Insulin - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including liraglutide.

Discontinue if pancreatitis is suspected. • Never share a XULTOPHY 100/3.6 pen between patients, even if the needle is changed. • Hyperglycemia or hypoglycemia with changes in insulin regimen : Make changes to a patient’s insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. • Overdose due to medication errors : XULTOPHY 100/3.6 contains two drugs.

Instruct patients to check label before injection since accidental mix-ups with insulin containing products can occur.

Do not exceed the maximum dose or administer with other GLP-1 receptor agonists. • Hypoglycemia: May be life-threatening.

Increase monitoring with changes to : dosage, concomitant drugs, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness. • Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. • Severe Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe.

XULTOPHY 100/3.6 is not recommended in patients with severe gastroparesis. • Hypersensitivity Reactions : Severe, life-threatening, generalized allergy, including anaphylaxis, angioedema, bronchospasm, hypotension, and shock can occur.

If a hypersensitivity reaction occurs, discontinue and treat per standard of care. • Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. • Hypokalemia : May be life-threatening.

Monitor potassium levels in patients at risk for hypokalemia and treat if indicated. • Fluid retention and congestive heart failure with use of thiazolidinediones (TZDs) : Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. • Pulmonary Aspiration During General Anesthesia or Deep Sedation : Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures.

Instruct patients to inform healthcare providers of any planned surgeries or procedures.

5.1 Risk of Thyroid C-cell Tumors Liraglutide, one of the components of XULTOPHY 100/3.6, causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology ] .

Malignant thyroid C-cell carcinomas were detected in rats and mice.

It is unknown whether XULTOPHY 100/3.6 will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined.

Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans.

XULTOPHY 100/3.6 is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2.

Counsel patients regarding the potential risk for MTC with the use of XULTOPHY 100/3.6 and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).

Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with XULTOPHY 100/3.6.

Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease.

Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L.

If serum calcitonin is measured and found to be elevated, the patient should be further evaluated.

Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.

5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including liraglutide, one of the components of XULTOPHY 100/3.6 [see Adverse Reactions ].

After initiation of XULTOPHY 100/3.6, observe patients carefully for signs and symptoms of acute pancreatitis, which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting.

If pancreatitis is suspected, discontinue XULTOPHY 100/3.6 and initiate appropriate management.

5.3 Never Share a XULTOPHY 100/3.6 Pen Between Patients XULTOPHY 100/3.6 pen must never be shared between patients, even if the needle is changed.

Sharing of the pen poses a risk for transmission of blood-borne pathogens.