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• Liraglutide causes dose-dependent and treatmentduration- dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether SAXENDA® 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) and Nonclinical Toxicology (13.1)].
• 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® 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 SAXENDA® [see Contraindications (4), Warnings and Precautions (5.1)].
SAXENDA® is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in:
• Adult patients with an initial body mass index (BMI) of [see Dosage and Administration (2.1)]:
• 30 kg/m2 or greater (obese), or
• 27 kg/m2 or greater (overweight) in the presence of at least
one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia)
• 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 (Cole Criteria, Table 2) [see Dosage and Administration (2.1)]
Limitations of Use
• SAXENDA® contains liraglutide and should not be coadministered with other liraglutide-containing products or with any other
GLP-1 receptor agonist (such as Ozempic).
• The safety and effectiveness of SAXENDA® in pediatric patients with type 2 diabetes have not been established.
• The safety and effectiveness of SAXENDA® in combination with other products intended for weight loss, including prescription
drugs, over-the-counter drugs, and herbal preparations, have not been established.
Select patients for SAXENDA® treatment as an adjunct to a reduced-calorie diet and increased physical activity for chronic
weight management based on the BMI values provided in Tables 1 and 2.
Adult and Pediatric Patients
BMI is calculated by dividing weight in (kilograms) by height (in meters) squared. A chart for determining BMI based on height and weight is provided in Table 1.
Pediatric Patients Aged 12 Years and Older BMI cut-offs for obesity in pediatric patients aged 12 years and older are presented in Table 2.
• Prior to initiation of SAXENDA®, train patients on proper
injection technique. Refer to the accompanying Instructions for
Use for complete administration instructions with illustrations.
• Inspect SAXENDA® visually prior to each injection. Only use if
solution is clear, colorless, and contains no particles.
Injection: 6 mg/mL clear, colorless solution in a 3 mL pre-filled,
single-patient-use pen that delivers doses of 0.6 mg, 1.2 mg,
1.8 mg, 2.4 mg, or 3 mg.
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 serious hypersensitivity reaction to liraglutide or
to any of the excipients in SAXENDA®. Serious hypersensitivity
reactions including anaphylactic reactions and angioedema
have been reported with SAXENDA® [see Warnings and
Precautions (5.7)].
• Pregnancy [see Use in Specific Populations (8.1)].
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 SAXENDA® 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.
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 (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 SAXENDA®. 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 greater than 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.
• Inject SAXENDA® subcutaneously once daily at any time of day,
without regard to the timing of meals.
• Inject SAXENDA® subcutaneously in the abdomen, thigh,
or upper arm. No dose 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)].
• If a dose is missed, resume the once-daily regimen as prescribed
with the next scheduled dose. Do not administer an extra dose or
increase the dose to make up for the missed dose.
• If more than 3 days have elapsed since the last SAXENDA®
dose, reinitiate SAXENDA® at 0.6 mg daily and follow the dose
escalation schedule in Table 3, to reduce the occurrence of
gastrointestinal adverse reactions associated with reinitiation of
treatment.
• Initiate SAXENDA® with a dose of 0.6 mg daily for one week.
Then follow the dose escalation schedule in Table 3 to minimize
gastrointestinal adverse reactions [see Adverse Reactions (6.1)].
Adult Patients
• For adults, the recommended dosage of SAXENDA® is 3 mg
daily, lower doses are for titration only.
• Discontinue SAXENDA® if the patient cannot tolerate the 3 mg
dose.
• If patients do not tolerate an increased dose during dose
escalation, consider delaying dose escalation for approximately
one additional week.
• Evaluate the change in body weight 16 weeks after initiating
SAXENDA® and discontinue SAXENDA® if the patient has not
lost at least 4% of baseline body weight, since it is unlikely that
the patient will achieve and sustain clinically meaningful weight
loss with continued treatment.
• In adult patients with type 2 diabetes, monitor blood glucose
prior to starting SAXENDA® and during SAXENDA® treatment.
Pediatric Patients
• For pediatric patients, the recommended maintenance dosage of
SAXENDA® is 3 mg daily. Pediatric patients who do not tolerate
3 mg daily may have their maintenance dose reduced to 2.4 mg
daily. Discontinue SAXENDA® if the patient cannot tolerate the
2.4 mg dose.
• If pediatric patients do not tolerate an increased dose during
dose escalation, the dose may also be lowered to the previous
level. Dose escalation for pediatric patients may take up to
8 weeks.
• Evaluate the change in BMI after 12 weeks on the maintenance
dose and discontinue SAXENDA® if the patient has not had a
reduction in BMI of at least 1% from baseline, since it is unlikely
that the patient will achieve and sustain clinically meaningful
weight loss with continued treatment.
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 of 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®.
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. The majority of SAXENDA®-treated patients with adverse
events of cholelithiasis and cholecystitis required cholecystectomy.
Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater in SAXENDA®-treated patients than in placebo-treated
patients even after accounting for the degree of weight loss. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.
5.4 Hypoglycemia
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
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.
Heart rate should be monitored at regular intervals consistent with
usual clinical practice. Patients should inform health care providers
of palpitations or feelings of a racing heartbeat while at rest during
SAXENDA® treatment. For patients who experience a sustained
increase in resting heart rate while taking SAXENDA®, SAXENDA®
should be discontinued.
5.6 Renal Impairment
In patients treated with GLP-1 receptor agonists, including
SAXENDA®, there have been reports of acute renal failure and
worsening of chronic renal failure, sometimes requiring hemodialysis
[see Adverse Reactions (6.2)]. Some of these events were
reported in patients without known underlying renal disease.
A majority of the reported events occurred in patients who had
experienced nausea, vomiting, or diarrhea leading to volume
depletion. Some of the reported events occurred in patients
receiving one or more medications known to affect renal function
or volume status. Altered renal function has been reversed in many
of the reported cases with supportive treatment and discontinuation
of potentially causative agents, including liraglutide. Use caution
when initiating or escalating doses of SAXENDA® in patients with
renal impairment [see Use in Specific Populations (8.6)].
5.7 Hypersensitivity Reactions
There have been reports of serious hypersensitivity reactions (e.g.,
anaphylactic reactions and angioedema) in patients treated with
SAXENDA® [see Contraindications (4) and Adverse Reactions
(6.1, 6.2)]. If a hypersensitivity reaction occurs, the patient should
discontinue SAXENDA® and other suspect medications and
promptly seek medical advice.
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®.
5.8 Suicidal Behavior and Ideation
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®.
Patients treated with SAXENDA® should be monitored for the
emergence or worsening of depression, suicidal thoughts or
behavior, and/or any unusual changes in mood or behavior.
Discontinue SAXENDA® in patients who experience suicidal
thoughts or behaviors. Avoid SAXENDA® in patients with a history
of suicidal attempts or active suicidal ideation.
• Risk of Thyroid C-Cell Tumors [see Warnings and Precautions
(5.1)]
• Acute Pancreatitis [see Warnings and Precautions (5.2)]
• Acute Gallbladder Disease [see Warnings and Precautions (5.3)]
• Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic
Therapy [see Warnings and Precautions (5.4)]
• Heart Rate Increase [see Warnings and Precautions (5.5)]
• Renal Impairment [see Warnings and Precautions (5.6)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
• Suicidal Behavior and Ideation [see Warnings and Precautions
(5.8)]
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 studies
of another drug and may not reflect the rates observed in practice.
SAXENDA® was evaluated for safety in 5 double-blind, placebo
controlled trials that included 3384 overweight or obese adult
patients treated with SAXENDA® for a treatment period up to 56
weeks (3 trials), 52 weeks (1 trial), and 32 weeks (1 trial) and one
trial of 56 weeks in 125 pediatric patients with obesity aged 12 years
and older [see Clinical Studies (14.1, 14.2)]. All patients received
study drug in addition to a reduced-calorie diet and increased
physical activity counseling. In the adult trials, patients received
SAXENDA® for a mean treatment duration of 46 weeks (median, 56
weeks). 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, a subset of patients (with abnormal glucose measurements
at randomization) [see Clinical Studies (14.1)] 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 a mean treatment duration
of 110 weeks (median, 159 weeks). For all trials, dosing was initiated
and increased weekly to reach the 3 mg dose.
In adult clinical trials, 9.8% of patients treated with SAXENDA®
and 4.3% of patients treated with placebo prematurely discontinued
treatment as a result of adverse reactions. The most common
adverse reactions leading to discontinuation were nausea (2.9%
versus 0.2% for SAXENDA® and placebo, respectively), vomiting
(1.7% versus less than 0.1%), and diarrhea (1.4% versus 0%).
Adverse reactions reported in greater than or equal to 2% of
SAXENDA®-treated adult patients and more frequently than in
placebo-treated patients are shown in Table 4. Adverse reactions
reported in greater than or equal to 3% of SAXENDA®-treated
pediatric patients and more frequently than in placebo-treated
patients are shown in Table 5.
1 The most common reactions, each reported by 1% to 2.5%
of SAXENDA®-treated patients and more commonly than by
placebo-treated patients, included erythema, pruritus, and rash at
the injection site.
2 Defined as blood glucose <54 mg/dL with or without symptoms
of hypoglycemia in patients with type 2 diabetes not on
concomitant insulin (Study 2, SAXENDA® N=423, Placebo
N=212). See text below for further information regarding hypoglycemia
in patients with and without type 2 diabetes. T2DM = type
2 diabetes mellitus
1 Defined as blood glucose <70 mg/dL with symptoms of hypoglycemia.
Pediatric patients did not have type 2 diabetes mellitus.
See text below for more detailed hypoglycemia information.
Hypoglycemia
Adult Patients with Type 2 Diabetes
In a clinical trial in adult 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. The doses of sulfonylureas
were reduced by 50% at the beginning of the trial per protocol. 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 adult 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.
Adult Patients without Type 2 Diabetes
In SAXENDA® clinical trials in adult patients without type 2 diabetes mellitus, there was no systematic capturing or reporting of hypoglycemia;
patients were not provided with blood glucose meters
or hypoglycemia diaries. Spontaneously reported symptomatic episodes of unconfirmed hypoglycemia were reported by 46
(1.6%) of 2962 SAXENDA®-treated patients and 19 (1.1%) of 1729 placebo-treated patients. Fasting plasma glucose values obtained
at routine clinic visits less than 54 mg/dL, irrespective of hypoglycemic symptoms, occurred in 2 (0.1%) SAXENDA®-treated patients and 1 (0.1%) placebo-treated patients. In a 56-week placebo-controlled clinical trial of pediatric patients
without type 2 diabetes mellitus in which blood glucose meters were provided, 19 (15.2%) of SAXENDA®-treated patients had hypoglycemia
with a blood glucose less than 70 mg/dL with symptoms as
compared to 5 (4.0%) of placebo-treated patients. Four (4) events of hypoglycemia defined as a plasma glucose less than 54 mg/ dL occurred in 2 (1.6%) of 125 SAXENDA®-treated patients and 1 event occurred in 1 (0.8%) of 126 placebo-treated patients. No
severe hypoglycemic episodes, defined as requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, occurred in the SAXENDA® treatment
group.
Gastrointestinal Adverse Reactions
In the adult clinical trials, approximately 68% of SAXENDA®-treated
patients and 39% of placebo-treated patients reported gastrointestinal disorders; the most frequently reported was nausea (39% and 14% of patients treated with SAXENDA® and placebo, respectively).
The percentage of patients reporting nausea declined as treatment continued. Other common adverse reactions that occurred at a higher incidence among SAXENDA®-treated patients included diarrhea, constipation, vomiting, dyspepsia, abdominal pain, dry
mouth, gastritis, gastroesophageal reflux disease, flatulence,
eructation and abdominal distension. Most episodes of gastrointestinal events were mild or moderate and did not lead to discontinuation of therapy (6.2% with SAXENDA® versus 0.8% with placebo discontinued treatment as a result of gastrointestinal adverse reactions). There have been reports of gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, associated with volume depletion and renal impairment.
In a pediatric clinical trial, 8.0% of patients treated with SAXENDA® versus no patients who received placebo discontinued treatment as a result of gastrointestinal adverse reactions. Most adverse reactions leading to discontinuation were due to vomiting and nausea (4.8% and 3.2% of SAXENDA®-treated patients, respectively).
Asthenia, Fatigue, Malaise, Dysgeusia and Dizziness
Events of asthenia, fatigue, malaise, dysgeusia and dizziness were mainly reported within the first 12 weeks of treatment with SAXENDA® and were often co-reported with gastrointestinal events
such as nausea, vomiting, and diarrhea.
Immunogenicity
The detection of antibody formation is highly dependent on the
sensitivity and specificity of the assay. Additionally, the observed
incidence of antibody (including neutralizing antibody) positivity
in an assay may be influenced by several factors including assay
methodology, sample handling, timing of sample collection,
concomitant medications, and underlying disease. For these
reasons, the incidence of antibodies to SAXENDA® cannot be
directly compared with the incidence of antibodies of other products.
Patients treated with SAXENDA® may develop anti-liraglutide
antibodies. Anti-liraglutide antibodies were detected in 42 (2.8%)
of 1505 SAXENDA®-treated adult patients with a post-baseline
assessment. Antibodies that had a neutralizing effect on liraglutide
in an in vitro assay occurred in 18 (1.2%) of 1505 SAXENDA®-
treated patients. Presence of antibodies may be associated with a
higher incidence of injection site reactions and reports of low blood
glucose. In clinical trials, these events were usually classified as
mild and resolved while patients continued on treatment.
In a pediatric clinical trial, anti-liraglutide antibodies were detected
in 14 (12%) of 117 SAXENDA®-treated patients with a post-baseline
assessment; 5 (4.3%) had persistent antibodies as defined by
more than 2 antibody visits at least 16 weeks apart. Two patients
(1.7%) remained positive throughout the follow-up period; 1 (0.9%)
had antibodies cross reactive to native GLP-1. No patients had
neutralizing antibodies.
Allergic Reactions
Urticaria was reported in 0.7% of SAXENDA®-treated patients and
0.5% of placebo-treated patients. Anaphylactic reactions, asthma,
bronchial hyperreactivity, bronchospasm, oropharyngeal swelling,
facial swelling, angioedema, pharyngeal edema, type IV hypersensitivity
reactions have been reported in patients treated with
liraglutide in clinical trials. Cases of anaphylactic reactions with
additional symptoms such as hypotension, palpitations, dyspnea,
and edema have been reported with marketed use of liraglutide.
Anaphylactic reactions may potentially be life-threatening.
Breast Cancer
In SAXENDA® clinical trials in adults, breast cancer confirmed
by adjudication was reported in 17 (0.7%) of 2379 SAXENDA®-
treated women compared with 3 (0.2%) of 1300 placebo-treated
women, including invasive cancer (13 SAXENDA®- and 2 placebotreated
women) and ductal carcinoma in situ (4 SAXENDA®- and 1
placebo-treated woman). The majority of cancers were estrogenand
progesterone-receptor positive. There were too few cases
to determine whether these cases were related to SAXENDA®.
In addition, there are insufficient data to determine whether
SAXENDA® has an effect on pre-existing breast neoplasia.
Papillary Thyroid Cancer
In SAXENDA® clinical trials in adults, papillary thyroid carcinoma
confirmed by adjudication was reported in 8 (0.2%) of 3291
SAXENDA®-treated patients compared with no cases among 1843
placebo-treated patients. Four of these papillary thyroid carcinomas
were less than 1 cm in greatest diameter and 4 were diagnosed in
surgical pathology specimens after thyroidectomy prompted by
findings identified prior to treatment.
Colorectal Neoplasms
In SAXENDA® clinical trials in adults, 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 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).
Cardiac Conduction Disorders
In SAXENDA® clinical trials in adults, 11 (0.3%) of 3384
SAXENDA®-treated patients compared with none of the 1941
placebo-treated patients had a cardiac conduction disorder,
reported as first degree atrioventricular block, right bundle branch
block, or left bundle branch block.
Hypotension
Adverse reactions related to hypotension (hypotension, orthostatic
hypotension, circulatory collapse, and decreased blood pressure)
were reported more frequently with SAXENDA® (1.1%) compared
with placebo (0.5%) in SAXENDA® clinical trials in adults. Systolic
blood pressure decreases to less than 80 mmHg were observed in
4 (0.1%) SAXENDA®-treated patients compared with no placebotreated
patients. One of the SAXENDA®-treated patients had
hypotension associated with gastrointestinal adverse reactions and
renal failure [see Warnings and Precautions (5.6)].
Laboratory Abnormalities
Liver Enzymes
Increases in alanine aminotransferase (ALT) greater than or equal
to 10 times the upper limit of normal were observed in 5 (0.15%)
SAXENDA®-treated patients (two of whom had ALT greater than 20
and 40 times the upper limit of normal) compared with 1 (0.05%)
placebo-treated patient during the SAXENDA® clinical trials.
Because clinical evaluation to exclude alternative causes of ALT and
aspartate aminotransferase (AST) increases was not done in most
cases, the relationship to SAXENDA® is uncertain. Some increases
in ALT and AST were associated with other confounding factors
(such as gallstones).
Serum Calcitonin
Calcitonin, a biological marker of MTC, was measured throughout
the clinical development program [see Warnings and Precautions
(5.1)]. More patients treated with SAXENDA® in the clinical trials
were observed to have high calcitonin values during treatment,
compared with placebo. The proportion of patients with calcitonin
greater than or equal to 2 times the upper limit of normal at the end
of the trial was 1.2% in SAXENDA®-treated patients and 0.6% in
placebo-treated patients. Calcitonin values greater than 20 ng/L at
the end of the trial occurred in 0.5% of SAXENDA®-treated patients
and 0.2% of placebo-treated patients; among patients with pretreatment serum calcitonin less than 20 ng/L, none had calcitonin elevations to greater than 50 ng/L at the end of the trial.
Serum Lipase and Amylase
Serum lipase and amylase were routinely measured in the
SAXENDA® clinical trials. Among SAXENDA®-treated patients,
2.1% had a lipase value at anytime during treatment of greater than
or equal to 3 times the upper limit of normal compared with 1.0% of
placebo-treated patients. 0.1% of SAXENDA®-treated patients had
an amylase value at anytime in the trial of greater than or equal to
3 times the upper limit of normal versus 0.1% of placebo-treated
patients. The clinical significance of elevations in lipase or amylase
with SAXENDA® is unknown in the absence of other signs and
symptoms of pancreatitis [see Warnings and Precautions (5.2)].
6.2 Post-Marketing Experience
The following adverse reactions have been reported during postapproval
use of liraglutide, the active ingredient of SAXENDA®.
Because these reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
7.1 Oral Medications
SAXENDA® causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide did not affect the absorption of the tested orally administered medications
to any clinically relevant degree. Nonetheless, monitor for potential consequences of delayed absorption of oral medications concomitantly
administered with SAXENDA®.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
SAXENDA® is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm [see Clinical Considerations]. 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 [see Animal Data]. 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
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 (see Data).
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.
8.4 Pediatric Use
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.
8.5 Geriatric Use
In the SAXENDA® clinical trials, 232 (6.9%) of the SAXENDA®-
treated patients were 65 years of age and over, and 17 (0.5%) of
the SAXENDA®-treated patients were 75 years of age and over. No
overall differences in safety or effectiveness were observed between
these patients and younger patients, but greater sensitivity of some
older individuals cannot be ruled out.
8.6 Renal Impairment
There is limited experience with SAXENDA® in patients with mild,
moderate, and severe renal impairment, including end-stage renal
disease. However, there have been postmarketing reports of acute
renal failure and worsening of chronic renal failure with liraglutide,
which may sometimes require hemodialysis [see Warnings and
Precautions (5.6) and Adverse Reactions (6.2)]. SAXENDA® should
be used with caution in this patient population [see Clinical Pharmacology
(12.3)].
8.7 Hepatic Impairment
There is limited experience in patients with mild, moderate, or
severe hepatic impairment. Therefore, SAXENDA® should be used
with caution in this patient population [see Clinical Pharmacology
(12.3)].
8.8 Gastroparesis
SAXENDA® slows gastric emptying. SAXENDA® has not been
studied in patients with pre-existing gastroparesis.
10 OVERDOSAGE
Overdoses have been reported in clinical trials and post-marketing
use of liraglutide. Effects have included severe nausea, severe
vomiting and severe hypoglycemia. In the event of overdosage,
appropriate supportive treatment should be initiated according to
the patient’s clinical signs and symptoms.
11 DESCRIPTION
SAXENDA® contains liraglutide, an analog of human GLP-1 and acts
as a GLP-1 receptor agonist. The peptide precursor of liraglutide,
produced by a process that includes expression of recombinant
DNA in Saccharomyces cerevisiae, has been engineered to be 97%
homologous to native human GLP-1 by substituting arginine for
lysine at position 34. Liraglutide is made by attaching a C-16 fatty
acid (palmitic acid) with a glutamic acid spacer on the remaining
lysine residue at position 26 of the peptide precursor. The molecular
formula of liraglutide is C172H265N43O51 and the molecular weight is
3751.2 Daltons. The structural formula (Figure 1) is:
Figure 1. Structural Formula of liraglutide
SAXENDA® injection is a sterile, aqueous, clear, colorless or
almost colorless solution for subcutaneous use. Each 1 mL of
SAXENDA® solution contains 6 mg of liraglutide and the following
inactive ingredients: disodium phosphate dihydrate, 1.42 mg;
propylene glycol, 14 mg; phenol, 5.5 mg; and water for injection.
SAXENDA® has a pH of approximately 8.15, hydrochloric acid
or sodium hydroxide may be added to adjust pH. Each pre-filled
pen contains a 3 mL solution of SAXENDA® equivalent to 18 mg
liraglutide (free-base, anhydrous).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1)
receptor agonist with 97% amino acid sequence homology to
endogenous human GLP-1(7-37). Like endogenous GLP-1,
liraglutide binds to and activates the GLP-1 receptor, a cellsurface
receptor coupled to adenylyl cyclase activation through
the stimulatory G-protein, Gs. Endogenous GLP-1 has a half-life
of 1.5-2 minutes due to degradation by the ubiquitous endogenous
enzymes, dipeptidyl peptidase 4 (DPP-4) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once-daily administration, is a result of self-association that delays absorption, plasma protein binding, and stability against metabolic degradation by DPP-4 and NEP.
GLP-1 is a physiological regulator of appetite and calorie intake, and
the GLP-1 receptor is present in several areas of the brain involved
in appetite regulation. In animal studies, peripheral administration
of liraglutide resulted in the presence of liraglutide in specific brain
regions regulating appetite, including the hypothalamus. Although
liraglutide activated neurons in brain regions known to regulate
appetite, specific brain regions mediating the effects of liraglutide
on appetite were not identified in rats.
12.2 Pharmacodynamics
Liraglutide lowers body weight through decreased calorie intake.
Liraglutide does not increase 24-hour energy expenditure.
As with other GLP-1 receptor agonists, liraglutide stimulates insulin
secretion and reduces glucagon secretion in a glucose-dependent
manner. These effects can lead to a reduction of blood glucose.
Cardiac Electrophysiology (QTc) in healthy volunteers
The effect of liraglutide on cardiac repolarization was tested in a QTc
study. Liraglutide at steady-state concentrations after daily doses
up to 1.8 mg did not produce QTc prolongation. The maximum
liraglutide plasma concentration (Cmax) in overweight and obese
subjects treated with liraglutide 3 mg is similar to the Cmax observed in the liraglutide QTc study in healthy volunteers.
12.3 Pharmacokinetics
Absorption – Following subcutaneous administration, maximum
concentrations of liraglutide are achieved at 11 hours post dosing.
The average liraglutide steady state concentration (AUCt/24)
reached approximately 116 ng/mL in obese (BMI 30-40 kg/m2)
subjects following administration of SAXENDA®. Liraglutide
exposure increased proportionally in the dose range of 0.6 mg
to 3 mg. The intra-subject coefficient of variation for liraglutide
AUC was 11% following single dose administration. Liraglutide
exposures were considered similar among three subcutaneous
injection sites (upper arm, abdomen, and thigh). Absolute bioavailability of liraglutide following subcutaneous administration is
approximately 55%.
Distribution – The mean apparent volume of distribution after
subcutaneous administration of liraglutide 3 mg is 20-25 L (for a
person weighing approximately 100 kg). The mean volume of distribution after intravenous administration of liraglutide is 0.07 L/kg. Liraglutide is extensively bound to plasma protein (greater than
98%).
Metabolism – During the initial 24 hours following administration
of a single [3H]-liraglutide dose to healthy subjects, the major
component in plasma was intact liraglutide. Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination.
Elimination – Following a [3H]-liraglutide dose, intact liraglutide
was not detected in urine or feces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or feces (6% and 5%, respectively). The majority of urine and feces radioactivity was excreted during the first 6-8 days. The mean apparent clearance following subcutaneous administration
of a single dose of liraglutide is approximately 0.9-1.4 L/h with an
elimination half-life of approximately 13 hours, making liraglutide
suitable for once daily administration.
Specific Populations
Elderly – Age had no effect on the pharmacokinetics of liraglutide
based on a pharmacokinetic study in healthy elderly subjects (65
to 83 years) and population pharmacokinetic analyses of data from
overweight and obese patients 18 to 82 years of age [see Use in
Specific Populations (8.5)].
Gender – Based on the results of population pharmacokinetic
analyses, females have 24% lower weight adjusted clearance of
SAXENDA® compared to males.
Race and Ethnicity – Race and ethnicity had no effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic analyses that included overweight and obese patients of Caucasian, Black, Asian and Hispanic/Non-Hispanic groups.
Body Weight – Body weight significantly affects the pharmacokinetics of liraglutide based on results of population pharmacokinetic analyses conducted in patients with body weight range of 60-234 kg. The exposure of liraglutide decreases as baseline body weight increases.
Pediatric – A population pharmacokinetic analysis was conducted
for SAXENDA® using data from 134 pediatric patients (12 to 17
years of age) with obesity. The liraglutide exposure in the pediatric
patients was similar to that in adults with obesity [see Use in
Specific Populations (8.4)].
Renal Impairment – The single-dose pharmacokinetics of liraglutide
were evaluated in patients with varying degrees of renal impairment.
Patients with mild (estimated creatinine clearance 50-80 mL/min) to severe (estimated creatinine clearance less than 30 mL/min) renal impairment and patients with end-stage renal disease requiring dialysis were included in the trial. Compared to healthy subjects, liraglutide AUC in mild, moderate, and severe renal impairment and in end-stage renal disease was on average 35%, 19%, 29% and 30% lower, respectively [see Use in Specific Populations (8.6)]. Hepatic Impairment – The single-dose pharmacokinetics of liraglutide were evaluated in patients with varying degrees of hepatic impairment. Patients with mild (Child Pugh score 5-6) to severe (Child Pugh score greater than 9) hepatic impairment were included in the trial. Compared to healthy subjects, liraglutide AUC in
subjects with mild, moderate and severe hepatic impairment was on average 11%, 14% and 42% lower, respectively [see Use in Specific
Populations (8.7)].
Drug Interactions
In vitro assessment of drug−drug interactions Liraglutide has low potential for pharmacokinetic drug-drug interactions
related to cytochrome P450 (CYP) and plasma protein
binding.
In vivo assessment of drug−drug interactions The drug-drug interaction studies were performed at steady state
with liraglutide 1.8 mg/day. The effect on rate of gastric emptying
was equivalent between liraglutide 1.8 mg and 3 mg (acetaminophen AUC0-300min). Administration of the interacting drugs was timed so that Cmax of liraglutide (8-12 h) would coincide with the absorption peak of the co-administered drugs.
Oral Contraceptives
A single dose of an oral contraceptive combination product
containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel
was administered under fed conditions and 7 hours after the dose of
liraglutide at steady state. Liraglutide lowered ethinylestradiol and
levonorgestrel Cmax by 12% and 13%, respectively. There was no
effect of liraglutide on the overall exposure (AUC) of ethinylestradiol.
Liraglutide increased the levonorgestrel AUC0-∞ by 18%.
Liraglutide delayed Tmax for both ethinylestradiol and levonorgestrel
by 1.5 h.
Digoxin
A single dose of digoxin 1 mg was administered 7 hours after the
dose of liraglutide at steady state. The concomitant administration
with liraglutide resulted in a reduction of digoxin AUC by 16%; Cmax
decreased by 31%. Digoxin median time to maximal concentration
(Tmax) was delayed from 1 h to 1.5 h.
Lisinopril
A single dose of lisinopril 20 mg was administered 5 minutes after
the dose of liraglutide at steady state. The co-administration with
liraglutide resulted in a reduction of lisinopril AUC by 15%; Cmax
decreased by 27%. Lisinopril median Tmax was delayed from 6 h to
8 h with liraglutide.
Atorvastatin
Liraglutide did not change the overall exposure (AUC) of atorvastatin
following a single dose of atorvastatin 40 mg, administered 5
hours after the dose of liraglutide at steady state. Atorvastatin Cmax
was decreased by 38% and median Tmax was delayed from 1 h to
3 h with liraglutide.
Acetaminophen
Liraglutide did not change the overall exposure (AUC) of acetaminophen
following a single dose of acetaminophen 1000 mg,
administered 8 hours after the dose of liraglutide at steady state.
Acetaminophen Cmax was decreased by 31% and median Tmax was
delayed up to 15 minutes.
Griseofulvin
Liraglutide did not change the overall exposure (AUC) of griseofulvin
following co-administration of a single dose of griseofulvin
500 mg with liraglutide at steady state. Griseofulvin Cmax increased
by 37% while median Tmax did not change.
Insulin Detemir
No pharmacokinetic interaction was observed between liraglutide and insulin detemir when separate subcutaneous injections of insulin detemir 0.5 Unit/kg (single-dose) and liraglutide 1.8 mg (steady state) were administered to patients with type 2 diabetes mellitus.
13 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, and 3 mg/kg/day
liraglutide administered by bolus subcutaneous injection yielding
systemic exposures 0.2-, 2-, 10- and 43-times the exposure in
obese humans, respectively, at the maximum recommended human dose (MRHD) of 3 mg/day based on plasma AUC comparison. A dose-related increase in benign thyroid C-cell adenomas was seen in the 1 and the 3 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 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 7-times the exposure in obese
humans, 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 and 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 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 mg/kg/day,
a high dose yielding an estimated systemic exposure 11-times the
exposure in obese humans at the MRHD, based on plasma AUC
comparison. In female rats, an increase in early embryonic deaths
occurred at 1 mg/kg/day. Reduced body weight gain and food
consumption were observed in females at the 1 mg/kg/day dose.
14 CLINICAL STUDIES
14.1 Weight Management Trials in Adults withOverweight or Obesity
The safety and efficacy of SAXENDA® for chronic weight
management in conjunction with reduced caloric intake and
increased physical activity were studied in three 56-week,
randomized, double-blind, placebo-controlled trials. In all studies,
SAXENDA® was titrated to 3 mg daily during a 4-week period. All
patients received instruction for a reduced-calorie diet (approximately
500 kcal/day deficit) and physical activity counseling
(recommended increase in physical activity of minimum 150 mins/
week) that began with the first dose of study medication or placebo
and continued throughout the trial.
Study 1 enrolled 3731 patients with obesity (BMI greater than or
equal to 30 kg/m2) or with overweight (BMI 27-29.9 kg/m2) and
at least one weight-related comorbid condition such as treated
or untreated dyslipidemia or hypertension; patients with type 2
diabetes mellitus were excluded. Patients were randomized in a
2:1 ratio to either SAXENDA® or placebo. Patients were stratified
based on the presence or absence of abnormal blood glucose
measurements at randomization. All patients were treated for up to
56 weeks. Those patients with abnormal glucose measurements at
randomization (2254 of the 3731 patients) were treated for a total of
160 weeks. At baseline, mean age was 45 years (range 18-78), 79%
were women, 85% were Caucasian, 10% were African American,
and 11% were Hispanic/Latino. Mean baseline body weight was
106.3 kg and mean BMI was 38.3 kg/m2.
Study 2 was a 56-week trial that enrolled 635 patients with type
2 diabetes and with either overweight or obesity (as defined
above). Patients were to have an HbA1c of 7-10% and be treated
with metformin, a sulfonylurea, or a glitazone as single agent or
in any combination, or with a reduced-calorie diet and physical
activity alone. Patients were randomized in a 2:1 ratio to receive
either SAXENDA® or placebo. The mean age was 55 years (range
18-82), 50% were women, 83% were Caucasian, 12% were African
American, and 10% were Hispanic/Latino. Mean baseline body
weight was 105.9 kg and mean BMI was 37.1 kg/m2.
Study 3 was a 56-week trial that enrolled 422 patients with obesity
(BMI greater than or equal to 30 kg/m2) or with overweight (BMI
27-29.9 kg/m2) and at least one weight-related comorbid condition
such as treated or untreated dyslipidemia or hypertension; patients
with type 2 diabetes mellitus were excluded. All patients were first
treated with a low-calorie diet (total energy intake 1200-1400 kcal/
day) in a run-in period lasting up to 12 weeks. Patients who lost at
least 5% of their screening body weight after 4 to 12 weeks during
the run-in were then randomized, with equal allocation, to receive
either SAXENDA® or placebo for 56 weeks. The mean age was
46 years (range 18-73), 81% were women, 84% were Caucasian,
13% were African American, and 7% were Hispanic/Latino. Mean
baseline body weight was 99.6 kg and mean BMI was 35.6 kg/m2.
The proportions of patients who discontinued study drug in the
56-week trials were 27% for the SAXENDA®-treated group and
35% for the placebo-treated group, and in the 160-week trial
the proportions of patients who discontinued were 47% and
55%, respectively. In the 56-week trials, approximately 10% of
patients treated with SAXENDA® and 4% of patients treated with
placebo discontinued treatment due to an adverse reaction [see
Adverse Reactions (6.1)]. The majority of patients who discontinued
SAXENDA® due to adverse reactions did so during the first
few months of treatment. In the 160-week trial the proportions of
patients who discontinued due to an adverse reaction was 13% and
6% for SAXENDA®- and placebo-treated patients, respectively.
Effect of SAXENDA® on Body Weight in 56-week Trials.
For Study 1 and Study 2, the primary efficacy parameters were mean
percent change in body weight and the percentages of patients
achieving greater than or equal to 5% and 10% weight loss from
baseline to week 56. For Study 3, the primary efficacy parameters
were mean percent change in body weight from randomization to
week 56, the percentage of patients not gaining more than 0.5%
body weight from randomization (i.e., after run-in) to week 56,
and the percentage of patients achieving greater than or equal to
5% weight loss from randomization to week 56. Because losing
at least 5% of fasting body weight through lifestyle intervention
during the 4- to 12-week run-in was a condition for their continued
participation in the randomized treatment period, the results may
not reflect those expected in the general population.
Table 6 presents the results for the changes in weight observed
in Studies 1, 2, and 3. After 56 weeks, treatment with SAXENDA®
resulted in a statistically significant reduction in weight compared
with placebo. Statistically significantly greater proportions of
patients treated with SAXENDA® achieved 5% and 10% weight
loss than those treated with placebo. In Study 3, statistically
significantly more patients randomized to SAXENDA® than placebo
had not gained more than 0.5% of body weight from randomization
to week 56.
SD = Standard Deviation; CI = Confidence Interval
* p < 0.0001 compared to placebo. Type 1 error was controlled across the three endpoints. Includes all randomized subjects who had a baseline body weight measurement. All available body weight data during the 56 week treatment period are included in the analysis. In Studies 1 and 2 missing values for week 56 were handled using multiple imputations analysis. In Study 3 missing values for week 56 were handled using weighted regression analysis.
The cumulative frequency distributions of change in body weight from baseline to week 56 are shown in Figure 2 for Studies 1 and 2. One way to interpret this figure is to select a change in body weight of interest on the horizontal axis and note the corresponding proportions of patients (vertical axis) in each treatment group who achieved at least that degree of weight loss. For example, note that the vertical line arising from -10% in Study 1 intersects the SAXENDA® and placebo curves at approximately 34% and 15%, respectively, which correspond to the values shown in Table 6.
Effect of SAXENDA® on Body Weight in a 160-week Trial (Study 1, Subset of Patients with Abnormal Blood Glucose at Randomization)
The numbers and percentages of patients known to have lost greater than or equal to 5% body weight at week 56 and/or week 160 in Study 1 (patients with abnormal glucose at randomization only) are summarized in Table 7 for descriptive purposes.
SD = Standard Deviation
Includes all randomized subjects who had a baseline body weight measurement. All available body
weight data at 56 and 160 weeks are included in the analysis.
Effect of SAXENDA® on Anthropometry and Cardiometabolic Parameters in 56-week Trials
Changes in waist circumference and cardiometabolic parameters with SAXENDA® are shown in Table
8 for Study 1 (patients without diabetes mellitus) and Table 9 for Study 2 (patients with type 2 diabetes).
Results from Study 3, which also enrolled patients without diabetes mellitus, were similar to Study 1.
Based on last observation carried forward method while on study drug
1 Least squares mean adjusted for treatment, country, sex, pre-diabetes status at screening, baseline
BMI stratum and an interaction between pre-diabetes status at screening and BMI stratum as fixed
factors, and the baseline value as covariate.
2 See Warnings and Precautions (5.5)
* Baseline value is the geometric mean
† Values are baseline median, median % change, and the Hodges-Lehmann estimate of the median
treatment difference.
14.2 Weight Management Trial in Pediatric Patients Ages 12
and Older with Obesity
SAXENDA® was evaluated in a 56-week, double-blind, randomized, parallel group, placebo controlled multicenter trial in 251 pubertal pediatric patients aged 12 to 17 years, with BMI corresponding to
30 kg/m2 or greater for adults by international cut-off points [see Dosage and Administration (2.1)] and BMI of 95th percentile or greater for age and sex (NCT02918279). After a 12-week lifestyle run-in period, patients were randomized 1:1 to SAXENDA® once-daily or placebo once-daily. The SAXENDA® dose was titrated to 3 mg over a 4- to 8-week period based on tolerability as judged by the investigator.
Escalation of the trial product was not allowed if the subject had a self-monitored plasma glucose (SMPG) < 56 mg/dL or < 70 mg/dL in the presence of symptoms of hypoglycemia during the week
prior to or during the dose escalation visits. The proportion of patients who reached the 3 mg dose was 82.4%; for 8.8% of patients 2.4 mg was the maximum tolerated dose.
The mean age was 14.5 years: 40.6% of patients were male, 87.6% were White, 0.8% were Asian, 8% were Black or African American; 22.3% were of Hispanic or Latino ethnicity. The mean baseline body
weight was 100.8 kg, and mean Body Mass Index (BMI) was 35.6 kg/m2.
The proportions of patients who discontinued study drug were 19.2% for the SAXENDA®-treated group and 20.6% for the placebo-treated group; 10.4% of patients treated with SAXENDA® and no patients
treated with placebo discontinued treatment due to an adverse reaction [see Adverse Reactions (6.1)].
The primary endpoint was change in BMI SDS. At baseline, mean BMI SDS was 3.14 in the SAXENDA® group and 3.20 in the placebo group. At week 56, treatment with SAXENDA® resulted in statistically
significant reduction in BMI SDS from baseline compared to placebo. The observed mean change in BMI SDS from baseline to week 56 was -0.23 in the SAXENDA® group and -0.00 in the placebo
group. The estimated treatment difference in BMI SDS reduction from baseline between SAXENDA® and placebo was -0.22 with a 95% confidence interval of -0.37, -0.08; p=0.0022.
The time course of change in BMI SDS with SAXENDA® and placebo from baseline through week 56
are depicted in Figure 5.
+/- standard error of mean
Number at week 56 are estimated means using multiple imputation (jump to reference) for patients
completing each scheduled visits.
Figure 5. Change from Baseline in BMI SDS
Changes in weight and BMI with SAXENDA® are shown in Table 10. Changes in waist circumference
and cardiometabolic parameters with SAXENDA® are shown in Table 11.
Full Analysis Set. For body weight and BMI, baseline values are means, changes from baseline at week 56 are estimated means (least-squares) and treatment contrasts at week 56 are estimated treatment differences. Missing observations were imputed from the placebo arm based on a jump to reference multiple (x100) imputation approach.
Full Analysis Set. Baseline values are means, changes from baseline at week 56 are estimated means (least-squares) and treatment contrasts at week 56 are estimated treatment differences.
Missing observations were imputed from the placebo arm based on a jump to reference multiple (x100) imputation approach.
** Baseline values are geometric means.
14.3 Cardiovascular Outcomes Trial of Liraglutide 1.8 mg in Adult Patients with Type 2 Diabetes and Cardiovascular Disease
Liraglutide 1.8 mg (Victoza®) is used in the treatment of type 2 diabetes mellitus in adults. The efficacy of liraglutide at doses below 3 mg daily has not been established for chronic weight management.
The LEADER trial (NCT01179048) randomized 9340 patients with inadequately controlled type 2 diabetes and cardiovascular disease to liraglutide 1.8 mg or placebo in addition to standard of care treatments for type 2 diabetes for a median duration of 3.5 years. Patients either were 50 years of age or older with established, stable cardiovascular, cerebrovascular, peripheral vascular disease, chronic renal failure or chronic heart failure (80% of patients), or were 60 years of age or older and had other specified risk factors of vascular disease (20% of patients).The population was 64% male, 78% Caucasian, 10% Asian and 8% Black; 12% of the population was Hispanic or Latino. In total, 96.8% of the patients completed the trial; vital status was known at the end of the trial for 99.7%. The primary endpoint was the time from randomization to first occurrence of a major adverse cardiovascular event (MACE) defined as: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. No increased risk for MACE was observed with liraglutide 1.8 mg. The total number of primary component MACE endpoints was 1302 (608 [13.0%] with liraglutide 1.8 mg and 694 [14.9%] with placebo).
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
SAXENDA® injection: 6 mg/mL clear, colorless solution in a 3 mL single-patient-use pre-filled pen that delivers doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg or 3 mg is available in the following package sizes:
3 x SAXENDA® pen NDC 0169-2800-13
5 x SAXENDA® pen NDC 0169-2800-15
16.2 Recommended Storage
Prior to first use, SAXENDA® should be stored in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze SAXENDA® and do not use SAXENDA® if it has been frozen. After initial use of the SAXENDA® pen, the pen can be stored for 30 days at controlled room temperature (59°F to 86°F; 15°C to 30°C) or in a refrigerator (36°F to 46°F; 2°C to 8°C). Keep the pen cap on when not in use. Protect SAXENDA® from excessive heat and sunlight. Always remove and safely discard the needle after each injection and store the SAXENDA® pen without an injection needle attached. This
will reduce the potential for contamination, infection, and leakage while also ensuring dosing accuracy.
17 PATIENT COUNSELING INFORMATION
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. Risk of Thyroid C-cell Tumors Inform patients that liraglutide causes benign and malignant thyroid C-cell tumors in mice and rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia or dyspnea) to their health care
provider [see Boxed Warning and Warnings and Precautions (5.1)].
Acute Pancreatitis Inform patients of the potential risk for acute pancreatitis. Explain that persistent severe abdominal
pain that may radiate to the back which may or may not be accompanied by vomiting is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue SAXENDA® promptly and contact their health care provider if persistent severe abdominal pain occurs.
Acute Gallbladder Disease Inform patients of the risk of acute gallbladder disease. Advise patients that substantial or rapid weight
loss can increase the risk of gallbladder disease, but that gallbladder disease may also occur in the absence of substantial or rapid weight loss. Instruct patients to contact their healthcare provider for appropriate clinical follow-up if gallbladder disease is suspected.
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.
Heart Rate Increase
Inform patients to report symptoms of sustained periods of heart pounding or racing while at rest to their healthcare provider. Discontinue SAXENDA® in patients who experience a sustained increase in resting heart rate.
Dehydration and Renal Impairment
Advise patients of the risk of dehydration due to gastrointestinal adverse reactions and to take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function, which in some cases may require dialysis.
Hypersensitivity Reactions
Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of SAXENDA®. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking SAXENDA® and seek medical advice promptly if such symptoms occur [see Warnings and
Precautions (5.7)].
Suicidal Behavior and Ideation
Advise patients to report emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Inform patients that if they experience suicidal thoughts or behaviors, they should stop taking SAXENDA®.
Jaundice and Hepatitis
Inform patients that jaundice and hepatitis have been reported during postmarketing use of liraglutide. Instruct patients to contact their healthcare provider if they develop jaundice.
Never Share a SAXENDA® Pen Between Patients
Inform patients that they should never share a SAXENDA® pen with another person, even if the needle is changed. Sharing of the pen between patients may pose a risk of transmission of infection.
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