Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Liraglutide Injection: 18 mg/3 mL (6 mg/mL) clear, colorless solution in a prefilled, single-patient-use pen that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg is available in the following package sizes: 2 x Liraglutide injection pen NDC 0480-3667-20 3 x Liraglutide injection pen NDC 0480-3667-22 16.2 Recommended Storage Prior to first use, liraglutide injection should be stored in a refrigerator between 36º to 46ºF (2º to 8ºC). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze liraglutide injection and do not use liraglutide injection if it has been frozen. After first use of the liraglutide injection pen, the pen can be stored for 30 days at controlled room temperature (59° to 86°F; 15° to 30°C) or in a refrigerator (36° to 46°F; 2° to 8°C). Keep the pen cap on when not in use. Protect liraglutide injection from excessive heat and sunlight. Always remove and safely discard the needle after each injection and store the liraglutide injection pen without an injection needle attached. This will reduce the potential for contamination, infection, and leakage while also ensuring dosing accuracy. Always use a new needle for each injection to prevent contamination.; Package/Label Display Panel – 2 Pens Carton Liraglutide injection 2 Pens 18 mg/3 mL (6 mg/mL) For Single-Patient-Use-Only NDC 0480- 3667 -20 List 366720 Each pen delivers doses of 0.6 mg, 1.2 mg or 1.8 mg. Subcutaneous use only Contains: 2 Liraglutide Injection Pens, Product Literature Dispense the enclosed Medication Guide to each patient Intended for use with NovoFine ® Nordisk disposable needles Discard pen 30 days after first use REFRIGERATE – DO NOT FREEZE Rx Only teva carton_2_pens; Package/Label Display Panel – 3 Pens Carton Liraglutide injection 3 Pens 18 mg/3 mL (6 mg/mL) For Single-Patient-Use-Only NDC 0480- 3667 -22 List 366722 Each pen delivers doses of 0.6 mg, 1.2 mg or 1.8 mg. Subcutaneous use only Contains: 3 Liraglutide Injection Pens, Product Literature Dispense the enclosed Medication Guide to each patient Intended for use with NovoFine ® Nordisk disposable needles Discard pen 30 days after first use REFRIGERATE – DO NOT FREEZE Rx Only teva carton_3_pens
- 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Liraglutide Injection: 18 mg/3 mL (6 mg/mL) clear, colorless solution in a prefilled, single-patient-use pen that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg is available in the following package sizes: 2 x Liraglutide injection pen NDC 0480-3667-20 3 x Liraglutide injection pen NDC 0480-3667-22 16.2 Recommended Storage Prior to first use, liraglutide injection should be stored in a refrigerator between 36º to 46ºF (2º to 8ºC). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze liraglutide injection and do not use liraglutide injection if it has been frozen. After first use of the liraglutide injection pen, the pen can be stored for 30 days at controlled room temperature (59° to 86°F; 15° to 30°C) or in a refrigerator (36° to 46°F; 2° to 8°C). Keep the pen cap on when not in use. Protect liraglutide injection from excessive heat and sunlight. Always remove and safely discard the needle after each injection and store the liraglutide injection pen without an injection needle attached. This will reduce the potential for contamination, infection, and leakage while also ensuring dosing accuracy. Always use a new needle for each injection to prevent contamination.
- Package/Label Display Panel – 2 Pens Carton Liraglutide injection 2 Pens 18 mg/3 mL (6 mg/mL) For Single-Patient-Use-Only NDC 0480- 3667 -20 List 366720 Each pen delivers doses of 0.6 mg, 1.2 mg or 1.8 mg. Subcutaneous use only Contains: 2 Liraglutide Injection Pens, Product Literature Dispense the enclosed Medication Guide to each patient Intended for use with NovoFine ® Nordisk disposable needles Discard pen 30 days after first use REFRIGERATE – DO NOT FREEZE Rx Only teva carton_2_pens
- Package/Label Display Panel – 3 Pens Carton Liraglutide injection 3 Pens 18 mg/3 mL (6 mg/mL) For Single-Patient-Use-Only NDC 0480- 3667 -22 List 366722 Each pen delivers doses of 0.6 mg, 1.2 mg or 1.8 mg. Subcutaneous use only Contains: 3 Liraglutide Injection Pens, Product Literature Dispense the enclosed Medication Guide to each patient Intended for use with NovoFine ® Nordisk disposable needles Discard pen 30 days after first use REFRIGERATE – DO NOT FREEZE Rx Only teva carton_3_pens
Overview
Liraglutide injection contains liraglutide, an analog of human GLP-1 and acts as a GLP-1 receptor agonist. The peptide precursor of liraglutide, produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae, has been engineered to be 97% homologous to native human GLP-1 by substituting arginine for lysine at position 34. Liraglutide is made by attaching a C-16 fatty acid (palmitic acid) with a glutamic acid spacer on the remaining lysine residue at position 26 of the peptide precursor. The molecular formula of liraglutide is C 172 H 265 N 43 O 51 and the molecular weight is 3751.2 Daltons. The structural formula ( Figure 1 ) is: Figure 1. Structural Formula of Liraglutide Liraglutide injection is a sterile, aqueous, clear, colorless or almost colorless solution for subcutaneous use. Each 1 mL of liraglutide injection solution contains 6 mg of liraglutide and the following inactive ingredients: disodium phosphate dihydrate, 1.42 mg; propylene glycol, 14 mg; phenol, 5.5 mg; and water for injection. Liraglutide injection has a pH of approximately 8.15, hydrochloric acid or sodium hydroxide may be added to adjust pH. Each prefilled pen contains a 3 mL solution of liraglutide equivalent to 18 mg liraglutide (free-base, anhydrous). figure-1
Indications & Usage
Liraglutide is indicated: • as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus, • to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease. Limitations of Use : Liraglutide should not be used in patients with type 1 diabetes mellitus. Liraglutide contains liraglutide and should not be coadministered with other liraglutide-containing products. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated: • as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus (1). • to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (1) . Limitations of Use : • Not for treatment of type 1 diabetes mellitus. • Should not be coadministered with other liraglutide-containing products.
Dosage & Administration
• Adult Patients : Initiate at 0.6 mg injected subcutaneously once daily for one week then increase to 1.2 mg daily. If additional glycemic control is required, increase the dose to 1.8 mg daily after one week of treatment with the 1.2 mg daily dose (2.1) . • Pediatric Patients : Initiate at 0.6 mg injected subcutaneously once daily for at least one week. If additional glycemic control is required increase the dose to 1.2 mg daily and if additional glycemic control is still required, increase the dose to 1.8 mg daily after at least one week of treatment with the 1.2 mg daily dose (2.1) . • Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles (2.3) . • Inject liraglutide subcutaneously once-daily at any time of day, independently of meals, in the abdomen, thigh or upper arm (2.3) . • When using liraglutide with insulin, administer as separate injections. Never mix. (2.3) . 2.1 Recommended Dosage Adult Patients • The recommended starting dosage of liraglutide is 0.6 mg injected subcutaneously once daily for one week. The 0.6 mg once daily dosage is intended to reduce gastrointestinal symptoms [see Adverse Reactions (6.1) ] during initial titration and is not effective for glycemic control in adults. • After one week at the 0.6 mg once daily dosage, increase the dosage to 1.2 mg injected subcutaneously once daily. • If additional glycemic control is required, increase the dosage to the maximum recommended dosage of 1.8 mg injected subcutaneously once daily after at least one week of treatment with the 1.2 mg once daily dosage. Pediatric Patients Aged 10 Years and Older • The recommended starting dosage of liraglutide is 0.6 mg injected subcutaneously once daily. • If additional glycemic control is required, increase the dosage in 0.6 mg increments after at least one week on the current dosage. • The maximum recommended dosage is 1.8 mg injected subcutaneously once daily. 2.2 Recommendations Regarding Missed Dose • Instruct patients who miss a dose of liraglutide to resume the once-daily dosage regimen as prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up for the missed dose. • If more than 3 days have elapsed since the last liraglutide dose, reinitiate liraglutide at 0.6 mg once daily to mitigate any gastrointestinal symptoms associated with reinitiation of treatment. Upon reinitiation, liraglutide should be titrated at the discretion of the healthcare provider. 2.3 Important Administration Instructions • Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles. • Inject liraglutide subcutaneously once daily at any time of day, independently of meals. • Inject liraglutide subcutaneously in the abdomen, thigh or upper arm. No dosage adjustment is needed if changing the injection site and/or timing. • Rotate injection sites within the same region in order to reduce the risk of cutaneous amyloidosis [see Adverse Reactions (6.2) ]. • When using liraglutide with insulin, administer as separate injections. Never mix. It is acceptable to inject liraglutide and insulin in the same body region but the injections should not be adjacent to each other.
Warnings & Precautions
• Pancreatitis : Postmarketing reports, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed (5.2) . • Never share a liraglutide pen between patients, even if the needle is changed (5.3) . • Hypoglycemia: Adult patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with liraglutide regardless of insulin and/or metformin use. Reduction in the dose of insulin secretagogues or insulin may be necessary (5.4) . • Acute Kidney Injury : Postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration which may sometimes require hemodialysis. Use caution when initiating or escalating doses of liraglutide in patients with renal impairment (5.5) . • Hypersensitivity Reactions : Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue liraglutide and promptly seek medical advice (5.6) . • Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated (5.7) . 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 [see Nonclinical Toxicology (13.1) ] . 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 >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 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. 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, liraglutide should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, liraglutide should not be restarted. In glycemic control 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. Liraglutide 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 development of pancreatitis on liraglutide. 5.3 Never Share a Liraglutide Pen Between Patients Liraglutide pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. 5.4 Hypoglycemia Adult patients receiving liraglutide in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with liraglutide regardless of insulin and/or metformin use. [see Adverse Reactions (6.1) , Drug Interactions (7.2) ] . 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 and pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.5 Acute Kidney Injury Liraglutide has not been found to be directly nephrotoxic in animal studies or clinical trials. There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis in liraglutide-treated patients [see Adverse Reactions (6.2) ] . 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 [see Adverse Reactions (6.1) ] . 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. Use caution when initiating or escalating doses of liraglutide in patients with renal impairment [see Use in Specific Populations (8.6)]. 5.6 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with liraglutide [see Adverse Reactions (6.2) ] . If a hypersensitivity reaction occurs, discontinue liraglutide; treat promptly per standard of care, and 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-receptor agonist because it is unknown whether such patients will be predisposed to these reactions with liraglutide. Liraglutide is contraindicated in patients who have had a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide [see Contraindications (4)]. 5.7 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In the LEADER trial [see Clinical Studies (14.3) ] , 3.1% of liraglutide-treated patients versus 1.9% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis [see Adverse Reactions (6.1) ]. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.
Boxed Warning
RISK OF THYROID C-CELL TUMORS • 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 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 [see Warnings and Precautions ( 5.1 ), Nonclinical Toxicology ( 13.1 )] . • 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 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 [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether 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 ( 5.1 , 13.1 ) . • Liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and the symptoms of thyroid tumors ( 4 , 5.1 ).
Contraindications
Liraglutide is contraindicated in patients with a: • personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1) ] . • serious hypersensitivity reaction to liraglutide or to any of the excipients in liraglutide. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide [see Warnings and Precautions (5.6) ]. • Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (4) . • Patients with a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide (4) .
Adverse Reactions
The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1) ] • Pancreatitis [see Warnings and Precautions (5.2) ] • Hypoglycemia [see Warnings and Precautions (5.4) ] • Acute Kidney Injury [see Warnings and Precautions (5.5) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.6) ] • Acute Gallbladder Disease [see Warnings and Precautions (5.7) ] • Most common adverse reactions (incidence ≥5%) in clinical trials are nausea, diarrhea, vomiting, decreased appetite, dyspepsia, constipation (6.1) . • Immunogenicity-related events, including urticaria, were more common among liraglutide-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials (12.6) . To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common Adverse Reactions The safety of liraglutide in patients with type 2 diabetes mellitus was evaluated in 5 glycemic control, placebo-controlled trials in adults and one trial of 52 weeks duration in pediatric patients 10 years of age and older [see Clinical Studies (14.1) ] . The data in Table 1 reflect exposure of 1,673 adult patients to liraglutide and a mean duration of exposure to liraglutide of 37.3 weeks. The mean age of adult patients was 58 years, 4% were 75 years or older and 54% were male. The population was 79% White, 6% Black or African American, 13% Asian; 4% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 9 years and a mean HbA 1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88% and moderately impaired in 12% of the pooled population. Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of liraglutide for the treatment of type 2 diabetes mellitus. These adverse reactions occurred more commonly on liraglutide than on placebo and occurred in at least 5% of patients treated with liraglutide. Overall, the type, and severity of adverse reactions in pediatric patients 10 years of age and older and above were comparable to that observed in the adult population. Table 1. Adverse reactions reported in ≥5% of Adult Patients Treated with Liraglutide for Type 2 Diabetes Mellitus Placebo N=661 Liraglutide 1.2 mg N=645 Liraglutide 1.8 mg N=1024 Adverse Reaction (%) (%) (%) Nausea 5 18 20 Diarrhea 4 10 12 Headache 7 11 10 Nasopharyngitis 8 9 10 Vomiting 2 6 9 Decreased appetite 1 10 9 Dyspepsia 1 4 7 Upper Respiratory Tract Infection 6 7 6 Constipation 1 5 5 Back Pain 3 4 5 Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights. In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 . Other Adverse Reactions Gastrointestinal Adverse Reactions In the pool of 5 glycemic control, placebo-controlled adult clinical trials, withdrawals due to gastrointestinal adverse reactions, occurred in 4.3% of liraglutide-treated patients and 0.5% of placebo-treated patients. Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2 to 3 months of the trials. Injection site reactions Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of liraglutide-treated adult patients in the five double-blind, glycemic control trials of at least 26 weeks duration. Less than 0.2% of liraglutide-treated patients discontinued due to injection site reactions. Hypoglycemia In 5 adult glycemic control, placebo-controlled clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 8 liraglutide-treated patients (7.5 events per 1000 patient-years). Of these 8 liraglutide-treated patients, 7 patients were concomitantly using a sulfonylurea. Table 2. Adult Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in 26-week Combination Therapy Placebo-controlled Trials Placebo Comparator Liraglutide Treatment Add-on to Metformin Placebo + Metformin (N = 121) Liraglutide + Metformin (N = 724) Patient not able to self-treat 0 0.1 (0.001) Patient able to self-treat 2.5 (0.06) 3.6 (0.05) Add-on to Glimepiride Placebo + Glimepiride (N = 114) Liraglutide + Glimepiride (N = 695) Patient not able to self-treat 0 0.1 (0.003) Patient able to self-treat 2.6 (0.17) 7.5 (0.38) Not classified 0 0.9 (0.05) Add-on to Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone (N = 175) Liraglutide + Metformin + Rosiglitazone (N = 355) Patient not able to self-treat 0 0 Patient able to self-treat 4.6 (0.15) 7.9 (0.49) Not classified 1.1 (0.03) 0.6 (0.01) Add-on to Metformin + Glimepiride Placebo + Metformin + Glimepiride (N = 114) Liraglutide + Metformin + Glimepiride (N = 230) Patient not able to self-treat 0 2.2 (0.06) Patient able to self-treat 16.7 (0.95) 27.4 (1.16) Not classified 0 0 “Patient not able to self-treat” is defined as an event requiring the assistance of another person for treatment. In a 26-week placebo-controlled clinical trial in pediatric patients 10 years of age and older with a 26-week open-label extension, 21.2% of liraglutide-treated patients (mean age 14.6 years) with type 2 diabetes mellitus, had hypoglycemia with a blood glucose <54 mg/dL with or without symptoms (335 events per 1000 patient years). No severe hypoglycemic episodes occurred in the liraglutide treatment group (severe hypoglycemia was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions). Papillary thyroid carcinoma In adult glycemic control trials of liraglutide, there were 7 reported cases of papillary thyroid carcinoma in patients treated with liraglutide and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Cholelithiasis and cholecystitis In adult glycemic control trials of liraglutide, the incidence of cholelithiasis was 0.3% in both liraglutide-treated and placebo-treated patients. The incidence of cholecystitis was 0.2% in both liraglutide-treated and placebo-treated patients. In the LEADER trial [see Clinical Studies (14.3) ] , the incidence of cholelithiasis was 1.5% (3.9 cases per 1000 patient years of observation) in adult liraglutide-treated and 1.1% (2.8 cases per 1000 patient years of observation) in placebo-treated patients, both on a background of standard of care. The incidence of acute cholecystitis was 1.1% (2.9 cases per 1000 patient years of observation) in adult liraglutide-treated and 0.7% (1.9 cases per 1000 patient years of observation) in placebo-treated patients. The majority of events required hospitalization or cholecystectomy. Laboratory Tests Bilirubin In the five adult glycemic control trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of liraglutide-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. Calcitonin Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. At the end of the adult glycemic control trials, adjusted mean serum calcitonin concentrations were higher in liraglutide-treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. Between group differences in adjusted mean serum calcitonin values were approximately 0.1 ng/L or less. Among adult patients with pretreatment calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of liraglutide-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients. The clinical significance of these findings is unknown. Lipase and Amylase In one adult glycemic control trial in renal impairment patients, a mean increase of 33% for lipase and 15% for amylase from baseline was observed for liraglutide-treated patients while placebo-treated patients had a mean decrease in lipase of 3% and a mean increase in amylase of 1%. In the LEADER trial, serum lipase and amylase were routinely measured. Among adult liraglutide-treated patients, 7.9% had a lipase value at any time during treatment of greater than or equal to 3 times the upper limit of normal compared with 4.5% of placebo-treated patients, and 1% of liraglutide-treated patients had an amylase value at any time during treatment of greater than or equal to 3 times the upper limit of normal versus 0.7% of placebo-treated patients. The clinical significance of elevations in lipase or amylase with liraglutide is unknown in the absence of other signs and symptoms of pancreatitis [see Warnings and Precautions (5.2) ]. Vital signs Liraglutide did not have adverse effects on blood pressure. Mean increases from baseline in heart rate of 2 to 3 beats per minute have been observed in adult patients treated with liraglutide compared to placebo. 6.2 Postmarketing Experience The following additional adverse reactions have been reported during post-approval use of liraglutide. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Gastrointestinal: Acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death, ileus • General Disorders and Administration Site Conditions: Allergic reactions: rash and pruritus • Hepatobiliary: Elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, cholelithiasis requiring cholecystectomy, hepatitis • Immune system: Angioedema and anaphylactic reactions • Metabolism and nutrition: Dehydration resulting from nausea, vomiting and diarrhea • Neoplasms: Medullary thyroid carcinoma • Nervous system: Dysgeusia, dizziness • Renal and urinary: Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis. • Skin and subcutaneous tissue: Cutaneous amyloidosis
Drug Interactions
• Effects of delayed gastric emptying on oral medications: Liraglutide delays gastric emptying and may impact absorption of concomitantly administered oral medications (7). 7.1 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide 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 did not affect the absorption of the tested orally administered medications to any clinically relevant degree [see Clinical Pharmacology (12.3) ] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin Liraglutide stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving liraglutide in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating liraglutide, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4) , Adverse Reactions (6.1) ].
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