Victoza, Saxenda

Diabetes Mellitus

Used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1 2 18 19

Has been used in combination with metformin, a sulfonylurea, or the combination of metformin and a sulfonylurea as an adjunct to diet and exercise for the management of type 2 diabetes mellitus.1 2 3 4 5 6 7 21

Not recommended as first-line therapy for patients inadequately controlled on diet and exercise alone because of uncertain relevance of liraglutide-induced rodent C-cell tumors to humans.1 8 16 (See Risk of Thyroid C-Cell Tumors under Cautions.)

Safety and efficacy not established in patients with a history of pancreatitis; consider other antidiabetic agents in such patients.1 (See Pancreatitis and Pancreatic Precancerous Changes under Cautions.)

Safety and efficacy in combination with prandial insulin not demonstrated.1 8

Not indicated for use in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1

Victoza and Saxenda both contain liraglutide; do not use concomitantly.1 24

Obesity

Used as an adjunct to caloric restriction and increased physical activity for the long-term management of body weight.24 26 27 28

Used in patients who are obese (pretreatment body mass index [BMI] ≥;30 kg/m2); also used in overweight patients (pretreatment BMI ≥;27 kg/m2) in the presence of a weight-related condition (e.g., hypertension, type 2 diabetes mellitus, dyslipidemia).24

Safety and efficacy in combination with other weight-loss products (prescription or OTC drugs, dietary or herbal supplements) not established.24

Safety and efficacy not established in patients with a history of pancreatitis.24 (See Pancreatitis and Pancreatic Precancerous Changes under Cautions.)

Safety and efficacy in combination with insulin not established in the management of obesity; do not use with insulin for obesity management.24

Saxenda and Victoza both contain liraglutide; do not use concomitantly.1 24

General

• Perform regular monitoring (e.g., blood glucose determinations, HbA1c) to determine therapeutic response in patients with type 2 diabetes mellitus.1

• When used for obesity, evaluate body weight after 16 weeks.24 Discontinue treatment in patients who do not experience a meaningful weight loss (≥4% baseline weight); such patients unlikely to achieve and sustain meaningful weight loss with continued liraglutide therapy.24

Administration

Administer by sub-Q injection using a prefilled injection pen;1 do not administer IV or IM.24

If a dose is missed, resume the regular schedule with the next scheduled dose; do not take an extra dose or increase the dose to replace a missed dose.1 24 If >3 days have elapsed since last dose, restart liraglutide at initial dosage and retitrate.1 24 (See Dosage under Dosage and Administration.)

Administer liraglutide and insulin as separate injections in patients receiving both drugs for diabetes mellitus; do not mix insulin and liraglutide.1 May inject liraglutide and insulin in the same body regions; however, do not administer injections adjacent to each other.1

Sub-Q Administration

Administer once daily without regard to meals.1 24

Administer into abdomen, thigh, or upper arm.1 24 29

Dosage

Adults

Initially, 0.6 mg daily.1 The 0.6 mg dosage is not effective for glycemic control; intended only as a starting dose to reduce GI intolerance.1

After 1 week, increase dosage to 1.2 mg daily.1 If needed, may increase dosage to 1.8 mg daily.1

If >3 days have elapsed since the last dose, reinitiate at 0.6 mg to minimize adverse GI effects and titrate dosage at the discretion of the clinician.1

Initially, 0.6 mg daily.1

Increase daily dosage by 0.6 mg at weekly intervals to maintenance dosage of 3 mg daily.24 (See Table 1.)

If dosage increase not tolerated (e.g., adverse GI effects), may delay dosage escalation for approximately 1 week.24 If 3-mg daily dosage not tolerated, discontinue therapy; efficacy not established at dosages <3 mg daily.24

If >3 days have elapsed since the last dose, reinitiate at 0.6 mg to minimize adverse GI effects; retitrate to maintenance dosage of 3 mg once daily.1

Special Populations

No special population dosage recommendations.1 24

Use caution when initiating liraglutide or escalating dosage in patients with renal impairment.1 24 (See Renal Effects under Cautions.)

Contraindications

• Personal or family history of MTC.1 8 16 24

• MEN 2.1 8 16 24

• Prior serious hypersensitivity to liraglutide or any component in the formulation.1 24

• Pregnancy (when used for obesity management).24 (See Pregnancy under Cautions.)

Warnings/Precautions

Warnings

Dose-dependent and treatment-duration-dependent thyroid C-cell tumors found at clinically relevant exposures in rats and mice.1 8 24 31 Cases of MTC reported in patients receiving liraglutide during postmarketing experience; data insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans.1 Unknown whether liraglutide causes thyroid C-cell tumors, including MTC, in humans; relevance to humans could not be ruled out by clinical or nonclinical studies.1 8 16 24 31 Therefore, do not use as first-line treatment for diabetes mellitus until additional studies completed.1 16

Very elevated serum calcitonin values may suggest MTC; such values generally exceed 50 ng/L in patients with MTC.1 24 Uncertain value of routine monitoring of serum calcitonin or thyroid ultrasound examinations; further evaluate patients if serum calcitonin is elevated or thyroid nodules noted on physical examination or neck imaging.1 8 24 31

To specifically evaluate the risk of MTC, manufacturer is required to establish a cancer registry to monitor the rate of this type of cancer in the US over a period of 15 years.16 17

Sensitivity Reactions

Serious hypersensitivity reactions (anaphylaxis, angioedema) reported.1 24 Discontinue liraglutide and other suspect medications and promptly seek medical advice if hypersensitivity reaction occurs.1 24 Use with caution in patients with a history of angioedema with another GLP-1 receptor agonist.1 24

Other Warnings and Precautions

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, reported during postmarketing experience.1 24 31 Pancreatitis also reported during clinical trials.1 24 31 FDA has been evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous cellular changes in patients with type 2 diabetes mellitus receiving incretin mimetics.36 37 FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete or when the agency has additional information to report.36

FDA has recommended that clinicians continue to follow the recommendations in the prescribing information for incretin mimetics.36 Observe patients carefully for manifestations of pancreatitis after drug initiation and dosage increases.1 24 31 36 Contact clinician promptly if symptoms of pancreatitis occur, including persistent severe abdominal pain that sometimes radiates to the back and that may or may not be accompanied by vomiting.1 24 Manufacturer states that if pancreatitis is suspected, promptly discontinue liraglutide and initiate appropriate management.1 8 24 If pancreatitis is confirmed, do not restart liraglutide.1 8 24

Safety and efficacy not established in patients with a history of pancreatitis;24 31 consider other antidiabetic agent in such patients.1 8

May increase the risk of acute gallbladder disease.24 Cholelithiasis and cholecystitis reported in clinical trials of obesity management; most cases required cholecystectomy.24

Although substantial or rapid weight loss can increase risk of cholelithiasis, the incidence of acute gallbladder disease was greater with liraglutide than with placebo in obesity clinical trials, even after accounting for the degree of weight loss.24 If cholelithiasis suspected, gallbladder studies and appropriate clinical follow-up are recommended.24

Do not share liraglutide (Victoza, Saxenda) injection pens among patients, even if the needle has been changed; sharing poses risk for transmission of blood-borne pathogens.1 23 24 25

Patients receiving liraglutide in combination with an insulin secretagogue (e.g., a sulfonylurea) or insulin may have an increased risk of hypoglycemia; reduction in sulfonylurea or insulin dosage may be necessary.1 24

Manufacturer states that insulin should not be used concomitantly in patients receiving liraglutide for the management of obesity.24

Monitor patients with type 2 diabetes mellitus for an increase in blood glucose when liraglutide is discontinued.24

Increases in heart rate observed with liraglutide therapy for obesity management.24 Resting heart rate >100 bpm reported.24 Clinical importance of elevated heart rate unknown, especially in patients with cardiovascular or cerebrovascular disease who had limited exposure to liraglutide in obesity clinical trials.24

Monitor heart rate regularly; if sustained increase in resting heart rate occurs during therapy, discontinue liraglutide.24

Acute renal failure and worsening of chronic renal failure (sometimes requiring hemodialysis) reported with GLP-1 receptor agonists, including liraglutide, during postmarketing experience.1 24 Some patients did not have known underlying renal disease.1 24 Other factors (nausea, vomiting, diarrhea, or dehydration) were present in most patients.1 24 Some patients received liraglutide in combination with one or more agents known to affect renal function or hydration status.1 24

Not found to be directly nephrotoxic in preclinical or clinical studies.1

Renal effects usually reversible with supportive treatment and discontinuance of potentially causative agents, including liraglutide.1 24 Use caution when initiating liraglutide or escalating dosage in patients with renal impairment.1 24

Suicidal ideation observed in clinical trials for obesity; suicide attempt reported in 1 patient.24

Monitor patients receiving liraglutide for emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.24 Discontinue in patients who experience suicidal thoughts or behaviors.24

Avoid use in patients with a history of suicidal attempts or active suicidal ideation.24

Macrovascular Outcomes

Evidence of macrovascular risk reduction with liraglutide or any other antidiabetic agent has not been conclusively demonstrated in controlled clinical trials.1

Effects on cardiovascular morbidity and mortality in patients receiving the drug for obesity management not established.24

Specific Populations

Victoza: Category C.1

Saxenda: Category X.24

Weight loss offers no potential benefit to pregnant women and may result in fetal harm.24 Manufacturer states that liraglutide is contraindicated for the management of obesity in pregnant women.24 Discontinue liraglutide for obesity management if patient is or plans to become pregnant.24

Liraglutide is distributed into milk in rats; not known whether distributed into milk in humans.1 24 Discontinue nursing or the drug, taking into account the importance of the drug to the woman.1 24

Safety and efficacy not established in children or adolescents younger than 18 years of age.1 24

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out. 1 24

Limited experience in patients with hepatic impairment; use caution.1 12 24

Limited experience in patients with renal impairment, including end-stage renal disease; use caution.1 11 24

Slows gastric emptying and potentially may affect absorption of concomitantly administered oral drugs. 1 (See Orally Administered Drugs under Interactions.) Has not been studied in patients with preexisting gastroparesis. 1 24

Common Adverse Effects

Management of type 2 diabetes mellitus: nausea,1 2 diarrhea,1 2 vomiting,1 2 constipation,1 2 upper respiratory tract infection,1 2 headache,1 2 influenza,1 2 urinary tract infection,1 2 dizziness,1 2 sinusitis,1 2 nasopharyngitis,1 2 back pain.1 2

Management of obesity: nausea,24 hypoglycemia (in patients with obesity and type 2 diabetes mellitus),24 diarrhea,24 constipation,24 vomiting,24 headache,24 decreased appetite,24 dyspepsia,24 fatigue,24 dizziness,24 abdominal pain,24 increased lipase concentrations,24 GERD,24 gastroenteritis,24 abdominal distention,24 eructation,24 urinary tract infection,24 flatulence,24 viral gastroenteritis,24 injection site erythema,24 injection site reaction,24 insomnia,24 dry mouth,24 asthenia,24 anxiety.24

Absorption

Bioavailability

Absolute: Approximately 55% after sub-Q administration.1 10 24

Peak plasma concentration achieved in 11 hours1 24 (range: 8-12 hours) following sub-Q administration.9 10 13 15 20

Duration

Sustained glucose-lowering activity for 24 hours after a dose of liraglutide at steady state.20

Distribution

Plasma Protein Binding

>98%.1 24

Elimination

Metabolism

Endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination.1 13 24 Dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP) likely involved in its degradation.13

Elimination Route

Only a minor portion of liraglutide-related metabolites excreted in urine (6%) or feces (5%).1 13 24

Half-life

13 hours after sub-Q administration.1 9 10 15 24

• Importance of reading manufacturer’s medication guide and the injection pen's patient instructions for use before starting liraglutide therapy and of reviewing this information each time the prescription is renewed.1 23 24 25 29 30

• Importance of informing patients that liraglutide causes benign and malignant thyroid C-cell tumors in mice and rats and that relevance of this finding to humans is unknown.1 23 24 25 Importance of counseling patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia, dyspnea) or a personal or family history of thyroid cancer, including MTC or MEN 2, to their clinician.1 23 24 25

• Importance of informing patients of potential risk of acute pancreatitis, which may be severe or fatal, with liraglutide therapy.1 23 24 25 Importance of patient informing clinicians about a history of pancreatitis, gallstones, alcoholism, or high triglyceride levels.1 23 24 25 Importance of informing patients about signs and symptoms of pancreatitis, including persistent severe abdominal pain sometimes radiating to the back that may or may not be accompanied by vomiting.1 23 24 25 Importance of instructing patients to discontinue liraglutide promptly and contact their clinician if persistent, severe abdominal pain occurs.1 23 24 25

• Importance of informing patients receiving liraglutide for obesity management of the risk of gallbladder disease, which can require cholecystectomy.24 Substantial or rapid weight loss increases the risk of cholelithiasis; however, cholelithiasis can occur in the absence of weight loss.24 25 Patients should be instructed to contact their clinician if they experience symptoms of gallbladder disease (e.g., abdominal pain, fever, jaundice, clay-colored stools).24 25

• Importance of informing patient of risk of hypoglycemia, particularly if concomitant therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin is used.1 Importance of reviewing signs, symptoms, and management of hypoglycemia.1 23

• Risk of increased resting heart rate; importance of advising patients that their heart rate should be measured periodically during therapy.24 25 Patients should be instructed to contact their clinician if they experience sustained palpitations or tachycardia at rest.24 25

• Importance of informing patients of risk of dehydration because of adverse GI reactions; advise patients to take precautions to avoid fluid depletion.1 23 Importance of informing patients of potential risk of worsening renal function, which may require dialysis in some cases.1 23

• Importance of informing patients of possibility of serious hypersensitivity reactions; instruct patients to discontinue liraglutide and promptly seek medical advice if hypersensitivity symptoms occur.1 23

• Potential risk of suicidality; importance of patients being alert to and immediately reporting emergence of suicidality, worsening depression, or unusual changes in mood or behavior.24 25

• Importance of informing patients that they should never share a liraglutide pen with another person, even if the needle is changed; sharing of the pen may pose a risk of transmission of infection.1 23 24 25

• Importance of informing patients of the potential risks and benefits of liraglutide and of alternative therapies. 1 23

• Importance of instructing patients with diabetes mellitus regarding self-monitoring of blood glucose, periodic HbA1c monitoring, adherence to meal planning, and regular physical exercise.1 23

• Importance of informing patients of the most common side effects, including headache, nausea, and diarrhea.1 23 24 Nausea is most common when first starting liraglutide, but decreases over time in most patients and does not typically require discontinuance of the drug.1 23 24

• Importance of reading manufacturer’s patient information (e.g., medication guide) and the injection pen user manual before starting liraglutide therapy and of reviewing this information each time the prescription is renewed.1 23

• Importance of cautioning patients not to take an extra dose of liraglutide to make up for a missed dose.1 23 If a dose is missed, patients should resume the once-daily regimen with the next scheduled dose.1 23

• Importance of informing patients that if >3 days have passed since the last dose, liraglutide should be reinitiated at dosage of 0.6 mg once daily to mitigate GI symptoms associated with reinitiation of treatment, then retitrated.1 23 24 (See Dosage under Dosage and Administration.)

• Importance of instructing patients to discontinue use of liraglutide for the management of obesity if 4% weight loss not achieved after 16 weeks of therapy.24

• Response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels towards the normal range.1 23

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 23 24

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., gallstones, hypertension, pancreatitis, history of alcoholism, high triglyceride concentrations, digestion problems, severe kidney disease, kidney transplant).1 23 24

• Importance of informing patients of other important precautionary information.1 24 (See Cautions.)