Liraglutide

5 WARNINGS AND PRECAUTIONS Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including liraglutide injection. Discontinue if pancreatitis is suspected. ( 5.2 ) Never Share a liraglutide injection Pen Between Patients, even if the needle is changed. ( 5.3 ) Hypoglycemia : Adult patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with liraglutide injection regardless of insulin and/or metformin use. Reduction in the dose of insulin secretagogues or insulin may be necessary. ( 5.4 ) A cute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.5 ) S evere Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe. Liraglutide injection is not recommended in patients with severe gastroparesis. ( 5.6 ) Hypersensitivity Reactions : Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue liraglutide injection and promptly seek medical advice. ( 5.7 ) Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.8 ) Pulmonary Aspiration During General Anesthesia or Deep Sedation : Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.9 ) 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 injection 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 injection 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 injection use in humans. Liraglutide injection 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 injection 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 injection. 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. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including liraglutide [see Adverse Reactions (6)] . After initiation of liraglutide injection, observe patients carefully for signs and symptoms of acute pancreatitis which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue liraglutide injection and initiate appropriate management. 5.3 Never Share a Liraglutide Injection Pen Between Patients Liraglutide injection pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. 5.4 Hypoglycemia Adult patients receiving liraglutide injection in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with liraglutide injection regardless of insulin and/or metformin use. [see Adverse Reactions ( 6.1 ), Drug Interactions ( 7.2 )] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications and pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.5 Acute Kidney Injury Due to Volume Depletion There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with liraglutide injection [see Adverse Reactions ( 6.2 )] . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions ( 6.1 )] . Monitor renal function in patients reporting adverse reactions to liraglutide injection that could lead to volume depletion, especially during dosage initiation and escalation of liraglutide injection [see Use in Specific Populations ( 8.6 )] . 5.6 Severe Gastrointestinal Adverse Reactions Use of GLP-1 receptor agonists, including liraglutide, has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions ( 6 )] . In liraglutide injection clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving liraglutide injection (1.2 mg 4.4 %, 1.8 mg 4.2 %) than placebo (1.1 %). Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists. Liraglutide injection is not recommended in patients with severe gastroparesis. 5.7 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with liraglutide injection [see Adverse Reactions ( 6.2 )] . If a hypersensitivity reaction occurs, discontinue liraglutide injection; treat promptly per standard of care, and monitor until signs and symptoms resolve. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-receptor agonist because it is unknown whether such patients will be predisposed to these reactions with liraglutide injection. Liraglutide injection is contraindicated in patients who have had a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide injection [see Contraindications ( 4 )] . 5.8 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated. 5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation Liraglutide injection delays gastric emptying [see Clinical Pharmacology ( 12.2 )] . There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking liraglutide injection, including whether modifying preoperative fasting recommendations or temporarily discontinuing liraglutide injection could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking liraglutide injection.

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] Hypoglycemia [see Warnings and Precautions ( 5.4 )] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.5 )] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.6 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥5%) in clinical trials are nausea, diarrhea, vomiting, decreased appetite, dyspepsia, constipation. ( 6.1 ) Immunogenicity-related events, including urticaria, were more common among liraglutide injection-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. ( 12.6 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common Adverse Reactions The safety of liraglutide injection in patients with type 2 diabetes mellitus was evaluated in 5 glycemic control, placebo-controlled trials in adults and one trial of 52 weeks duration in pediatric patients 10 years of age and older [see Clinical Studies ( 14.1 )] . The data in Table 1 reflect exposure of 1,673 adult patients to liraglutide injection and a mean duration of exposure to liraglutide injection of 37.3 weeks. The mean age of adult patients was 58 years, 4% were 75 years or older and 54% were male. The population was 79% White, 6% Black or African American, 13% Asian; 4% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 9 years and a mean HbA 1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88% and moderately impaired in 12% of the pooled population. Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of liraglutide injection for the treatment of type 2 diabetes mellitus. These adverse reactions occurred more commonly on liraglutide injection than on placebo and occurred in at least 5% of patients treated with liraglutide injection. Overall, the type, and severity of adverse reactions in pediatric patients 10 years of age and older and above were comparable to that observed in the adult population. Table 1: Adverse reactions reported in ≥ 5% of Adult Patients Treated with Liraglutide Injection for Type 2 Diabetes Mellitus Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights. Placebo N=661 Liraglutide 1.2 mg N= 645 Liraglutide 1.8 mg N= 1024 Adverse Reaction (%) (%) (%) Nausea 5 18 20 Diarrhea 4 10 12 Headache 7 11 10 Nasopharyngitis 8 9 10 Vomiting 2 6 9 Decreased appetite 1 10 9 Dyspepsia 1 4 7 Upper Respiratory Tract Infection 6 7 6 Constipation 1 5 5 Back Pain 3 4 5 In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 . Other Adverse Reactions Gastrointestinal Adverse Reactions: In the pool of 5 glycemic control, placebo-controlled adult clinical trials, withdrawals due to gastrointestinal adverse reactions, occurred in 4.3% of liraglutide injection-treated patients and 0.5% of placebo-treated patients. Severe gastrointestinal adverse reactions were reported more frequently among patients receiving liraglutide injection (1.2 mg 4.4 %, 1.8 mg 4.2 %) than placebo (1.1 %). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2 to 3 months of the trials. Injection site reactions: Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of liraglutide injection-treated adult patients in the five double-blind, glycemic control trials of at least 26 weeks duration. Less than 0.2% of liraglutide injection-treated patients discontinued due to injection site reactions. Hypoglycemia: In 5 adult glycemic control, placebo-controlled clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 8 liraglutide injection-treated patients (7.5 events per 1,000 patient-years). Of these 8 liraglutide injection-treated patients, 7 patients were concomitantly using a sulfonylurea. Table 2: Adult Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in 26-Week Combination Therapy Placebo- controlled Trials “Patient not able to self-treat” is defined as an event requiring the assistance of another person for treatment. Placebo Comparator Liraglutide Injection Treatment Add-on to Metformin Placebo + Metformin (N = 121) Liraglutide Injection + Metformin (N = 724) Patient not able to self-treat 0 0.1 (0.001) Patient able to self-treat 2.5 (0.06) 3.6 (0.05) Add-on to Glimepiride Placebo + Glimepiride (N = 114) Liraglutide Injection + Glimepiride (N = 695) Patient not able to self-treat 0 0.1 (0.003) Patient able to self-treat 2.6 (0.17) 7.5 (0.38) Not classified 0 0.9 (0.05) Add-on to Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone (N = 175) Liraglutide Injection + Metformin + Rosiglitazone (N = 355) Patient not able to self-treat 0 0 Patient able to self-treat 4.6 (0.15) 7.9 (0.49) Not classified 1.1 (0.03) 0.6 (0.01) Add-on to Metformin + Glimepiride Placebo + Metformin + Glimepiride (N = 114) Liraglutide Injection + Metformin + Glimepiride (N = 230) Patient not able to self-treat 0 2.2 (0.06) Patient able to self-treat 16.7 (0.95) 27.4 (1.16) Not classified 0 0 In a 26-week placebo-controlled clinical trial in pediatric patients 10 years of age and older with a 26-week open-label extension, 21.2% of liraglutide injection-treated patients (mean age 14.6 years) with type 2 diabetes mellitus, had hypoglycemia with a blood glucose <54 mg/dL with or without symptoms (335 events per 1,000 patient years). No severe hypoglycemic episodes occurred in the liraglutide injection treatment group (severe hypoglycemia was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions). Papillary thyroid carcinoma: In adult glycemic control trials of liraglutide injection, there were 7 reported cases of papillary thyroid carcinoma in patients treated with liraglutide injection and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1,000 patient- years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Pancreatitis In glycemic control trials of liraglutide injection, there have been 13 cases of pancreatitis among liraglutide injection -treated patients and 1 case in a comparator (glimepiride) treated patient (2.7 vs. 0.5 cases per 1,000 patient-years). Nine of the 13 cases with liraglutide injection were reported as acute pancreatitis and four were reported as chronic pancreatitis. In one case in a liraglutide injection-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. Cholelithiasis and cholecystitis: In adult glycemic control trials of liraglutide injection, the incidence of cholelithiasis was 0.3% in both liraglutide injection- treated and placebo-treated patients. The incidence of cholecystitis was 0.2% in both liraglutide injection-treated and placebo-treated patients. Laboratory Tests Bilirubin: In the five adult glycemic control trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4% of liraglutide injection-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. Calcitonin: Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. At the end of the adult glycemic control trials, adjusted mean serum calcitonin concentrations were higher in liraglutide injection-treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. Between group differences in adjusted mean serum calcitonin values were approximately 0.1 ng/L or less. Among adult patients with pretreatment calcitonin 20 ng/L occurred in 0.7% of liraglutide injection-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients. The clinical significance of these findings is unknown. Lipase and Amylase: In one adult glycemic control trial in renal impairment patients, a mean increase of 33% for lipase and 15% for amylase from baseline was observed for liraglutide injection-treated patients while placebo-treated patients had a mean decrease in lipase of 3% and a mean increase in amylase of 1%. The clinical significance of elevations in lipase or amylase with liraglutide injection is unknown in the absence of other signs and symptoms of pancreatitis [see Warnings and Precautions ( 5.2 )]. Vital signs Liraglutide injection did not have adverse effects on blood pressure. Mean increases from baseline in heart rate of 2 to 3 beats per minute have been observed in adult patients treated with liraglutide injection compared to placebo. 6.2 Postmarketing Experience The following additional adverse reactions have been reported during post-approval use of liraglutide injection. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. G astrointestinal: Acute pancreatitis; hemorrhagic and necrotizing pancreatitis sometimes resulting in death; ileus, intestinal obstruction, severe constipation including fecal impaction, nausea, vomiting and diarrhea leading to dehydration H epatobiliary: Elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, cholelithiasis requiring cholecystectomy, hepatitis Hypersensitivity: Angioedema, anaphylactic reactions, pruritus N eoplasms: Medullary thyroid carcinoma Neurologic: Dysgeusia, dizziness, dysesthesia P ulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. Renal : Acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis; and increased serum creatinine Skin and subcutaneous tissue: Cutaneous amyloidosis, alopecia

8 USE IN SPECIFIC POPULATIONS Pregnancy: Liraglutide injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ( 8.1 ) 8.1 Pregnancy Risk Summary 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 (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 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. 8.2 Lactation Risk Summary There are no data on the presence of liraglutide injection in human milk, the effects on the breastfed infant, or the effects on milk production. Liraglutide was present in milk of lactating rats ( see Data) . Developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for liraglutide injection and any potential adverse effects on the breastfed infant from liraglutide injection or from the underlying maternal condition. Data In lactating rats, liraglutide was present unchanged in milk at concentrations approximately 50% of maternal plasma concentrations. 8.4 Pediatric Use 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 10 to 17 years of age with type 2 diabetes mellitus, a pediatric pharmacokinetic study, and studies in adults with type 2 diabetes mellitus [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.1 , 14.2 )] . The risk of hypoglycemia was higher with liraglutide injection in pediatric patients regardless of insulin and/or metformin use [see Adverse Reactions ( 6.1 )] . The safety and effectiveness of liraglutide injection have not been established in pediatric patients less than 10 years of age. 8.5 Geriatric Use In the liraglutide injection treatment arms of the glycemic control trials, a total of 832 (19.3%) of the patients were 65 to 74 years of age and 145 (3.4%) were 75 years of age and over [see Clinical Studies ( 14.1 )] . No overall differences in safety or effectiveness for liraglutide injection have been observed between patients 65 years of age and older and younger patients. 8.6 Renal Impairment No dose adjustment of liraglutide injection is recommended for patients with renal impairment [see Clinical Pharmacology ( 12.3 )]. The safety and efficacy of liraglutide injection was evaluated in a 26-week clinical study that included patients with moderate renal impairment (eGFR 30 to 60 mL/min/1.73 m 2 ) [see Clinical Studies ( 14.1 )]. There is limited experience with liraglutide injection in patients with end stage renal disease. 8.7 Hepatic Impairment There is limited experience in patients with mild, moderate or severe hepatic impairment. Therefore, liraglutide injection should be used with caution in this patient population. No dose adjustment of liraglutide injection is recommended for patients with hepatic impairment [see Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Risk Summary 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 (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 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.