellitus are listed in Tables 1 and 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. 181 pediatric patients 1 year of age and older with type 1 diabetes were exposed to RYZODEG 70/30 with a mean exposure duration to RYZODEG 70/30 of 16 weeks. The mean age was 10.5 years: 22.5% were ages 1-5 years, 33.5% were ages 6-11 years, and 44% were ages 12-17 years. 48.9% were male, 92.9% were White, 4.4% were Black or African American and 8.2% were Hispanic. The mean body mass index (BMI) was 19.2 kg/m 2 . The mean duration of diabetes was 4.4 years and the mean HbA 1c at baseline was 8.1%. A history of neuropathy and nephropathy at baseline was reported in 2.2% and 0.5%, respectively. Common adverse reactions in RYZODEG 70/30 treated children with type 1 diabetes mellitus were similar to the adverse reactions listed in Table 1. Table 1: Adverse Reactions Occurring in ≥5% of RYZODEG 70/30-Treated Adult Patients with Type 1 Diabetes Mellitus Adverse Reaction RYZODEG 70/30 (N=362) Nasopharyngitis 24.6% Headache 9.7% Upper respiratory tract infection 9.1% Influenza 6.9% Table 2: Adverse Reactions Occurring in ≥5% of RYZODEG 70/30-Treated Adult Patients with Type 2 Diabetes Mellitus Adverse Reaction RYZODEG 70/30 (N=998) Nasopharyngitis 11.1% Upper respiratory tract infection 5.7% Headache 5.6% Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including RYZODEG 70/30 [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 RYZODEG 70/30 with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that occur in clinical practice. Rates of hypoglycemia by trial are shown in Table 3 for type 1 diabetes in adult and pediatric patients and Table 4 for type 2 diabetes in adults treated with RYZODEG 70/30 [see Clinical Studies ( 14 )]. Severe hypoglycemia in 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 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 Patients with Type 1 Diabetes Experiencing at Least One Episode of Severe Hypoglycemia or Novo Nordisk Hypoglycemia § on RYZODEG 70/30 in Adult and Pediatric Clinical Trials *OD: once daily **BID: twice daily Study A RYZODEG 70/30 OD* + Insulin Aspart BID**, Adults 52 weeks (N=362) Study F RYZODEG 70/30 OD* + Insulin Aspart TID***, Pediatrics 16 weeks (N=181) Severe hypoglycemia ± Percent of patients 13.3% 6.1% Novo Nordisk hypoglycemia § Percent of patients 95.0% 92.8% ***TID: three times daily ± 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). § 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 RYZODEG 70/30 in Adult Clinical Trials *OD: once daily **BID: twice daily ***OAD: oral anti-diabetic 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). Study B RYZODEG 70/30 OD* insulin naïve, previously on 2 or more OADs*** Study C RYZODEG 70/30 OD* previously on basal insulin OD and 1 or more OADs*** Study D RYZODEG 70/30 BID** previously on OD*/BID premix/self-mix, ±OADs*** Study E RYZODEG 70/30 BID** previously on OD*/BID basal/premix/self-mix, ±OADs*** (N=265) (N=230) (N=224) (N=279) Severe hypoglycemia Percent of patients 0.4% 0% 3.1% 1.4% Novo Nordisk hypoglycemia Percent of patients 49.8% 52.6% 66.1% 73.5% Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including RYZODEG 70/30 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 0.5% of patients treated with RYZODEG 70/30. Lipodystrophy Long-term use of insulin, including RYZODEG 70/30, 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 was reported in 0.1% of patients treated with RYZODEG 70/30. Injection Site Reactions Patients taking RYZODEG 70/30 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 2.0% of patients treated with RYZODEG 70/30. Weight Gain Weight gain can occur with insulin therapy, including RYZODEG 70/30, and has been attributed to the anabolic effects of insulin. In the clinical program, patients with type 1 diabetes treated with RYZODEG 70/30 gained an average of 2.8 kg and patients with type 2 diabetes treated with RYZODEG 70/30 gained an average of 1.6 kg. Peripheral Edema Insulin, including RYZODEG 70/30, may cause sodium retention and edema. In the clinical program, peripheral edema occurred in 2.2% of patients with type 1 diabetes mellitus and 1.8% of patients with type 2 diabetes mellitus treated with RYZODEG 70/30. 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 RYZODEG 70/30 with the incidence of antibodies in other studies or to other products, may be misleading. In studies of adult type 1 diabetes patients, 95.9% of patients who received RYZODEG 70/30 once daily were positive for anti-insulin antibodies (AIA) at least once during the studies, including 89% that were positive at baseline, while 13% of these patients were positive for anti-IAsp antibodies at least once during the studies, including 6.4% who were positive at baseline. In studies of type 2 diabetes patients, 67.5% of patients who received RYZODEG 70/30 once daily were positive for AIA at least once during the studies, including 45.4% that were positive at baseline, while 17.1% of these patients were positive for anti-IAsp antibodies at least once during the studies, including 12.3% who 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.

<table width="100%"> <col width="50%"/> <col width="50%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Reaction</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">RYZODEG 70/30 (N=362)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nasopharyngitis</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>24.6%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>9.7%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Upper respiratory tract infection</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>9.1%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Influenza</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>6.9%</paragraph> </td> </tr> </tbody> </table>

<table width="100%"> <col width="50%"/> <col width="50%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Reaction</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">RYZODEG 70/30 (N=998)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nasopharyngitis</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>11.1%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Upper respiratory tract infection</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5.7%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>5.6%</paragraph> </td> </tr> </tbody> </table>

<table width="100%"> <col width="21%"/> <col width="39%"/> <col width="39%"/> <tfoot> <tr> <td align="left" colspan="7" styleCode="Botrule" valign="top">*OD: once daily</td> </tr> <tr> <td align="left" colspan="7" styleCode="Botrule" valign="top">**BID: twice daily</td> </tr> </tfoot> <tbody> <tr> <td styleCode="Rrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Study A</content> </paragraph> <paragraph> <content styleCode="bold">RYZODEG 70/30 OD* + Insulin Aspart BID**,</content> </paragraph> <paragraph> <content styleCode="bold">Adults </content> </paragraph> <paragraph> <content styleCode="bold">52 weeks</content> </paragraph> <paragraph> <content styleCode="bold">(N=362)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Study F </content> </paragraph> <paragraph> <content styleCode="bold">RYZODEG 70/30 OD* + Insulin Aspart TID***, </content> </paragraph> <paragraph> <content styleCode="bold">Pediatrics</content> </paragraph> <paragraph> <content styleCode="bold">16 weeks</content> </paragraph> <paragraph> <content styleCode="bold">(N=181)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"/> <td valign="middle"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Severe hypoglycemia</content> ^&#xB1; </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Percent of patients</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>13.3%</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>6.1%</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Novo Nordisk hypoglycemia^&#xA7; </content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>Percent of patients</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>95.0%</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>92.8%</paragraph> </td> </tr> </tbody> </table>