Xultophy 100 / 3.6

Xultophy 100/3.6 is contraindicated:

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 (13.1)]. 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.

Pancreatitis

Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide, one of the components of Xultophy 100/3.6. In clinical trials of liraglutide, there have been 13 cases of pancreatitis among liraglutide-treated patients and 1 case in a comparator (glimepiride) treated patient (2.7 vs. 0.5 cases per 1000 patient-years). Nine of the 13 cases with liraglutide were reported as acute pancreatitis and four were reported as chronic pancreatitis. In one case in a liraglutide-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse.

After initiation of Xultophy 100/3.6, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Xultophy 100/3.6 should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, restarting Xultophy 100/3.6 is not recommended. Consider antidiabetic therapies other than Xultophy 100/3.6 in patients with a history of pancreatitis.

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.

Hyperglycemia or Hypoglycemia with Changes in Xultophy 100/3.6 Regimen

Changes in Xultophy 100/3.6 regimen may affect glycemic control and predispose to hypoglycemia or hyperglycemia [see Warnings and Precautions (5.5)]. These changes should be made cautiously and only under medical supervision and the frequency of blood glucose monitoring should be increased. Adjustments in concomitant oral anti-diabetic treatment may be needed. When converting from basal insulin therapies or liraglutide to Xultophy 100/3.6 follow dosing recommendations [see Dosage and Administration (2.1,2.2)].

Overdose due to Medication Errors

Xultophy 100/3.6 contains two drugs: insulin degludec and liraglutide. Administration of more than 50 units of Xultophy 100/3.6 daily can result in overdose of the liraglutide component. Do not exceed the 1.8 mg maximum recommended dose of liraglutide or use with other glucagon-like peptide-1 receptor agonists.

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.

Hypoglycemia

Hypoglycemia is the most common adverse reaction of insulin containing products, including Xultophy 100/3.6 [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). Xultophy 100/3.6 (an insulin-containing product) or any insulin, should not be used during episodes of hypoglycemia [seeContraindications (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) [seeDrug Interactions (7.1)], 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 [seeClinical Pharmacology (12.2)] and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin containing products, the glucose lowering effect time course of Xultophy 100/3.6 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 (7.1)]. 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.

Acute Kidney Injury

There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis in patients treated with liraglutide, one of the components of Xultophy 100/3.6 [see Adverse Reactions (6.3)]. Some of these events were reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Some of the reported events occurred in patients receiving one or more medications known to affect renal function or hydration status. Altered renal function has been reversed in many of the reported cases with supportive treatment and discontinuation of potentially causative agents, including liraglutide. Advise patients of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion.

Hypersensitivity and Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, angioedema, bronchospasm, hypotension, and shock can occur with Xultophy 100/3.6.Allergic reactions (manifested with signs and symptoms such as urticaria, rash, pruritus) have been reported with Xultophy 100/3.6. There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with liraglutide, one of the components of Xultophy 100/3.6 [see Adverse Reactions (6.3)]. If a hypersensitivity reaction occurs, discontinue Xultophy 100/3.6; treat per standard of care and monitor until symptoms and signs resolve.

Angioedema has also been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to angioedema with Xultophy 100/3.6. Xultophy 100/3.6 is contraindicated in patients who have had hypersensitivity reactions to insulin degludec, liraglutide or one of the excipients of these products [see Contraindications (4)].

Hypokalemia

All insulin-containing products, including Xultophy 100/3.6, 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).

Fluid Retention and Congestive Heart Failure with Concomitant Use of a PPAR Gamma Agonist

Peroxisome proliferator-activated receptor (PPAR)-gamma agonists can cause dose related fluid retention, particularly when used in combination with insulin containing products, including Xultophy 100/3.6. Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with insulin containing products, including Xultophy 100/3.6 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.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Xultophy 100/3.6 or any other antidiabetic drug.

Mechanism of Action

Xultophy 100/3.6

Xultophy 100/3.6 is a combination product consisting of insulin degludec and liraglutide.

Insulin degludec

The primary activity of insulin degludec is the 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.

Liraglutide

Liraglutide is a Glucagon-Like Peptide-1 (GLP-1) receptor agonist that increases glucose-dependent insulin release, decreases glucagon secretion, and slows gastric emptying.

Pharmacodynamics

Following a single dose administration, Xultophy 100/3.6 has a duration of action reflecting the combination of the individual glucodynamic action profiles of insulin degludec and liraglutide.

Following once daily administration, Xultophy 100/3.6 lowers fasting plasma glucose levels and postprandial glucose levels.

Cardiac Electrophysiology (QTc):

Xultophy 100/3.6

The effect of Xultophy 100/3.6 on QTc has not been studied.

Liraglutide

The effect of liraglutide, one of the components of Xultophy 100/3.6, on cardiac repolarization was tested in a QTc study. Liraglutide, at steady state concentrations with daily doses up to 1.8 mg, did not produce QTc prolongation.

Pharmacokinetics

Overall, the pharmacokinetics of insulin degludec and liraglutide were not affected in a clinically relevant manner when administered as Xultophy 100/3.6.

Absorption

In patients with type 2 diabetes (mean body weight 87.5 kg) reaching the maximum daily dose (50 units/1.8 mg) of Xultophy 100/3.6, the estimated mean steady-state exposure (AUC 0-24 h) of insulin degludec was 113 h*nmol/L and of liraglutide 1227 h*ng/mL based on population pharmacokinetic analysis. The corresponding maximum concentrations were 5196 pmol/L for insulin degludec and 55 ng/mL for liraglutide. Steady state concentrations of insulin degludec and liraglutide are reached after 2-3 days of daily administration.

Distribution

Insulin degludec and liraglutide are extensively bound to plasma proteins >99% and >98%, respectively.

Metabolism

Insulin degludec

Degradation of insulin degludec is similar to that of human insulin; all metabolites formed are inactive.

Liraglutide

During the initial 24 hours following administration of a single [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination.

Elimination

The half-life of insulin degludec is approximately 25 hours and the half-life of liraglutide is approximately 13 hours.

Specific Populations

Geriatrics

Age had no clinically relevant effect on the pharmacokinetics of Xultophy 100/3.6 based on results from a population pharmacokinetic analysis including adult patients up to 83 years treated with Xultophy 100/3.6 [see Use in Specific Populations (8.5)].

Gender, race and ethnicity

Gender, race or ethnic origin had no clinically relevant effect on the pharmacokinetics of Xultophy 100/3.6 based on results from a population pharmacokinetic analysis.

Body weight

The effect of body weight on the exposure level of the components of Xultophy 100/3.6 was investigated in the population pharmacokinetic analysis. Exposure levels decreased with increase in baseline body weight for both insulin degludec and liraglutide.

Renal Impairment

Xultophy 100/3.6

There is limited experience with Xultophy 100/3.6 in patients with mild and moderate renal impairment. Xultophy 100/3.6 has not been studied in patients with severe renal impairment [see Warnings and Precautions (5.7)].

Insulin degludec

Insulin degludec has been studied in a pharmacokinetic study in 32 subjects (n=6/group) with normal or impaired renal function/end-stage renal disease following administration of a single dose (0.4U/kg) of insulin degludec. Renal function was defined using creatinine clearance (Clcr) as follows: >80 mL/min (normal), 50-80 mL/min (mild), 30-50 mL/min (moderate) and <30 mL/min (severe). Subjects requiring dialysis were classified as having end-stage renal disease (ESRD). Total exposure (AUCIDeg,0-120h,SD) of insulin degludec was similar in subjects with normal and impaired renal function. No clinically relevant difference in the pharmacokinetics of insulin degludec was identified between healthy subjects and subjects with renal impairment. Hemodialysis did not affect clearance of insulin degludec (CL/FIDeg,SD) in subjects with ESRD [see Warnings and Precautions (5.7)].

Liraglutide

The single-dose pharmacokinetics of liraglutide were evaluated in subjects with varying degrees of renal impairment. Subjects with mild (estimated creatinine clearance 50-80 mL/min) to severe (estimated creatinine clearance <30 mL/min) renal impairment and subjects with end-stage renal disease requiring dialysis were included in the trial. Compared to healthy subjects, liraglutide AUC in mild, moderate, and severe renal impairment and in end-stage renal disease was on average 35%, 19%, 29% and 30% lower, respectively [see Warnings and Precautions (5.7)].

Hepatic impairment

Xultophy 100/3.6

Xultophy 100/3.6 has not been studied in patients with hepatic impairment.

Insulin degludec

Insulin degludec 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 dose (0.4U/kg) of insulin degludec. Hepatic function was defined using Child-Pugh Scores ranging from 5 (mild hepatic impairment) to 15 (severe hepatic impairment). No clinically relevant differences in the pharmacokinetics of insulin degludec were identified between healthy subjects and subjects with hepatic impairment [see Hepatic Impairment (8.7)].

Liraglutide

The single-dose pharmacokinetics of liraglutide were evaluated in subjects with varying degrees of hepatic impairment. Subjects with mild (Child Pugh score 5-6) to severe (Child Pugh score > 9) hepatic impairment were included in the trial. Compared to healthy subjects, liraglutide AUC in subjects with mild, moderate and severe hepatic impairment was on average 11%, 14% and 42% lower, respectively.

Drug interactions

In vitro assessment of drug-drug interactions

In vitro data suggest that the potential for pharmacokinetic drug interactions related to CYP interaction and protein binding is low for both the liraglutide and insulin degludec components of Xultophy 100/3.6.

The delay of gastric emptying with liraglutide one of the components of Xultophy 100/3.6 may influence absorption of concomitantly administered oral medicinal products. Interaction studies did not show any clinically relevant delay of absorption.

In vivo assessment of drug-drug interactions

Liraglutide

The drug-drug interaction studies were performed at steady state with liraglutide 1.8 mg/day. Before administration of concomitant treatment, subjects underwent a 0.6 mg weekly dose increase to reach the maximum dose of 1.8 mg/day. Administration of the interacting drugs was timed so that Cmax of liraglutide (8-12 h) would coincide with the absorption peak of the co-administered drugs.

Digoxin

A single dose of digoxin 1 mg was administered 7 hours after the dose of liraglutide at steady state. The concomitant administration with liraglutide resulted in a reduction of digoxin AUC by 16%; Cmax decreased by 31%. Digoxin median time to maximal concentration (Tmax) was delayed from 1 h to 1.5 h.

Lisinopril

A single dose of lisinopril 20 mg was administered 5 minutes after the dose of liraglutide at steady state. The co-administration with liraglutide resulted in a reduction of lisinopril AUC by 15%; Cmax decreased by 27%. Lisinopril median Tmax was delayed from 6 h to 8 h with liraglutide.

Atorvastatin

Liraglutide did not change the overall exposure (AUC) of atorvastatin following a single dose of atorvastatin 40 mg, administered 5 hours after the dose of liraglutide at steady state. Atorvastatin Cmax was decreased by 38% and median Tmax was delayed from 1 to 3 hours with liraglutide.

Acetaminophen

Liraglutide did not change the overall exposure (AUC) of acetaminophen following a single dose of acetaminophen 1000 mg, administered 8 hours after the dose of liraglutide at steady state. Acetaminophen Cmax was decreased by 31% and median Tmax was delayed up to 15 minutes.

Griseofulvin

Liraglutide did not change the overall exposure (AUC) of griseofulvin following co-administration of a single dose of griseofulvin 500 mg with liraglutide at steady state. Griseofulvin Cmax increased by 37% while median Tmax did not change.

Oral Contraceptives

A single dose of an oral contraceptive combination product containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel was administered under fed conditions and 7 hours after the dose of liraglutide at steady state. Liraglutide lowered ethinylestradiol and levonorgestrel Cmax by 12% and 13%, respectively. There was no effect of liraglutide on the overall exposure (AUC) of ethinylestradiol. Liraglutide increased the levonorgestrel AUC0-∞ by 18%. Liraglutide delayed Tmax for both ethinylestradiol and levonorgestrel by 1.5 hours.

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.

Recommended Storage

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 8:

Table 8: Storage Conditions for Xultophy 100/3.6 Pen

Xultophy®100/3.6

NDC 0169-2911-15

List: 291115

(insulin degludec and liraglutide injection)

For Single Patient Use Only

100 units/mL and 3.6 mg/mL

With each unit of insulin degludec, the pen

also delivers 0.036 mg of liraglutide

5x3 mL Prefilled Pens

For subcutaneous use only

Rx Only

Recommended for use with NovoFine®,

Novofine® Plus or NovoTwist® disposable needles.

Must be refrigerated until first use.

Store at 36°F – 46°F (2°C – 8°C).

Do not freeze.

Protect from light.