Class: Antidiabetic agent/Glucagonlike peptide 1 receptor agonist
- Injection, solution 6 mg/mL
Activates the glucagonlike peptide 1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. Liraglutide increases intracellular cyclic adenosine monophosphate (cAMP), leading to insulin release in the presence of elevated glucose concentrations; also decreases glucagon secretion in a glucose-dependent manner. The mechanism of blood glucose lowering also involves a delay in gastric emptying.
T max is achieved at 8 to 12 h postdosing. C max and AUC were 35 ng/mL and 960 ng•h/mL, respectively, for a single subcutaneous dose of 0.6 mg. Absolute bioavailability is approximately 55%.
Mean Vd is approximately 13 L. Plasma protein binding is more than 98%.
Endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination.
Excreted in urine and feces, 6% and 5%, respectively. The mean Cl of a single dose is approximately 1.2 L/h with an elimination half-life of approximately 13 h.
Special PopulationsRenal Function Impairment
The AUC in mild, moderate, and severe renal impairment, and in ESRD was on average 35%, 19%, 29%, and 30% lower, respectively.Hepatic Function Impairment
The AUC in patients with mild, moderate, and severe hepatic impairment was on average 11%, 14%, and 42% lower, respectively.Elderly
Age had no effect on the pharmacokinetics of liraglutide.Children
Liraglutide has not been studied in pediatric patients.Gender
Women have 34% lower weight-adjusted Cl compared with men.Race
Race and ethnicity had no effect on the pharmacokinetics of liraglutide.Body weight
The exposure of liraglutide 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. Liraglutide was not studied in patients with a body weight of more than 160 kg.
Indications and Usage
As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Personal or family history of medullary thyroid carcinoma; multiple endocrine neoplasia syndrome type 2 (MEN 2); hypersensitivity reaction to liraglutide or to any of the product components.
Dosage and AdministrationAdults
Subcutaneous Initial dosage of 0.6 mg/day for 1 wk. After 1 week at 0.6 mg/day, the daily dose should be increased to 1.2 mg. If the 1.2 mg dose does not result in acceptable glycemic control, the daily dose can be increased to 1.8 mg.
- Administer once daily at any time of day, independently of meals.
- Inject subcutaneously in the abdomen, thigh, or upper arm.
- When initiating liraglutide, consider reducing the dose of coadministered insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycemia.
- 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.
- Liraglutide solution should be clear and colorless, and contain no particles.
- If a dose is missed, the once-daily regimen should be resumed as prescribed with the next scheduled dose. An extra dose or increase in dose should not be taken to make up for the missed dose.
- Based on the elimination half-life, patients should be advised to reinitiate liraglutide at 0.6 mg if more than 3 days have elapsed since the last liraglutide dose. This approach will mitigate any GI symptoms associated with reinitiation of treatment. Upon reinitiation, liraglutide should be titrated at the discretion of the prescribing health care provider.
Prior to first use, store in refrigerator between 36° and 46°F. Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze and do not use if it has been frozen. After initial use, the pen can be stored for 30 days at 59° to 86°F or in a refrigerator between 36° and 46°F. Keep the pen cap on when not in use. Protect pen from excessive heat and sunlight. Store the pen without an injection needle attached to reduce the potential for contamination, infection, and leakage, while also ensuring dosing accuracy.
Drug InteractionsAcetaminophen, atorvastatin, digoxin
These agents may have decreased C max and a delayed T max during coadministration.Antidiabetic agents (eg, insulin, sulfonylureas)
Coadministration may increase the risk of hypoglycemia. A lower dose of the antidiabetic agent may be needed.Griseofulvin
C max may be increased.Oral medications
Liraglutide causes a delay of gastric emptying, and thereby has the potential to affect the absorption of coadministered oral medications. Coadminister with caution.
Nausea (28%); diarrhea (17%); vomiting (11%); constipation (10%).
Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis (postmarketing).
Angioedema and anaphylactoid reactions (postmarketing).
Elevated bilirubin (4%).
Headache (9%); injection-site reactions (2%); hypoglycemia; malignant neoplasm; papillary thyroid carcinoma; dehydration resulting from nausea, vomiting, and diarrhea (postmarketing).
Liraglutide causes dose-dependent and treatment duration–dependent thyroid C-cell tumors at clinically relevant exposures in rats and mice. Human relevance could not be ruled out by clinical and nonclinical studies. Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients with MEN 2. Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Counsel patients regarding the risk and symptoms of thyroid tumors.
Monitor glycemic response to liraglutide. After initiation and dose increases of liraglutide, observe patients carefully for signs and symptoms of pancreatitis.
Category C .
Safety and efficacy not established.
Greater sensitivity of some older individuals cannot be ruled out.
Angioedema and anaphylactoid reactions have been reported.
Use with caution; worsening chronic renal failure, sometimes requiring hemodialysis, has been reported.
Use with caution.
Liraglutide slows gastric emptying.
Anti-liraglutide antibodies may develop. Nonserious upper respiratory tract infections occurred more frequently among liraglutide-treated antibody-positive patients. Patients with anti-liraglutide antibodies were not more likely to develop reactions related to immunogenicity.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with liraglutide or any other antidiabetic drug.
Acute pancreatitis has been reported. Discontinue treatment and do not resume if it develops.
Acute renal failure and worsening of chronic renal failure has been reported.
Severe nausea and vomiting.
- Instruct patients to read the Medication Guide before starting therapy and to reread it each time the prescription is renewed.
- Inform patients that liraglutide causes benign and malignant thyroid C-cell tumors in mice and rats and that the human relevance of this finding is unknown. Counsel patients to report symptoms of thyroid tumors (eg, a lump in the neck, dysphagia, persistent hoarseness, dyspnea) to their health care provider.
- Advise patients of the potential risk of dehydration due to GI adverse reactions and to take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function, which in some cases may require dialysis.
- Inform patients that persistent severe abdominal pain, which may radiate to the back and may (or may not) be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue liraglutide promptly and to contact their health care provider if persistent severe abdominal pain occurs.
- Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of liraglutide.
- Counsel patients that they should never share a liraglutide pen with another person, even if the needle is changed. Sharing of the pen between patients may pose a risk of transmission of infection.
- Inform patients of the potential risks and benefits of liraglutide and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA 1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress, such as fever, trauma, infection, or surgery, medication requirements may change; advise patients to seek medical advice promptly.
- Advise patients that the most common side effects of liraglutide are headache, nausea, and diarrhea. Nausea is most common when first starting liraglutide, but decreases over time in the majority of patients and does not typically require discontinuation of liraglutide.
- Instruct patients to inform their health care provider or pharmacist if they develop any unusual symptom or if any known symptom persists or worsens.
- Inform patients not to take an extra dose of liraglutide to make up for a missed dose. If a dose is missed, the once-daily regimen should be resumed as prescribed with the next scheduled dose. If more than 2 days have elapsed since the last dose, advise patients to reinitiate at 0.6 mg to mitigate GI symptoms associated with reinitiation of treatment.
Copyright © 2009 Wolters Kluwer Health.