Xultophy 100/3.6 (Page 10 of 12)

14.4 Cardiovascular Outcomes Trials in Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Conducted with Liraglutide 1.8 mg and Insulin Degludec

The effect of XULTOPHY 100/3.6 on the risk of cardiovascular outcomes in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease has not been established. The studies below were conducted with liraglutide 1.8 mg and insulin degludec, individually.

VICTOZA (liraglutide 1.8 mg)

The LEADER trial (NCT01179048) randomized 9340 patients with inadequately controlled type 2 diabetes and cardiovascular disease to liraglutide 1.8 mg or placebo in addition to standard of care treatments for type 2 diabetes for a median follow up of 3.5 years.

Patients either were 50 years of age or older with established, stable cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or chronic heart failure (80% of patients) or were 60 years of age or older and had other specified risk factors for cardiovascular disease (20% of patients). The population was 64% male, 78% Caucasian, 10% Asian, and 8% Black; 12% of the population was Hispanic or Latino. The mean duration of type 2 diabetes was 13 years, the mean HbA1c was 8.7% and the mean BMI was 33 kg/m2 ; the mean eGFR at baseline was 79 mL/min/1.73 m2.

In total, 96.8% of the patients completed the trial; vital status was available for 99.7%. The primary endpoint was the time from randomization to first occurrence of a major adverse cardiovascular event (MACE) defined as: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. No increased risk for MACE was observed with liraglutide 1.8 mg. The total number of primary component MACE endpoints was 1302 (608[13.0%] with liraglutide 1.8 mg and 694 [14.9%] with placebo).

TRESIBA (insulin degludec)

The DEVOTE trial (NCT01959529) randomized 7,637 patients with inadequately controlled type 2 diabetes and cardiovascular disease to either insulin degludec or insulin glargine U-100. Each was administered once-daily in addition to standard of care treatments for diabetes for a median duration of follow up of 2 years.

Patients either were 50 years of age or older and had established, stable cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or chronic heart failure (85% of patients) or were 60 years of age or older and had other specified risk factors for cardiovascular disease (15% of patients). The population was 63% male, 76% White 11% Black or African American, and 10% Asian; 15% of the population was Hispanic or Latino. The mean HbA1c was 8.4% and the mean BMI was 33.6 kg/m2. The baseline mean eGFR was 68 mL/min/1.73m2.

In total, 98% of the patients completed the trial; vital status was known at the end of the trial for 99%. The primary endpoint was the time from randomization to the first occurrence of a major adverse cardiovascular event (MACE), defined as: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. No increased risk for MACE was observed with insulin degludec when compared to insulin glargine U-100. The total number of primary MACE endpoints was 681 (325 [8.5%] with insulin degludec and 356 [9.3%] with insulin glargine).

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

XULTOPHY 100/3.6 is an injection supplied as a sterile, clear, colorless solution in a 3 mL pre-filled, disposable, single-patient use pen injector. The XULTOPHY 100/3.6 pen dials in one unit increments.

Dosage Unit/Strength

Package size

NDC #

3 mL single-patient-use XULTOPHY 100/3.6 pen

(100 units/mL insulin degludec and 3.6 mg/mL liraglutide)

Package of 5

0169-2911-15

16.2 Recommended Storage

Dispense in the original sealed carton with the enclosed Instructions for Use.

Prior to first use, XULTOPHY 100/3.6 should be stored between 2°C and 8°C (36°F to 46°F) until the expiration date printed on the label. Store prefilled pens in the carton so they will stay clean and protected from light. Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze. Do not use XULTOPHY 100/3.6 if it has been frozen.

After first use, the XULTOPHY 100/3.6 pen can be stored for 21 days at controlled room temperature (59°F to 86°F; 15°C to 30°C) or in a refrigerator (36°F to 46°F; 2°C to 8°C). Keep all XULTOPHY 100/3.6 pens away from direct heat and light.

Always remove the needle after each injection and store the XULTOPHY 100/3.6 pen without a needle attached. This prevents contamination and/or infection, or leakage of the XULTOPHY 100/3.6 pen, and will ensure accurate dosing. Always use a new needle for each injection to prevent contamination.

The storage conditions are summarized in Table 11:

Table 11: Storage Conditions for XULTOPHY 100/3.6 Pen

Prior to first use

After first use

Refrigerated
36°F to 46°F
(2°C to 8°C)

Room Temperature
59°F to 86°F
(15°C to 30°C)

Refrigerated
36°F to 46°F
(2°C to 8°C)

Until expiration date

21 Days

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)

Risk of Thyroid C-cell Tumors

Inform patients that liraglutide, one of the components of XULTOPHY 100/3.6, causes benign and malignant thyroid C-cell tumors in mice and rats and that the human relevance of this finding is unknown. Patients should be counseled to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia or dyspnea) to their physician [ see Boxed Warning and Warnings and Precautions (5.1)].

Dehydration and Renal Failure

Advise patients of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Patients should be informed of the potential risk for worsening renal function, which in some cases may require dialysis [see Warnings and Precautions (5.7)].

Pancreatitis

Inform patients of the potential risk for pancreatitis. Explain that persistent severe abdominal pain that may radiate to the back and which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue XULTOPHY 100/3.6 promptly and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.2)].

Acute Gallbladder Disease

Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up.

Overdose due to Medication Errors

Inform patients that XULTOPHY 100/3.6 contains two drugs: insulin degludec and liraglutide. Accidental mix-ups between insulin products have been reported. To avoid medication errors between XULTOPHY 100/3.6 (an insulin containing product) and other insulin products, instruct patients to always check the label before each injection.

Advise patients that the administration of more than 50 units of XULTOPHY 100/3.6 daily can result in overdose of the liraglutide component. Instruct patients not to administer concurrently with other glucagon-like peptide-1 receptor agonists.

Hyperglycemia or Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin products. Inform patients of the symptoms of hypoglycemia. Inform patients that the ability to concentrate and react may be impaired as a result of hypoglycemia [see Warnings and Precautions (5.6)]. 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 hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions (5.4)].

Never Share a XULTOPHY 100/3.6 Pen Between Patients

Advise patients that they must never share a XULTOPHY 100/3.6 pen with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens.

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of liraglutide, one of the components of XULTOPHY 100/3.6.

If symptoms of hypersensitivity reactions occur, patients must stop taking XULTOPHY 100/3.6 and seek medical advice promptly [see Warnings and Precautions (5.8)].

Hepatobiliary Disorders

Inform patients that hepatobiliary disorders including elevations of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis have been reported during postmarketing use of liraglutide. Instruct patients to contact their physician if they develop jaundice.

Pregnancy

Instruct female patients of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Date of Issue: 11/2019

Version: 5

© 2016 – 2019 Novo Nordisk

Novo Nordisk® , VICTOZA® , TRESIBA® and XULTOPHY® 100/3.6 are registered trademarks of Novo Nordisk A/S.

PATENT Information: http://novonordisk-us.com/patients/products/product-patents.html

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

For information about XULTOPHY 100/3.6 contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536

1-800-727-6500

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