Drug Safety-related Labeling Changes (SrLC)

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SAXENDA (NDA-206321)

(LIRAGLUTIDE RECOMBINANT)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/20/2023 (SUPPL-16)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Post-Marketing Experience

Additions and/or revisions underlined:

…

Gastrointestinal Disorders

Acute pancreatitis, hemorrhagic and necrotizing pancreatitis, sometimes resulting in death, ileus

…

12/04/2020 (SUPPL-12)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

SAXENDA is contraindicated in:

• Patients with a personal or family history of medullary thyroid carcinoma (MTC) or patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)].

• Patients with a prior serious hypersensitivity reaction to liraglutide or to any of the excipients in SAXENDA [see Warnings and Precautions (5.7)].

5 Warnings and Precautions

5.2 Acute Pancreatitis

(Additions and/or revisions underlined)

Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide. After initiation of SAXENDA, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, SAXENDA should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, SAXENDA should not be restarted.

In SAXENDA clinical trials in adults, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3291 SAXENDA-treated patients and 2 (0.1%) of 1843 placebo-treated patients. In addition, there were 2 cases of acute pancreatitis in SAXENDA-treated patients who prematurely withdrew from these clinical trials, occurring 74 and 124 days after the last dose. There were 2 additional cases in SAXENDA-treated patients, 1 during an off-treatment follow-up period within 2 weeks of discontinuing SAXENDA, and 1 that occurred in a patient who completed treatment and was off-treatment for 106 days.

In a SAXENDA pediatric clinical trial, pancreatitis was not independently adjudicated. Pancreatitis was reported in 1 (0.8%) SAXENDA-treated patient and resulted in treatment discontinuation.

Liraglutide has been studied in a limited number of adult patients with a history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on SAXENDA.

5.4 Hypoglycemia

(Additions and/or revisions underlined)

Adult patients with type 2 diabetes mellitus on an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia with use of SAXENDA, including severe hypoglycemia. In patients with type 2 diabetes, monitor blood glucose prior to starting SAXENDA and during SAXENDA treatment [see Dosage and Administration (2) and Adverse Reactions (6.1)].

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 of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

In the pediatric clinical trial, patients did not have type 2 diabetes but were provided with blood glucose meters. Clinically significant hypoglycemia, defined as blood glucose <54 mg/dL, occurred in 1.6% of the SAXENDA- treated patients compared to 0.8% of placebo-treated patients [see Adverse Reactions (6.1)]. Inform all pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.5 Heart Rate Increase

(Additions and/or revisions underlined)

Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed with routine clinical monitoring in SAXENDA-treated adult patients compared to placebo in clinical trials. More patients treated with SAXENDA, compared with placebo, had changes from baseline at two consecutive visits of more than 10 bpm (34% versus 19%, respectively) and 20 bpm (5% versus 2%, respectively). At least one resting heart rate exceeding 100 bpm was recorded for 6% of SAXENDA-treated patients compared with 4% of placebo-treated patients, with this occurring at two consecutive study visits for 0.9% and 0.3%, respectively. Tachycardia was reported as an adverse reaction in 0.6% of SAXENDA-treated patients and in 0.1% of placebo-treated patients.

In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, SAXENDA treatment was associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo.

In a pediatric clinical trial, mean increases from baseline in resting heart rate of 3 to 7 bpm were observed with SAXENDA treatment.

5.8 Suicidal Behavior and Ideation

(Additions and/or revisions underlined)

In SAXENDA adult clinical trials, 9 (0.3%) of 3384 SAXENDA-treated patients and 2 (0.1%) of the 1941 placebo-treated patients reported suicidal ideation; one of these SAXENDA-treated patients attempted suicide.

In a SAXENDA pediatric clinical trial, 1 (0.8%) of the 125 SAXENDA-treated patients died by suicide. There was insufficient information to establish a causal relationship to SAXENDA.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of SAXENDA as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management have been established in pediatric patients aged 12 years and older with body weight above 60 kg and an initial BMI corresponding to 30 kg/m2 or greater for adults (obese) by international cut-offs (see Table 2). Use of SAXENDA for this indication is supported by a 56-week double- blind, placebo-controlled clinical trial in 251 pediatric patients aged 12 to 17 years, a pharmacokinetic study in pediatric patients, and studies in adults with obesity [see Clinical Pharmacology (12.3) and Clinical Studies (14.1,14.2)].

In the pediatric clinical trial, there was one death due to suicide in a SAXENDA-treated patient [see Warnings and Precautions (5.8)]; one SAXENDA-treated patient had an event of pancreatitis [see Warnings and Precautions (5.2)]; more episodes of hypoglycemia confirmed by self blood glucose monitoring occurred in SAXENDA-treated patients compared to placebo [see Warnings and Precautions (5.4) and Adverse Reactions (6.1); and mean increases in resting heart rate of 3 to 7 bpm from baseline were observed with SAXENDA- treated patients [see Warnings and Precautions (5.5)].

The safety and effectiveness of SAXENDA have not been established in patients less than 12 years of age.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Instructions

Advise patients to take SAXENDA exactly as prescribed. Instruct patients to follow the dose escalation schedule and to not take more than the recommended dose.

Instruct adult patients to discontinue SAXENDA if they have not achieved 4% weight loss by 16 weeks of treatment. Instruct pediatric patients 12 years of age and older to discontinue SAXENDA if they have not achieved a BMI reduction of 1% from baseline after 12 weeks on the maintenance dose.

Hypoglycemia

Inform pediatric patients of the risk of hypoglycemia and educate all patients on the signs and symptoms of hypoglycemia. Inform adult patients with type 2 diabetes mellitus on an insulin secretagogue (e.g., sulfonylurea) or insulin that they may have an increased risk of hypoglycemia when using SAXENDA and to report signs and/or symptoms of hypoglycemia to their healthcare provider.

12/04/2020 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

SAXENDA is contraindicated in:

• Patients with a personal or family history of medullary thyroid carcinoma (MTC) or patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)].

• Patients with a prior serious hypersensitivity reaction to liraglutide or to any of the excipients in SAXENDA [see Warnings and Precautions (5.7)].

5 Warnings and Precautions

5.2 Acute Pancreatitis

(Additions and/or revisions underlined)

Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide. After initiation of SAXENDA, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, SAXENDA should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, SAXENDA should not be restarted.

In SAXENDA clinical trials in adults, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3291 SAXENDA-treated patients and 2 (0.1%) of 1843 placebo-treated patients. In addition, there were 2 cases of acute pancreatitis in SAXENDA-treated patients who prematurely withdrew from these clinical trials, occurring 74 and 124 days after the last dose. There were 2 additional cases in SAXENDA-treated patients, 1 during an off-treatment follow-up period within 2 weeks of discontinuing SAXENDA, and 1 that occurred in a patient who completed treatment and was off-treatment for 106 days.

In a SAXENDA pediatric clinical trial, pancreatitis was not independently adjudicated. Pancreatitis was reported in 1 (0.8%) SAXENDA-treated patient and resulted in treatment discontinuation.

Liraglutide has been studied in a limited number of adult patients with a history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on SAXENDA.

5.4 Hypoglycemia

(Additions and/or revisions underlined)

Adult patients with type 2 diabetes mellitus on an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia with use of SAXENDA, including severe hypoglycemia. In patients with type 2 diabetes, monitor blood glucose prior to starting SAXENDA and during SAXENDA treatment [see Dosage and Administration (2) and Adverse Reactions (6.1)].

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 of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

In the pediatric clinical trial, patients did not have type 2 diabetes but were provided with blood glucose meters. Clinically significant hypoglycemia, defined as blood glucose <54 mg/dL, occurred in 1.6% of the SAXENDA- treated patients compared to 0.8% of placebo-treated patients [see Adverse Reactions (6.1)]. Inform all pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.5 Heart Rate Increase

(Additions and/or revisions underlined)

Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed with routine clinical monitoring in SAXENDA-treated adult patients compared to placebo in clinical trials. More patients treated with SAXENDA, compared with placebo, had changes from baseline at two consecutive visits of more than 10 bpm (34% versus 19%, respectively) and 20 bpm (5% versus 2%, respectively). At least one resting heart rate exceeding 100 bpm was recorded for 6% of SAXENDA-treated patients compared with 4% of placebo-treated patients, with this occurring at two consecutive study visits for 0.9% and 0.3%, respectively. Tachycardia was reported as an adverse reaction in 0.6% of SAXENDA-treated patients and in 0.1% of placebo-treated patients.

In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, SAXENDA treatment was associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo.

In a pediatric clinical trial, mean increases from baseline in resting heart rate of 3 to 7 bpm were observed with SAXENDA treatment.

5.8 Suicidal Behavior and Ideation

(Additions and/or revisions underlined)

In SAXENDA adult clinical trials, 9 (0.3%) of 3384 SAXENDA-treated patients and 2 (0.1%) of the 1941 placebo-treated patients reported suicidal ideation; one of these SAXENDA-treated patients attempted suicide.

In a SAXENDA pediatric clinical trial, 1 (0.8%) of the 125 SAXENDA-treated patients died by suicide. There was insufficient information to establish a causal relationship to SAXENDA.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of SAXENDA as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management have been established in pediatric patients aged 12 years and older with body weight above 60 kg and an initial BMI corresponding to 30 kg/m2 or greater for adults (obese) by international cut-offs (see Table 2). Use of SAXENDA for this indication is supported by a 56-week double- blind, placebo-controlled clinical trial in 251 pediatric patients aged 12 to 17 years, a pharmacokinetic study in pediatric patients, and studies in adults with obesity [see Clinical Pharmacology (12.3) and Clinical Studies (14.1,14.2)].

In the pediatric clinical trial, there was one death due to suicide in a SAXENDA-treated patient [see Warnings and Precautions (5.8)]; one SAXENDA-treated patient had an event of pancreatitis [see Warnings and Precautions (5.2)]; more episodes of hypoglycemia confirmed by self blood glucose monitoring occurred in SAXENDA-treated patients compared to placebo [see Warnings and Precautions (5.4) and Adverse Reactions (6.1); and mean increases in resting heart rate of 3 to 7 bpm from baseline were observed with SAXENDA- treated patients [see Warnings and Precautions (5.5)].

The safety and effectiveness of SAXENDA have not been established in patients less than 12 years of age.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Instructions

Advise patients to take SAXENDA exactly as prescribed. Instruct patients to follow the dose escalation schedule and to not take more than the recommended dose.

Instruct adult patients to discontinue SAXENDA if they have not achieved 4% weight loss by 16 weeks of treatment. Instruct pediatric patients 12 years of age and older to discontinue SAXENDA if they have not achieved a BMI reduction of 1% from baseline after 12 weeks on the maintenance dose.

Hypoglycemia

Inform pediatric patients of the risk of hypoglycemia and educate all patients on the signs and symptoms of hypoglycemia. Inform adult patients with type 2 diabetes mellitus on an insulin secretagogue (e.g., sulfonylurea) or insulin that they may have an increased risk of hypoglycemia when using SAXENDA and to report signs and/or symptoms of hypoglycemia to their healthcare provider.

12/04/2020 (SUPPL-14)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

SAXENDA is contraindicated in:

• Patients with a personal or family history of medullary thyroid carcinoma (MTC) or patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)].

• Patients with a prior serious hypersensitivity reaction to liraglutide or to any of the excipients in SAXENDA [see Warnings and Precautions (5.7)].

5 Warnings and Precautions

5.2 Acute Pancreatitis

(Additions and/or revisions underlined)

Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide. After initiation of SAXENDA, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, SAXENDA should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, SAXENDA should not be restarted.

In SAXENDA clinical trials in adults, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3291 SAXENDA-treated patients and 2 (0.1%) of 1843 placebo-treated patients. In addition, there were 2 cases of acute pancreatitis in SAXENDA-treated patients who prematurely withdrew from these clinical trials, occurring 74 and 124 days after the last dose. There were 2 additional cases in SAXENDA-treated patients, 1 during an off-treatment follow-up period within 2 weeks of discontinuing SAXENDA, and 1 that occurred in a patient who completed treatment and was off-treatment for 106 days.

In a SAXENDA pediatric clinical trial, pancreatitis was not independently adjudicated. Pancreatitis was reported in 1 (0.8%) SAXENDA-treated patient and resulted in treatment discontinuation.

Liraglutide has been studied in a limited number of adult patients with a history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on SAXENDA.

5.4 Hypoglycemia

(Additions and/or revisions underlined)

Adult patients with type 2 diabetes mellitus on an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia with use of SAXENDA, including severe hypoglycemia. In patients with type 2 diabetes, monitor blood glucose prior to starting SAXENDA and during SAXENDA treatment [see Dosage and Administration (2) and Adverse Reactions (6.1)].

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 of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

In the pediatric clinical trial, patients did not have type 2 diabetes but were provided with blood glucose meters. Clinically significant hypoglycemia, defined as blood glucose <54 mg/dL, occurred in 1.6% of the SAXENDA- treated patients compared to 0.8% of placebo-treated patients [see Adverse Reactions (6.1)]. Inform all pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.5 Heart Rate Increase

(Additions and/or revisions underlined)

Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed with routine clinical monitoring in SAXENDA-treated adult patients compared to placebo in clinical trials. More patients treated with SAXENDA, compared with placebo, had changes from baseline at two consecutive visits of more than 10 bpm (34% versus 19%, respectively) and 20 bpm (5% versus 2%, respectively). At least one resting heart rate exceeding 100 bpm was recorded for 6% of SAXENDA-treated patients compared with 4% of placebo-treated patients, with this occurring at two consecutive study visits for 0.9% and 0.3%, respectively. Tachycardia was reported as an adverse reaction in 0.6% of SAXENDA-treated patients and in 0.1% of placebo-treated patients.

In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, SAXENDA treatment was associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo.

In a pediatric clinical trial, mean increases from baseline in resting heart rate of 3 to 7 bpm were observed with SAXENDA treatment.

5.8 Suicidal Behavior and Ideation

(Additions and/or revisions underlined)

In SAXENDA adult clinical trials, 9 (0.3%) of 3384 SAXENDA-treated patients and 2 (0.1%) of the 1941 placebo-treated patients reported suicidal ideation; one of these SAXENDA-treated patients attempted suicide.

In a SAXENDA pediatric clinical trial, 1 (0.8%) of the 125 SAXENDA-treated patients died by suicide. There was insufficient information to establish a causal relationship to SAXENDA.

03/25/2020 (SUPPL-11)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions and revisions underlined)

…

Hypoglycemia

 

Patients with Type 2 Diabetes

In a clinical trial in patients with type 2 diabetes mellitus and overweight (excess weight) or obesity, severe hypoglycemia (defined as requiring the assistance of another person) occurred in 3 (0.7%) of 422 Saxenda- treated patients (all taking a sulfonylurea) and in none of the 212 placebo-treated patients. In this trial, among patients taking a sulfonylurea, hypoglycemia defined as a plasma glucose less than 54 mg/dL with or without symptoms occurred in 31 (28.2%) of 110 Saxenda-treated patients and 7 (12.7%) of 55 placebo-treated patients. Because Saxenda can lower blood glucose, the doses of sulfonylureas were reduced by 50% at the beginning of the trial per protocol. The frequency of hypoglycemia may be higher if the dose of sulfonylurea is not reduced. Among patients not taking a sulfonylurea, blood glucose less than 54 mg/dL with or without symptoms occurred in 22 (7.1%) of 312 Saxenda-treated patients and 7 (4.5%) of 157 placebo-treated patients.

 

In a Saxenda clinical trial in patients with overweight (excess weight) or obesity with type 2 diabetes mellitus treated with basal insulin and Saxenda in combination with a reduced-calorie diet and increased physical activity and up to 2 oral anti-diabetes medications, severe hypoglycemia was reported by 3 (1.5%) of 195 Saxenda-treated patients and 2 (1.0%) of 197 placebo-treated patients. No meaningful difference in hypoglycemia, defined as blood glucose less than 54 mg/dL with or without symptoms, was reported between groups.

Patients without Type 2 Diabetes

…

10/19/2018 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Acute Pancreatitis

(Additions and/or revisions are underlined)

Liraglutide has been studied in a limited number of patients with a history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on Saxenda.

5.7 Hypersensitivity Reactions

(Additions and/or revisions are underlined)

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-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with Saxenda.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to labeling)

04/26/2017 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Acute Pancreatitis

In Saxenda clinical trials, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3291 Saxenda-treated patients and 2 (0.1%) of 1843 placebo-treated patients. In addition, there were 2 cases of acute pancreatitis in Saxenda-treated patients who prematurely withdrew from these clinical trials, occurring 74 and 124 days after the last dose. There were 2 additional cases in Saxenda-treated patients, 1 during an off-treatment follow-up period within 2 weeks of discontinuing Saxenda, and 1 that occurred in a patient who completed treatment and was off-treatment for 106 days.

5.3 Acute Gallbladder Disease

In Saxenda clinical trials, 2.2% of Saxenda-treated patients reported adverse events of cholelithiasis versus 0.8% of placebo-treated patients. The incidence of cholecystitis was 0.8% in Saxenda-treated patients versus 0.4% in placebo-treated patients.

5.8 Suicidal Behavior and Ideation

In Saxenda clinical trials, 9 (0.3%) of 3384 Saxenda-treated patients and 2 (0.1%) of the 1941 placebo-treated

patients …

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Baseline characteristics included a mean age of 47 years, 71% women, 85% white, 39% with hypertension, 15% with type 2 diabetes, 34% with dyslipidemia, 29% with a BMI greater than 40 kg/m2, and 9% with cardiovascular disease. In one of the 56-week trials, subsets of patients (with abnormal glucose measurements at randomization) were enrolled for a placebo-controlled 160-week period instead, followed by a 12-week off-treatment follow-up. For those participating in this 160-week period, patients received Saxenda for mean treatment duration of 110 weeks (median, 159 weeks). For all trials, dosing was initiated and increased weekly to reach the 3 mg dose.

Breast Cancer

In Saxenda clinical trials, breast cancer confirmed by adjudication was reported in 17 (0.7%) of 2379 …

Papillary Thyroid Cancer

In Saxenda clinical trials, papillary thyroid carcinoma confirmed by adjudication was reported in 8 (0.2%) of

3291 …

Colorectal Neoplasms

In Saxenda clinical trials, benign colorectal neoplasms (mostly colon adenomas) confirmed by adjudication were reported in 20 (0.6%) of 3291 Saxenda-treated patients compared with 7 (0.4%) of 1843 placebo-treated patients. Six positively adjudicated cases of malignant colorectal carcinoma neoplasms were reported in 5 Saxenda-treated patients (0.2%, mostly adenocarcinomas) and 1 in a placebo-treated patient (0.1%, neuroendocrine tumor of the rectum).

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; revised as below:

Risk Summary

SAXENDA is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. There are no available data with liraglutide in pregnant women to inform a drug associated risk for major birth defects and miscarriage. SAXENDA should not be used during pregnancy. If a patient wishes to become pregnant, or pregnancy occurs, treatment with SAXENDA should be discontinued.

Animal reproduction studies identified increased adverse embryofetal 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 3 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 and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryofetal risk

A minimum weight gain, and no weight loss, is recommended for all pregnant women, including those who are already overweight or obese, due to the necessary weight gain that occurs in maternal tissues during pregnancy.

Animal Data

Liraglutide has been shown to be teratogenic in rats at or above 0.8-times systemic exposures in obese humans resulting from the maximum recommended human dose (MRHD) of 3 mg/day based on plasma area under the time-concentration curve (AUC) comparison. Liraglutide has been shown to cause reduced growth and increased total major abnormalities in rabbits at systemic exposures below exposure in obese humans at the MRHD based on plasma AUC comparison.

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 exposure in obese

humans 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 exposure in obese humans at the MRHD of 3 mg/day at all doses, based on plasma AUC comparison. 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), greater than or equal to 0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), greater than or equal to 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 exposure in obese humans at the MRHD of 3 mg/day based on plasma AUC comparison. 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 F2 generation rats descended from liraglutide-treated rats compared to F2 generation rats descended from controls, but differences did not reach statistical significance for any group.

8.2 Lactation

PLLR conversion; revised as below:

Risk Summary

There are no data on the presence of liraglutide in human milk, the effects on the breastfed infant, or effects on milk production.  Liraglutide was present in the milk of lactating rats.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SAXENDA and any potential adverse effects on the breastfed infant from SAXENDA or from the underlying maternal condition.

Data

In lactating rats, liraglutide was present unchanged in milk at concentrations approximately 50% of maternal plasma concentrations.

04/26/2017 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Acute Pancreatitis

In Saxenda clinical trials, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3291 Saxenda-treated patients and 2 (0.1%) of 1843 placebo-treated patients. In addition, there were 2 cases of acute pancreatitis in Saxenda-treated patients who prematurely withdrew from these clinical trials, occurring 74 and 124 days after the last dose. There were 2 additional cases in Saxenda-treated patients, 1 during an off-treatment follow-up period within 2 weeks of discontinuing Saxenda, and 1 that occurred in a patient who completed treatment and was off-treatment for 106 days.

5.3 Acute Gallbladder Disease

In Saxenda clinical trials, 2.2% of Saxenda-treated patients reported adverse events of cholelithiasis versus 0.8% of placebo-treated patients. The incidence of cholecystitis was 0.8% in Saxenda-treated patients versus 0.4% in placebo-treated patients.

5.8 Suicidal Behavior and Ideation

In Saxenda clinical trials, 9 (0.3%) of 3384 Saxenda-treated patients and 2 (0.1%) of the 1941 placebo-treated

patients …

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Baseline characteristics included a mean age of 47 years, 71% women, 85% white, 39% with hypertension, 15% with type 2 diabetes, 34% with dyslipidemia, 29% with a BMI greater than 40 kg/m2, and 9% with cardiovascular disease. In one of the 56-week trials, subsets of patients (with abnormal glucose measurements at randomization) were enrolled for a placebo-controlled 160-week period instead, followed by a 12-week off-treatment follow-up. For those participating in this 160-week period, patients received Saxenda for mean treatment duration of 110 weeks (median, 159 weeks). For all trials, dosing was initiated and increased weekly to reach the 3 mg dose.

Breast Cancer

In Saxenda clinical trials, breast cancer confirmed by adjudication was reported in 17 (0.7%) of 2379 …

Papillary Thyroid Cancer

In Saxenda clinical trials, papillary thyroid carcinoma confirmed by adjudication was reported in 8 (0.2%) of

3291 …

Colorectal Neoplasms

In Saxenda clinical trials, benign colorectal neoplasms (mostly colon adenomas) confirmed by adjudication were reported in 20 (0.6%) of 3291 Saxenda-treated patients compared with 7 (0.4%) of 1843 placebo-treated patients. Six positively adjudicated cases of malignant colorectal carcinoma neoplasms were reported in 5 Saxenda-treated patients (0.2%, mostly adenocarcinomas) and 1 in a placebo-treated patient (0.1%, neuroendocrine tumor of the rectum).

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; revised as below:

Risk Summary

SAXENDA is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. There are no available data with liraglutide in pregnant women to inform a drug associated risk for major birth defects and miscarriage. SAXENDA should not be used during pregnancy. If a patient wishes to become pregnant, or pregnancy occurs, treatment with SAXENDA should be discontinued.

Animal reproduction studies identified increased adverse embryofetal 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 3 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 and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryofetal risk

A minimum weight gain, and no weight loss, is recommended for all pregnant women, including those who are already overweight or obese, due to the necessary weight gain that occurs in maternal tissues during pregnancy.

Animal Data

Liraglutide has been shown to be teratogenic in rats at or above 0.8-times systemic exposures in obese humans resulting from the maximum recommended human dose (MRHD) of 3 mg/day based on plasma area under the time-concentration curve (AUC) comparison. Liraglutide has been shown to cause reduced growth and increased total major abnormalities in rabbits at systemic exposures below exposure in obese humans at the MRHD based on plasma AUC comparison.

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 exposure in obese

humans 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 exposure in obese humans at the MRHD of 3 mg/day at all doses, based on plasma AUC comparison. 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), greater than or equal to 0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), greater than or equal to 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 exposure in obese humans at the MRHD of 3 mg/day based on plasma AUC comparison. 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 F2 generation rats descended from liraglutide-treated rats compared to F2 generation rats descended from controls, but differences did not reach statistical significance for any group.

8.2 Lactation

PLLR conversion; revised as below:

Risk Summary

There are no data on the presence of liraglutide in human milk, the effects on the breastfed infant, or effects on milk production.  Liraglutide was present in the milk of lactating rats.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SAXENDA and any potential adverse effects on the breastfed infant from SAXENDA or from the underlying maternal condition.

Data

In lactating rats, liraglutide was present unchanged in milk at concentrations approximately 50% of maternal plasma concentrations.

09/22/2016 (SUPPL-3)

Approved Drug Label (PDF)

Boxed Warning

WARNING: RISK OF THYROID C-CELL TUMORS

Change in 2nd bullet, 1st sentence:

• Saxenda 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 of MTC with use of Saxenda … (addition is underlined).

5 Warnings and Precautions

5.1 Risk of Thyroid C-cell Tumors

• Saxenda 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 Saxenda and inform them of symptoms of thyroid tumors...(additions underlined)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Before taking Saxenda, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had problems with your pancreas, kidneys or liver. (addition underlined)

• Reformatted; please refer to label.

 

Patient Counseling Information

• Reformatted; subsection numbers have been removed. Headings and information stay the same; please refer to label.