Liraglutide-Insulin Degludec

Liraglutide-Insulin Degludec is a combination medication used to treat the symptoms of Type 2 Diabetes Mellitus. 

• Liraglutide-Insulin Degludec is available under the following different brand names: Xultophy

Common side effects of Liraglutide-Insulin Degludec include:

• Stuffy or runny nose,
• Sore throat,
• Headache,
• Nausea,
• Diarrhea,
• Increased blood levels of lipase,
• Cough,
• Sneezing,
• Fever,
• Nasal breathing,
• Dizziness,
• Lightheadedness,
• Sweating,
• Confusion,
• Drowsiness,
• Headache,
• Blurred vision,
• Slurred speech,
• Shakiness,
• Fast heartbeat,
• Anxiety,
• Irritability,
• Mood changes,
• Hunger,
• Weakness, and
• Feeling jittery

Serious side effects of Liraglutide-Insulin Degludec include:

• Hives,
• Difficulty breathing,
• Swelling of the face, lips, tongue, or throat,
• Severe stomach pain with or without vomiting,
• Loss of appetite,
• Puffiness around the eyes,
• Fatigue,
• Dry or itching skin,
• Difficulty sleeping,
• Fever,
• Chills,
• Yellowing of the eyes or skin (jaundice),
• Clay-colored stools,
• Dark urine,
• Constipation,
• Heart palpitations,
• Fatigue,
• Muscle weakness or spasms,
• Tingling or numbness,
• Shortness of breath,
• Rapid or irregular heartbeat, and
• Swelling in the legs or ankles

Rare side effects of Liraglutide-Insulin Degludec include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors;
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Subcutaneous injection

• 3.6 mg/100 units per mL
• Available as a 3-mL single-use pen

Type 2 Diabetes Mellitus

Adult dosage

• The pen delivers doses from 10-50 units with each injection
• Each dosage unit contains 1 unit of insulin degludec and 0.036 mg of liraglutide
• Use alternative antidiabetic products if patients require a daily dosage persistently below 16 units or over 50 units

Starting dose

• Discontinue basal insulin or GLP-1 agonist before initiating liraglutide-Insulin Degludec
• Patients who are naïve to basal insulin or GLP-1 agonists: insulin degludec 10 units/liraglutide 0.36 mg Subcutaneous once a day
• Patients currently on basal insulin or a GLP-1 agonist: insulin degludec 16 units/liraglutide 0.58 mg Subcutaneous once a day

Dose titration

• May titrate dose upwards or downwards by 2 units every 3-4 days based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal until the desired fasting plasma glucose is achieved
• To minimize the risk of hypoglycemia or hyperglycemia, additional titration may be needed
• Changes in physical activity, meal patterns (ie, macronutrient content or timing of food intake), or renal or hepatic function

During acute illness

• When used with other medications

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

Liraglutide-Insulin Degludec has severe interactions with no other drugs.

• Liraglutide-Insulin Degludec has serious interactions with the following drugs:
  • ethanol
  • macimorelin
• Liraglutide-Insulin Degludec has moderate interactions with at least 231 other drugs.
• Liraglutide-Insulin Degludec has minor interactions with the following drugs:
  • acetaminophen
  • acetaminophen IV
  • digoxin
  • lovastatin
  • stevia

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all your products. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, or if you have health questions or concerns.

Contraindications

• Patients with a personal or family history of MTC and patients with MEN 2 (See Black Box Warnings)
• During episodes of hypoglycemia
• Hypersensitivity to either of the active drugs or any excipients; serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Liraglutide-Insulin Degludec?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Liraglutide-Insulin Degludec?”

Cautions 

• Do not share insulin pens between patients
• No clinical studies have established conclusive evidence of macrovascular risk reduction with any antidiabetic drugs
• The product contains two drugs, insulin degludec, and liraglutide; daily administration of more than 50 units of this drug combination can result in an 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 reported; to avoid medication errors between this drug combination (an insulin-containing product) and other insulin products, instruct patients to always check the label before each injection
• Acute gallbladder disease, such as cholelithiasis or cholecystitis reported with liraglutide, a component of this drug combination; the majority of events required hospitalization or cholecystectomy; if cholelithiasis suspected, gallbladder studies and appropriate clinical follow-up are indicated
• All insulin-containing products cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalaemia; untreated hypokalaemia may cause respiratory paralysis, ventricular arrhythmia, and death; monitor potassium levels in patients at risk for hypokalaemia if indicated (.g, patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations)
• 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
  • Cases of MTC in patients treated with liraglutide were reported in the postmarketing period; data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans
  • Counsel patients regarding a potential risk for MTC with the use of the drug and inform them of symptoms of thyroid tumors (.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 this drug; 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 above 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
  • Postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, was observed in patients treated with liraglutide, one of the components of this drug combination; clinical causality not established; some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse that was present when pancreatitis observed
  • After initiation of therapy, observe patients 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, therapy should promptly be discontinued and appropriate management initiated; if pancreatitis confirmed, restarting therapy not recommended
  • Liraglutide, one of the components of this drug combination, has been studied in a limited number of patients with a history of pancreatitis; it is unknown if patients with a history of pancreatitis are at higher risk for the development of pancreatitis on liraglutide
• Hyperglycemia or hypoglycemia with changes in insulin regimen
  • Changes in an insulin regimen (.g, insulin strength, manufacturer, type, injection site, or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia; repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis reported to result in hyperglycemia, and a sudden change in injection site (to an unaffected area) reported to result in hypoglycemia
  • Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring; advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia; adjustments in concomitant oral anti-diabetic treatment may be needed; when initiating therapy, follow dosing recommendations
• Hypoglycemia
  • Hypoglycemia is the most common adverse reaction of insulin-containing products; the long-acting effect of insulin degludec may delay recovery from hypoglycemia compared to shorter-acting insulins; 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 (eg, driving or operating other machinery)
  • An insulin-containing product or any insulin, should not be used during episodes of hypoglycemia; hypoglycemia can happen suddenly and symptoms may differ in each 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 (eg, beta-blockers), or in patients who experience recurrent hypoglycemia
  • The risk of hypoglycemia generally increases with the intensity of glycemic control; the risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose-lowering effect of insulin is maximal; as with all insulin containing products, the glucose-lowering effect time course of this drug combination 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 injection site blood supply and temperature
  • Other factors which may increase the risk of hypoglycemia include changes in meal pattern (eg, macronutrient content or timing of meals), changes in the level of physical activity, or changes to co-administered medication; patients with renal or hepatic impairment may be at higher risk of 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 this drug combination; 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 have 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 reactions
  • Severe, life-threatening, generalized allergies, including anaphylaxis, angioedema, bronchospasm, hypotension, and shock can occur with this drug combination; allergic reactions (manifested with signs and symptoms such as urticaria, rash, and pruritus) have been reported with this drug combination; there have been postmarketing reports of serious hypersensitivity (manifested with swelling of tongue and lips, diarrhea, nausea, tiredness, and itching), including anaphylactic reactions and angioedema generalized skin reactions, bronchospasm, hypotension, and shock, reported with liraglutide, one of the components of this drug combination
  • If a hypersensitivity reaction occurs, discontinue therapy and treat promptly per standard of care; monitor until signs and symptoms resolve; anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists
  • Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with this drug combination
  • This drug combination is contraindicated in patients who have had hypersensitivity reactions to insulin degludec, liraglutide, or one of the excipients of these products
• Fluid retention and congestive heart failure
  • Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists can cause dose-related fluid retention, particularly when used in combination with insulin-containing products, including this drug combination; fluid retention may lead to or exacerbate congestive heart failure
  • Patients treated with insulin-containing products, including this drug combination 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
• Drug interaction overview
  • Drugs that may increase hypoglycemia risk
  • May require dose reduction and increased glucose monitoring frequency if coadministered with drugs that cause hypoglycemia
  • Examples include antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (.g, octreotide), and sulfonamide antibiotics
  • Drugs that may decrease the blood-glucose-lowering effect of liraglutide-Insulin Degludec
  • May require a dose increase and increased glucose monitoring frequency if coadministered with drugs that increase blood glucose
  • Examples include atypical antipsychotics (.g, olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (.g, in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (.g, albuterol, epinephrine, terbutaline), and thyroid hormones
  • Drugs that may increase or decrease the blood-glucose-lowering effects of liraglutide-Insulin Degludec
  • Dose adjustment in increased blood glucose monitoring may be required
  • Examples include alcohol, beta-blockers, clonidine, and lithium salts; pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia
  • Drugs that may blunt signs and symptoms of hypoglycemia
  • Increase the frequency of blood glucose monitoring
  • Examples include beta-blockers, clonidine, guanethidine, and reserpine

Pregnancy and Lactation

• Based on animal reproduction studies, there may be risks to the fetus from exposure to liraglutide during pregnancy
• Use during pregnancy only if the potential benefit justifies the potential risk to the fetus
• There are no available data with insulin degludec or liraglutide in pregnant women to inform a drug-associated risk for major birth defects or miscarriage
• There are clinical considerations regarding the risks of diabetes in pregnancy; poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications; poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, macrosomia related morbidity
• Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes
• Lactation
  • There are no data on the presence of liraglutide or insulin degludec in human milk, its effects on the breastfed infant, or milk production; in lactating rats, insulin degludec and liraglutide were present in milk
  • Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or the underlying maternal condition