Liraglutide

• •
  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 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.

  ), Nonclinical Toxicology (

  13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

  A 104-week carcinogenicity study was conducted in male and female CD-1 mice at doses of 0.03, 0.2, 1.0, and 3.0 mg/kg/day liraglutide administered by bolus subcutaneous injection yielding systemic exposures 0.2-, 2-, 10- and 45-times the human exposure, respectively, at the MRHD of 1.8 mg/day based on plasma AUC comparison. A dose-related increase in benign thyroid C-cell adenomas was seen in the 1.0 and the 3.0 mg/kg/day groups with incidences of 13% and 19% in males and 6% and 20% in females, respectively. C-cell adenomas did not occur in control groups or 0.03 and 0.2 mg/kg/day groups. Treatment-related malignant C-cell carcinomas occurred in 3% of females in the 3.0 mg/kg/day group. Thyroid C-cell tumors are rare findings during carcinogenicity testing in mice. A treatment-related increase in fibrosarcomas was seen on the dorsal skin and subcutis, the body surface used for drug injection, in males in the 3 mg/kg/day group. These fibrosarcomas were attributed to the high local concentration of drug near the injection site. The liraglutide concentration in the clinical formulation (6 mg/mL) is 10-times higher than the concentration in the formulation used to administer 3 mg/kg/day liraglutide to mice in the carcinogenicity study (0.6 mg/mL).

  A 104-week carcinogenicity study was conducted in male and female Sprague Dawley rats at doses of 0.075, 0.25 and 0.75 mg/kg/day liraglutide administered by bolus subcutaneous injection with exposures 0.5-, 2- and 8-times the human exposure, respectively, resulting from the MRHD based on plasma AUC comparison. A treatment-related increase in benign thyroid C-cell adenomas was seen in males in 0.25 and 0.75 mg/kg/day liraglutide groups with incidences of 12%, 16%, 42%, and 46% and in all female liraglutide-treated groups with incidences of 10%, 27%, 33%, and 56% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. A treatment-related increase in malignant thyroid C-cell carcinomas was observed in all male liraglutide-treated groups with incidences of 2%, 8%, 6%, and 14% and in females at 0.25 and 0.75 mg/kg/day with incidences of 0%, 0%, 4%, and 6% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. Thyroid C-cell carcinomas are rare findings during carcinogenicity testing in rats.

  Studies in mice demonstrated that liraglutide-induced C-cell proliferation was dependent on the GLP-1 receptor and that liraglutide did not cause activation of the REarranged during Transfection (RET) proto-oncogene in thyroid C-cells.

  Human relevance of thyroid C-cell tumors in mice and rats is unknown and has not been determined by clinical studies or nonclinical studies

  [see Boxed Warning, Warnings and Precautions (5.1)]

  .

  Liraglutide was negative with and without metabolic activation in the Ames test for mutagenicity and in a human peripheral blood lymphocyte chromosome aberration test for clastogenicity. Liraglutide was negative in repeat-dose

  in vivo

  micronucleus tests in rats.

  In rat fertility studies using subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide, males were treated for 4 weeks prior to and throughout mating and females were treated 2 weeks prior to and throughout mating until gestation day 17. No direct adverse effects on male fertility was observed at doses up to 1.0 mg/kg/day, a high dose yielding an estimated systemic exposure 11-times the human exposure at the MRHD, based on plasma AUC. In female rats, an increase in early embryonic deaths occurred at 1.0 mg/kg/day. Reduced body weight gain and food consumption were observed in females at the 1.0 mg/kg/day dose.

  )]

  .
• •
  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 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).

  ), Warnings and Precautions (

  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.

  )]

  .

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.

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.

• •
  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 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.
  .
• •
  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 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.
  .
• •Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles
  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.
  .
• •Inject liraglutide subcutaneously once-daily at any time of day, independently of meals, in the abdomen, thigh or upper arm
  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.
  .
• •When using liraglutide with insulin, administer as separate injections. Never mix.
  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.
  .

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.

• •Pregnancy: Liraglutide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus
  8.1 Pregnancy

  Risk Summary

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

  [see Animal Data]

  .

  The estimated background risk of major birth defects for women with uncontrolled pre-gestational diabetes (Hemoglobin A_1c>7) is 6 to 10%. The major birth defect rate has been reported to be as high as 20 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 2 to 4% and 15 to 20%, respectively.

  Clinical Considerations

  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.

  Animal Data

  Female rats given subcutaneous doses of 0.1, 0.25 and 1.0 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 1.0 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 F₂generation rats descended from liraglutide-treated rats compared to F₂generation rats descended from controls, but differences did not reach statistical significance for any group.
  .