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Liraglutide

Pronunciation

(lir a GLOO tide)

Index Terms

  • NN2211

Dosage Forms

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

Solution Pen-injector, Subcutaneous:

Saxenda: 18 mg/3 mL (3 mL) [contains phenol, propylene glycol]

Victoza: 18 mg/3 mL (3 mL) [contains phenol, propylene glycol]

Brand Names: U.S.

  • Saxenda
  • Victoza

Pharmacologic Category

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

Pharmacology

Liraglutide is a long acting analog of human glucagon-like peptide-1 (GLP-1) (an incretin hormone) which increases glucose-dependent insulin secretion, decreases inappropriate glucagon secretion, increases B-cell growth/replication, slows gastric emptying, and decreases food intake. Liraglutide administration results in decreases in hemoglobin A1c by approximately 1%.

Distribution

Vd: SubQ: ~13 to 25 L; IV: 0.07 L/kg

Metabolism

Endogenously metabolized by dipeptidyl peptidase IV (DPP-IV) and endogenous endopeptidases (Croom, 2009); metabolism occurs slower than that seen with native GLP-1

Excretion

Urine (6%, as metabolites); feces (5%, as metabolites)

Time to Peak

Plasma: to 12 hours

Half-Life Elimination

~13 hours

Protein Binding

>98%

Special Populations Note

Body weight: Exposure decreases with an increase in baseline body weight; however, the 1.2 mg and 1.8 mg daily doses of liraglutide provided adequate systemic exposures over the body weight range of 40 to 160 kg.

Use: Labeled Indications

Chronic weight management (Saxenda): As an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index of 30 kg/m2 or greater (obese) or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (eg, hypertension, type 2 diabetes mellitus, dyslipidemia)

Diabetes mellitus, type 2 (Victoza): As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; risk reduction of major cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease.

Contraindications

Prior serious hypersensitivity to liraglutide or any component of the formulation; history of or family history of MTC; patients with multiple endocrine neoplasia syndrome type 2 (MEN2); pregnancy (Saxenda).

Canadian labeling: Additional contraindications (not in US labeling): Pregnancy (Saxenda, Victoza); breastfeeding

Dosing: Adult

Chronic weight management (Saxenda): SubQ: Initial: 0.6 mg once daily for one week; increase by 0.6 mg daily at weekly intervals to a target dose of 3 mg once daily. If the patient cannot tolerate an increased dose during dose escalation, consider delaying dose escalation for one additional week. If the 3 mg daily dose is not tolerated, discontinue use as efficacy has not been established at lower doses.

Note: Evaluate change in body weight 16 weeks after initiation of therapy; discontinue if at least 4% of baseline body weight loss has not been achieved.

Diabetes mellitus, type 2 (Victoza): SubQ: Initial: 0.6 mg once daily for 1 week; then increase to 1.2 mg once daily; if optimal glycemic response not achieved, may increase further to 1.8 mg once daily.

Note: Initial dose is intended to reduce GI symptoms; does not provide effective glycemic control.

Concomitant use with insulin and/or insulin secretagogues (eg, sulfonylurea): Reduced dose of insulin and/or insulin secretagogues may be needed

Missed doses: In the event of a missed dose, the once daily regimen can be resumed with the next scheduled dose (an extra dose or an increase in the next dose should not be attempted); if >3 days have passed since the last liraglutide dose, reinitiate therapy at 0.6 mg/day to avoid GI symptoms and titrate according to prescriber discretion.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary; use with caution when initiating therapy and with dose escalation. There is limited data in patients with ESRD.

Dosing: Hepatic Impairment

No dosage adjustment necessary; use with caution due to limited experience.

Administration

SubQ: Inject subcutaneously in the upper arm, thigh, or abdomen. Do not inject intravenously or intramuscularly. Administer without regard to meals or time of day. Change needle with each administration. Use only if clear, colorless, and free of particulate matter. Do not share pens between patients even if needle is changed. If using concomitantly with insulin, administer as separate injections (do not mix); may inject in the same body region as insulin, but not adjacent to one another.

Dietary Considerations

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

Storage

Prior to initial use, store at 2°C to 8°C (36°F to 46°F); after initial use, may be stored at 2°C to 8°C (36°F to 46°F) or at 15°C to 30°C (59°F to 86°F). Do not freeze (discard if freezing occurs) or store directly adjacent to the refrigerator cooling element. Protect from heat and light. Pen should be discarded 30 days after initial use.

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

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

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

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

Insulins: Liraglutide may enhance the hypoglycemic effect of Insulins. 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

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

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

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

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones 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

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

Sulfonylureas: Glucagon-Like Peptide-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

Obesity:

>10%:

Cardiovascular: Increased heart rate (>10 bpm from baseline: 34%; >20 bpm from baseline: 5%)

Central nervous system: Headache (14%)

Endocrine & metabolic: Hypoglycemia (Type 2 diabetics: Combination therapy with sulfonylurea: 44%; monotherapy: 16%; nondiabetic patients: 2% to 3%)

Gastrointestinal: Nausea (39%), diarrhea (21%), constipation (19%), vomiting (16%)

1% to 10%:

Cardiovascular: Tachycardia (6%; one resting heart rate >100 bpm)

Central nervous system: Fatigue (8%), dizziness (7%)

Gastrointestinal: Decreased appetite (10%), dyspepsia (10%), abdominal distension (5%), abdominal pain (5%), eructation (5%), gastroenteritis (5%), gastroesophageal reflux disease (5%), increased serum lipase (5%; >3 x ULN: 2%), upper abdominal pain (5%), flatulence (4%), viral gastroenteritis (3%), cholelithiasis (2%), xerostomia (2%)

Genitourinary: Urinary tract infection (4%)

Immunologic: Antibody development (3%; neutralizing: 1%)

Local: Injection site reactions (3% to 14%; including erythema [1% to 3%], itching [1% to 3%], rash [1% to 3%])

Neuromuscular & skeletal: Weakness (2%)

Type 2 diabetes mellitus: Incidence reported in monotherapy trials unless otherwise specified.

>10%:

Central nervous system: Headache (10% to 11%)

Gastrointestinal: Gastrointestinal disease (43%), nausea (18% to 20%), diarrhea (10% to 12%)

Infection: Infection (patients with antibodies: 40%)

Respiratory: Upper respiratory tract infection (7%; patients with antibodies: 11%)

1% to 10%:

Gastrointestinal: Decreased appetite (9% to 10%), dyspepsia (combination trials: 9%, monotherapy: 4% to 7%), vomiting (6% to 9%), increased serum lipase (8%), constipation (5%), cholelithiasis (2%), cholecystitis (1%), increased amylase (1%)

Hepatic: Hyperbilirubinemia (monotherapy and combination trials: 4%)

Immunologic: Antibody development (≤9%; neutralizing antibodies: 2%)

Local: Injection site reactions (monotherapy and combination trials: 2% [includes rash, erythema])

Neuromuscular & skeletal: Back pain (4% to 5%)

Respiratory: Nasopharyngitis (9% to 10%)

<1% (Limited to important or life-threatening; any indication): Acute renal failure, asthma, benign gastrointestinal neoplasm (colorectal), carcinoma (papillary thyroid), cholecystitis, cholestasis, chronic renal failure (exacerbation), first degree atrioventricular block, hepatitis, hypersensitivity reaction, increased susceptibility to infection, left bundle branch block, malignant neoplasm (including colorectal carcinoma), malignant neoplasm of breast, medullary thyroid carcinoma, pancreatitis (including acute, chronic, hemorrhagic, and necrotizing), papillary thyroid carcinoma, right bundle branch block, suicidal ideation, systolic hypotension, thyroid disease (C-cell hyperplasia)

ALERT: U.S. Boxed Warning

Thyroid C-cell tumor risk:

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, because the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined.

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 (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 liraglutide.

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: Use may be associated with the development of anti-liraglutide antibodies. Antibody formation was not associated with a loss of efficacy; however, patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1C.

• Cardiovascular effects: Increased resting heart rate has been observed in placebo controlled trials; monitoring is recommended. Discontinue use in patients who experience a sustained increase in resting heart rates.

• Gallbladder disease: Use of GLP-1 agonists may increase risk of gallbladder and bile duct disease (Faillie 2016). Cholelithiasis and cholecystitis have been reported in patients treated with liraglutide with the majority of patients requiring requiring hospitalization or cholecystectomy; gallbladder studies and further clinical assessment are indicated if cholelithiasis is suspected.

• 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 reactions: Serious hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported with use; permanently discontinue therapy in the event of a hypersensitivity reaction. Use with caution in patients with a history of anaphylaxis or angioedema to other GLP-1 receptor agonists; potential for cross-sensitivity is unknown.

• Pancreatitis: Cases of acute and chronic pancreatitis (including fatal and nonfatal, hemorrhagic or necrotizing pancreatitis) have been reported; 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. It is not known if liraglutide increases risk for development of pancreatitis in patients with a history of pancreatitis.

• Psychiatric effects: Suicidal behavior, with one case of attempted suicide, has been reported in patients treated for obesity; monitor for new or worsening depression, suicidal thoughts or behavior, or unusual changes in mood or behavior. Discontinue use if suicidal thoughts or behaviors occur. Avoid use in patients with history of suicidal attempts or active suicidal ideation.

• Renal effects: Acute renal failure and chronic renal failure exacerbation (including severe cases requiring hemodialysis) have been reported; 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: Slows gastric emptying; has not been studied in patients with preexisting gastroparesis.

• Hepatic impairment: Use with caution in patients with hepatic impairment; limited experience.

• Renal impairment: Use with caution in patients with renal impairment, particularly during initiation of therapy and dose escalation.

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: Diabetes mellitus: Victoza is not recommended for first-line therapy in patients inadequately controlled on diet and exercise alone. Do not use in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis; not a substitute for insulin. Saxenda is not indicated for the treatment of type 2 diabetes; concomitant use with insulin is not recommended.

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

Monitoring Parameters

Plasma glucose, HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2017b]); renal function; signs/symptoms of pancreatitis; triglycerides; signs/symptoms of gallbladder disease; emergence of worsening depression, suicidal thoughts/behavior, changes in behavior; heart rate; body weight (at week 16 when used for chronic weight management)

Pregnancy Considerations

Use of liraglutide for chronic weight management is contraindicated in pregnant women (lack of potential benefit and possible fetal harm). An increased risk of adverse maternal and fetal outcomes is associated with obesity; however, medications for weight loss therapy are not recommended at conception or during pregnancy (ACOG 156 2015).

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2017c; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 137 2013; ADA 2017c; Blumer 2013; Kitzmiller 2008). Agents other than liraglutide are currently recommended to treat diabetes in pregnant women (ACOG 137 2013; ADA 2017c; Blumer 2013).

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 headache, diarrhea, constipation, nausea, vomiting, lack of appetite, rhinitis, pharyngitis, abdominal pain, loss of strength and energy, 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 kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), dizziness, passing out, tachycardia, abnormal heartbeat, mood changes, behavioral changes, depression, suicidal ideation, 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 health care 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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