VICTOZA

Victoza contains liraglutide, a synthetic analog of human glucagon-like peptide-1(GLP-1) and acts as a GLP-1 receptor agonist.

Label, 1 Liraglutide is 97% similar to native human GLP-1, differing primarily 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 of the peptide precursor.

Liraglutide was granted FDA approval on

January 25, 2010.

Saxenda, a formulation of liraglutide intended for weight loss, is indicated as an adjunct to diet and exercise for chronic weight management in adult patients who are obese (BMI≥30 kg/m 2 ), or who are overweight (BMI≥27 kg/m 2 ) and have at least one weight-related comorbidity.

It is also indicated for chronic weight management in pediatric patients ≥12 years old who weigh ≥60 kg and have an initial BMI corresponding to obesity based on international cut-offs.

Victoza, a formulation of liraglutide used in diabetes, is indicated as an adjunct to diet and exercise to improve glycemic control in patients ≥10 years old with type 2 diabetes mellitus.

It is also indicated to reduce the risk of major adverse cardiovascular events in adult patients with type 2 diabetes and established cardiovascular disease.

Liraglutide is also available in combination with insulin degludec as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus.

Liraglutide is a once-daily

GLP-1 derivative for the treatment of type 2 diabetes Label, 2.

The prolonged action of liraglutide is achieved by attaching a fatty acid molecule at position of the GLP-1 molecule, enabling it to bind reversibly to albumin within the subcutaneous tissue and bloodstream and be released slowly over time Label, 2, 3.

Binding with albumin results in slower degradation and reduced elimination of liraglutide from the circulation by the kidneys compared to GLP-1 2, 3.

The effect of liraglutide is the increased secretion of insulin and decreased secretion of glucagon in response to glucose as well as slower gastric emptying Label.

Liraglutide also does not adversely affect glucagon secretion in response to low blood sugar Label, 2.

Bioavailability of liraglutide after subcutaneous injection is approximately 55% Label and maximum concentrations are reached after 11.7 hours 1.

Liraglutide is less sensitive to metabolism than the endogenous GLP-1 and so is more slowly metabolized by dipeptidyl peptidase-4 and neutral endopeptidase to various smaller polypeptides which have not all been structurally determined 1.

A portion of

Liraglutide may be completely metabolized to carbon dioxide and water 1.

6% excreted in urine and 5% excreted in feces 1.

Terminal half life of 13 hours 1.

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There is no clinical significance of race or ethnicity on the safety or efficacy of liraglutide Label.

Geriatric patients do not experience clinically significant differences in pharmacokinetics though patients at an especially advanced age may be more susceptible to adverse effects Label.

Female patients have reduced clearance of liraglutide but no dose adjustment is necessary Label.

The risk and benefit of liraglutide in pregnancy must be weighed before prescribing Label.

In animal studies, liraglutide is associated with an increased risk of embryonic death and fetal abnormalities though an HbA1c > 7 is also associated with a 20-25% risk of birth defects Label.

In animal studies, liraglutide is present in the milk of lactating rats at half the plasma concentration of the mother but these results may not translate to humans Label.

Because it is not known if liraglutide is present in breast milk and the effects on infants are also unknown, the risk and benefit of liraglutide in breastfeeding must be considered before prescribing Label.

Liraglutide was shown to be safe and effective in patients up to 160 kg in weight but has not been studied in patients at a higher weight Label.

A patient's weight significantly affects the pharmacokinetics of liraglutide Label.

Liraglutide has not been investigated for use in pediatric patients Label.

No dosage adjustments are necessary in patients with renal impairment but studies have not been performed in patients with end stage renal disease Label.

There are no recommendations on dosage adjustment in patients with hepatic impairment, though caution should still be exercised when prescribing to this population Label.

Liraglutide injection 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) . serious hypersensitivity reaction to liraglutide or to any of the excipients in liraglutide injection.

Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide injection.

Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.

Patients with a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide injection.

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.

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.

Inspect visually prior to each injection.

Only use if solution is clear, colorless, and contains no particles.

Inject liraglutide injection subcutaneously once-daily at any time of day, independently of meals, in the abdomen, thigh or upper arm.

When using liraglutide injection with insulin, administer as separate injections.

Never mix. 2.1 Recommended Dosage Adult Patients The recommended starting dosage of liraglutide injection is 0.6 mg injected subcutaneously once daily for one week.

The 0.6 mg once daily dosage is intended to reduce the risk of gastrointestinal adverse reactions 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.

Aged 10 Years and Older The recommended starting dosage of liraglutide injection 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, to reduce the risk of gastrointestinal adverse reactions.

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 injection 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 injection dose, reinitiate liraglutide injection at 0.6 mg once daily to reduce the risk of gastrointestinal adverse reactions associated with reinitiation of treatment.

Upon reinitiation, liraglutide injection should be titrated at the discretion of the healthcare provider. 2.3 Important Administration Instructions Inspect visually prior to each injection.

Inject liraglutide injection subcutaneously once daily at any time of day, independently of meals.

Inject liraglutide injection 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.

Never mix.

It is acceptable to inject liraglutide injection and insulin in the same body region but the injections should not be adjacent to each other.

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 70748-346-02 3 x Liraglutide Injection Pen NDC 70748-346-03 Recommended Storage Prior to first use, liraglutide injection should be stored in a refrigerator between 36ºF to 46ºF (2ºC 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°F to 86°F (15°C to 30°C) or in a refrigerator 36°F to 46°F (2°C 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.

Based on animal reproduction studies, there may be risks to the fetus from exposure to liraglutide injection during pregnancy.

Liraglutide injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal reproduction studies identified increased adverse developmental outcomes from exposure during pregnancy.

Liraglutide exposure was associated with early embryonic deaths and an imbalance in some fetal abnormalities in pregnant rats administered liraglutide during organogenesis at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 1.8 mg/day. In pregnant rabbits administered liraglutide during organogenesis, decreased fetal weight and an increased incidence of major fetal abnormalities were seen at exposures below the human exposures at the MRHD.

The estimated background risk of major birth defects for women with uncontrolled pre-gestational diabetes (Hemoglobin A 1C >7) is to 10%.

The major birth defect rate has been reported to be as high as to 25% in women with a Hemoglobin A 1C >10.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Disease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications.

Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Female rats given subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide beginning 2 weeks before mating through gestation day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the human exposure at the MRHD based on plasma AUC comparison.

The number of early embryonic deaths in the 1 mg/kg/day group increased slightly.

Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses.

Mottled liver and minimally kinked ribs occurred at the highest dose.

The incidence of fetal malformations in liraglutide-treated groups exceeding concurrent and historical controls were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day. Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation day 6 through day 18 inclusive, had estimated systemic exposures less than the human exposure at the MRHD of 1.8 mg/day at all doses, based on plasma AUC.

Liraglutide decreased fetal weight and dose-dependently increased the incidence of total major fetal abnormalities at all doses.

The incidence of malformations exceeded concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), ≥ 0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), ≥ 0.025 mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood vessels).

Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor skeletal variations were observed.

Visceral abnormalities occurred in blood vessels, lung, liver, and esophagus.

Bilobed or bifurcated gallbladder was seen in all treatment groups, but not in the control group.

In pregnant female rats given subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide from gestation day 6 through weaning or termination of nursing on lactation day 24, estimated systemic exposures were 0.8-, 3-, and 11-times human exposure at the MRHD of 1.8 mg/day, based on plasma AUC.

A slight delay in parturition was observed in the majority of treated rats.

Group mean body weight of neonatal rats from liraglutide-treated dams was lower than neonatal rats from control group dams.

Bloody scabs and agitated behavior occurred in male rats descended from dams treated with 1 mg/kg/day liraglutide.

Group mean body weight from birth to postpartum day 14 trended lower in F 2 generation rats descended from liraglutide-treated rats compared to F 2 generation rats descended from controls, but differences did not reach statistical significance for any group.

The safety and effectiveness of liraglutide injection as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients 10 years of age and older.

Use of liraglutide injection for this indication is supported by a 26-week placebo-controlled clinical trial and a 26-week open-label extension in 134 pediatric patients to 17 years of age with type 2 diabetes mellitus, a pediatric pharmacokinetic study, and studies in adults with type 2 diabetes mellitus.

The risk of hypoglycemia was higher with liraglutide injection in pediatric patients regardless of insulin and/or metformin use.

The safety and effectiveness of liraglutide injection have not been established in pediatric patients less than 10 years of age.

In the liraglutide injection treatment arms of the glycemic control trials, a total of 832 (19.3%) of the patients were to 74 years of age and 145 (3.4%) were 75 years of age and over.

No overall differences in safety or effectiveness for liraglutide injection have been observed between patients 65 years of age and older and younger patients.