INTERACTIONS Effects of delayed gastric emptying on oral medications: Liraglutide injection delays gastric emptying and may impact absorption of concomitantly administered oral medications ( 7 ).
7.1 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide injection causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide injection did not affect the absorption of the tested orally administered medications to any clinically relevant degree <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide injection.
7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin Liraglutide injection stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving liraglutide injection in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating liraglutide injection, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 )]</span>.
AND PRECAUTIONS Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, including liraglutide. Discontinue if pancreatitis is suspected. ( 5.2 )
Acute Gallbladder
Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.3 ) Hypoglycemia: Can occur in adults when liraglutide is used with an insulin secretagogue (e.g. a sulfonylurea) or insulin. The risk may be lowered by a reduction in the dose of concomitantly administered insulin secretagogues or insulin. In the pediatric clinical trial, patients did not have type 2 diabetes. Hypoglycemia occurred in liraglutide-treated pediatric patients. Inform all patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. ( 5.4 )
Heart Rate
Increase: Monitor heart rate at regular intervals. ( 5.5 )
Acute Kidney Injury
Due to Volume Depletion: Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.6 )
Severe Gastrointestinal Adverse
Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. Liraglutide is not recommended in patients with severe gastroparesis. ( 5.7 )
Hypersensitivity
Reactions: Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue liraglutide and other suspect medications and promptly seek medical advice. ( 5.8 )
Suicidal
Behavior and Ideation: Monitor for depression or suicidal thoughts. Discontinue liraglutide if symptoms develop. ( 5.9 )
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. ( 5.10 )
5.1 Risk of Thyroid C-cell Tumors Liraglutide 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 <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( 13.1 )]</span> . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether liraglutide 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. Liraglutide 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 liraglutide 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 liraglutide. 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 greater than 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> . After initiation of liraglutide, 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, discontinue liraglutide injection and initiate appropriate management.
5.3 Acute Gallbladder Disease In liraglutide clinical trials in adults, 2.2% of liraglutide-treated patients reported adverse events of cholelithiasis versus 0.8% of placebo-treated patients. The incidence of cholecystitis was 0.8% in liraglutide-treated patients versus 0.4% in placebo-treated patients. The majority of liraglutide-treated patients with adverse events of cholelithiasis and cholecystitis required cholecystectomy. Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater in liraglutide-treated patients than in placebo-treated patients even after accounting for the degree of weight loss. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.
5.4 Hypoglycemia Adult patients with type 2 diabetes mellitus on an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia with use of liraglutide, including severe hypoglycemia. In patients with type 2 diabetes, monitor blood glucose prior to starting liraglutide and during liraglutide treatment <span class="opacity-50 text-xs">[see Dosage and Administration ( 2 ) and Adverse Reactions ( 6.1 )]</span> . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. In the pediatric clinical trial, patients did not have type 2 diabetes but were provided with blood glucose meters. Clinically significant hypoglycemia, defined as blood glucose <54 mg/dL, occurred in 1.6% of the liraglutide-treated patients compared to 0.8% of placebo-treated patients <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. Inform all pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.
5.5 Heart Rate Increase Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed with routine clinical monitoring in liraglutide-treated adult patients compared to placebo in clinical trials. More patients treated with liraglutide, compared with placebo, had changes from baseline at two consecutive visits of more than 10 bpm (34% versus 19%, respectively) and 20 bpm (5% versus 2%, respectively). At least one resting heart rate exceeding 100 bpm was recorded for 6% of liraglutide-treated patients compared with 4% of placebo-treated patients, with this occurring at two consecutive study visits for 0.9% and 0.3%, respectively. Tachycardia was reported as an adverse reaction in 0.6% of liraglutide-treated patients and in 0.1% of placebo-treated patients. In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, liraglutide treatment was associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo. In a pediatric clinical trial, mean increases from baseline in resting heart rate of 3 to 7 bpm were observed with liraglutide treatment. Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should inform health care providers of palpitations or feelings of a racing heartbeat while at rest during liraglutide treatment. For patients who experience a sustained increase in resting heart rate while taking liraglutide, liraglutide should be discontinued.
5.6 Acute Kidney Injury Due to Volume Depletion There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with liraglutide <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . The majority of the reported events occurred in patients who had experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Monitor renal function in patients reporting adverse reactions to liraglutide that could lead to volume depletion, especially during dosage initiation and escalation <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span> .
5.7 Severe Gastrointestinal Adverse Reactions Use of GLP-1 receptor agonists, including liraglutide, has been associated with gastrointestinal adverse reactions, sometimes severe <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> . In liraglutide clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving liraglutide (4.8%) than placebo (1.4 %). Liraglutide is not recommended in patients with severe gastroparesis.
5.8 Hypersensitivity Reactions There have been reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with liraglutide <span class="opacity-50 text-xs">[see Contraindications ( 4 ) and Adverse Reactions ( 6.1 , 6.2 )]</span> . If a hypersensitivity reaction occurs, the patient should discontinue liraglutide injection and other suspect medications and promptly seek medical advice. 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 liraglutide.
5.9 Suicidal Behavior and Ideation In liraglutide adult clinical trials, 9 (0.3%) of 3,384 liraglutide-treated patients and 2 (0.1%) of the 1,941 placebo-treated patients reported suicidal ideation; one of these liraglutide-treated patients attempted suicide. In a liraglutide pediatric clinical trial, 1 (0.8%) of the 125 liraglutide-treated patients died by suicide. There was insufficient information to establish a causal relationship to liraglutide. Patients treated with liraglutide should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue liraglutide in patients who experience suicidal thoughts or behaviors. Avoid liraglutide in patients with a history of suicidal attempts or active suicidal ideation.
5.10 Pulmonary Aspiration During General Anesthesia or Deep Sedation Liraglutide delays gastric emptying <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking liraglutide, including whether modifying preoperative fasting recommendations or temporarily discontinuing liraglutide could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking liraglutide.