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Insulin Degludec and Liraglutide

Pronunciation

(IN su lin de GLOO dek & lir a GLOO tide)

Index Terms

  • Degludec Insulin and Liraglutide
  • Liraglutide and Insulin Degludec

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Pen-injector, Subcutaneous:

Xultophy: 100/3.6: Insulin degludec 100 units and liraglutide 3.6 mg per mL (3 mL) [contains phenol]

Brand Names: U.S.

  • Xultophy

Pharmacologic Category

  • Antidiabetic Agent, Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist
  • Insulin, Long-Acting

Pharmacology

Refer to individual agents.

Use: Labeled Indications

Diabetes mellitus, type 2: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus inadequately controlled on basal insulin (<50 units daily) or liraglutide (≤1.8 mg daily).

Contraindications

Hypersensitivity to insulin degludec, liraglutide, or any component of the formulation; history of or family history of medullary thyroid carcinoma (MTC); patients with multiple endocrine neoplasia syndrome type 2 (MEN2); during episodes of hypoglycemia

Dosing: Adult

Diabetes mellitus, type 2: SubQ: Note: Alternative antidiabetic agents should be used if patient persistently requires dosages <16 units or requires dosages >50 units.

Initial: 16 units (insulin degludec 16 units/liraglutide 0.58 mg) once daily; titrate dose upward or downward every 3 to 4 days in increments of 2 units (insulin degludec 2 units/liraglutide 0.072 mg) per glycemic response. Usual range: 16 units (insulin degludec 16 units/liraglutide 0.58 mg) to 50 units (insulin degludec 50 units/liraglutide 1.8 mg) once daily; if necessary, dose may be temporarily titrated down to 10 to 15 units (insulin degludec 10 to 15 units/liraglutide 0.36 to 0.54 mg) once daily. Maximum dose: 50 units (insulin degludec 50 units/liraglutide 1.8 mg)/day

Missed dose: Resume with next regularly scheduled dose; do not administer an extra dose or increase dose to account for missed dose. If more than 3 days have elapsed since last dose, reinitiate at the initial dosage (insulin degludec 16 units/liraglutide 0.58 mg) once daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild or moderate impairment: There are no specific dosage adjustments provided in the manufacturer's labeling (limited experience); however, dosage adjustments may be necessary as insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.

Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied)

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (combination product has not been studied). Insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.

Administration

For SubQ use only. Do not administer IM, IV, or via an insulin pump. Cold injections should be avoided. Inject into the abdomen, thigh, or upper arm. Rotate injection sites for each dose; do not use the same site for each injection to avoid lipodystrophy. Administer once daily at the same time each day with or without food. Do not split the dose. Solution should appear clear and colorless; do not use if particulate matter or coloration is seen. Do not mix or dilute with any other insulin or solution.

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy

Storage

Prior to initial use, store pens at 2°C to 8°C (36°F to 46°F). Do not freeze (discard if frozen). Protect from light. After initial use, may store for up to 21 days at room temperature (15ºC to 30°C [59ºF to 86°F]) or under refrigeration (2ºC to 8ºC [36ºF to 46ºF]). Replace the pen cap after each use, do not store with needle attached.

Drug Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Beta-Blockers: May enhance the hypoglycemic effect of Insulin. Exceptions: Levobunolol; Metipranolol. Monitor therapy

DPP-IV Inhibitors: May enhance the hypoglycemic effect of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulin. Monitor therapy

Edetate Disodium: May enhance the hypoglycemic effect of Insulin. Monitor therapy

GLP-1 Agonists: May enhance the hypoglycemic effect of Insulin. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Exceptions: Liraglutide. Consider therapy modification

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulin: Liraglutide may enhance the hypoglycemic effect of Insulin. Management: If liraglutide is used for the treatment of diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided if liraglutide is used exclusively for weight loss (Saxenda). Consider therapy modification

Liraglutide: May enhance the hypoglycemic effect of Insulin. Management: If liraglutide is used for the treatment of diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided if liraglutide is used exclusively for weight loss (Saxenda). Consider therapy modification

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Metreleptin: May enhance the hypoglycemic effect of Insulin. Management: Insulin dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely. Consider therapy modification

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pioglitazone: May enhance the adverse/toxic effect of Insulin. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure. Consider therapy modification

Pramlintide: May enhance the hypoglycemic effect of Insulin. Management: Upon initiation of pramlintide, decrease mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and individualize further insulin dose adjustments based on glycemic control. Consider therapy modification

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Rosiglitazone: Insulin may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Avoid combination

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

SGLT2 Inhibitors: May enhance the hypoglycemic effect of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Sulfonylureas: GLP-1 Agonists may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Adverse Reactions

See individual agents.

>10%: Immunologic: Antibody development (2% to 11%; antibody formation has not been associated with reduced efficacy)

1% to 10%:

Central nervous system: Headache (9%)

Gastrointestinal: Diarrhea (8%), nausea (8%), increased serum lipase (7%)

Local: Injection site reaction (3%; mild and transitory)

Respiratory: Nasopharyngitis (10%), upper respiratory tract infection (6%)

Frequency not defined:

Cardiovascular: Increased heart rate

Endocrine & metabolic: Hypoglycemia

Local: Hypertrophy at injection site, lipoatrophy at injection site

>1% (Limited to important or life-threatening): Abdominal distension, abdominal pain, allergic skin reaction, anaphylaxis, constipation, decreased appetite, dyspepsia, eructation, flatulence, gastritis, gastroesophageal reflux disease, hypersensitivity reaction, severe hypoglycemia, urticaria, vomiting

ALERT: U.S. Boxed Warning

Thyroid C-cell tumor risk:

Liraglutide, one of the components of insulin degludec/liraglutide, causes dose-dependent and treatment duration–dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether insulin degludec/liraglutide causes 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.

Insulin degludec/liraglutide is contraindicated in patients with a personal or family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of insulin degludec/liraglutide and inform them of symptoms of thyroid tumors (eg, 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 insulin degludec/liraglutide.

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: Development of antibodies to insulin and liraglutide may occur. In clinical trials with insulin degludec/liraglutide combination, antibody formation was not associated with reduced efficacy. In clinical trials with liraglutide, patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1C.

• GI symptoms: Most common reactions are gastrointestinal related; these symptoms may be dose-related and may decrease in frequency/severity with gradual titration and continued use.

• Hypersensitivity: Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with liraglutide and with insulin degludec; discontinue use if hypersensitivity reactions occur and treat promptly as indicated. It is not known if patients with a history of hypersensitivity to other GLP-1 agonists are at increased risk for hypersensitivity reactions with liraglutide; patients with prior serious reactions to similar agents should be monitored closely.

• Hypoglycemia: The most common adverse effect of insulin is hypoglycemia. The timing of hypoglycemia differs among various insulin formulations. Hypoglycemia may result from increased work or exercise without eating; use of long-acting insulin preparations (eg, insulin degludec, insulin detemir, insulin glargine) may delay recovery from hypoglycemia. Profound and prolonged episodes of hypoglycemia may result in convulsions, unconsciousness, temporary or permanent brain damage or even death. Insulin requirements may be altered during illness, emotional disturbances or other stressors. Instruct patients to use caution with ethanol; may increase risk of hypoglycemia. Monitor for loss of glycemic control when making dosage adjustments.

• Hypokalemia: Insulin (especially IV insulin) causes a shift of potassium from the extracellular space to the intracellular space, possibly producing hypokalemia. If left untreated, hypokalemia may result in respiratory paralysis, ventricular arrhythmia and even death. Use with caution in patients at risk for hypokalemia (eg, loop diuretic use). Monitor serum potassium and supplement potassium when necessary.

• Pancreatitis: Cases of acute and chronic pancreatitis (including fatal and nonfatal, hemorrhagic or necrotizing pancreatitis) have been reported with GLP-1 receptor agonists; monitor for signs and symptoms of pancreatitis (eg, persistent severe abdominal pain which may radiate to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue use. Do not resume unless an alternative etiology of pancreatitis is confirmed. Use with caution in patients with a history of pancreatitis, cholelithiasis, and/or alcohol abuse; limited data regarding use in patients with a history of pancreatitis. Consider antidiabetic therapies other than liraglutide in patients with a history of pancreatitis.

• Renal effects: Acute renal failure and chronic renal failure exacerbation (including severe cases requiring hemodialysis) have been reported with liraglutide; some cases have been reported in patients with no known preexisting renal disease. Reports primarily occurred in patients with nausea, vomiting, diarrhea, or dehydration. Renal dysfunction was usually reversible with appropriate corrective measures, including discontinuation of liraglutide. Risk may be increased in patients receiving concomitant medications affecting renal function and/or hydration status.

• Thyroid tumors: [US Boxed Warning] Dose-dependent and treatment duration–dependent thyroid C-cell tumors have developed in animal studies with liraglutide therapy; it is unknown whether liraglutide will cause thyroid C-cell tumors, including MTC, in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Patients should be counseled on the potential risk of MTC with the use of liraglutide and informed of symptoms of thyroid tumors (eg, neck mass, dysphagia, dyspnea, persistent hoarseness). Use is contraindicated in patients with a personal or a family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2). Consultation with an endocrinologist is recommended in patients who develop elevated calcitonin concentrations or have thyroid nodules detected during imaging studies or physical exam. Routine monitoring of serum calcitonin or using thyroid ultrasound monitoring is of uncertain value for early detection of MTC in patients treated with liraglutide.

Disease-related concerns:

• Gastroparesis: Liraglutide slows gastric emptying; has not been studied in patients with preexisting gastroparesis.

• Hepatic impairment: Use with caution in patients with hepatic impairment, insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely. Dosage adjustments may be necessary.

• Renal impairment: Use with caution in patients with renal impairment. Dosage adjustments may be necessary.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Multiple dose injection pens: According to the Centers for Disease Control and Prevention (CDC), pen-shaped injection devices should never be used for more than one person (even when the needle is changed) because of the risk of infection. The injection device should be clearly labeled with individual patient information to ensure that the correct pen is used (CDC 2012).

Other warnings/precautions:

• Appropriate use: Not approved for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus (insulin-dependent, IDDM).

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Refer to individual agents.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience rhinitis, pharyngitis, common cold symptoms, headache, nausea, vomiting, abdominal pain, flatulence, lack of appetite, diarrhea, constipation, weight gain, or injection site irritation. Have patient report immediately to prescriber signs of thyroid cancer (new lump or swelling in the neck, pain in the front of the neck, persistent cough, persistent change in voice like hoarseness, or difficulty swallowing or breathing), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of gallstones (pain in the upper right abdominal area, right shoulder area, or between the shoulder blades; jaundice; or fever with chills), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), vision changes, dizziness, passing out, slurred speech, seizures, change in skin to thick or thin at injection site, mood changes, shortness of breath, excessive weight gain, swelling of arms or legs, or signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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