Included as part of the PRECAUTIONS section.
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]. 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.
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, 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.
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
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. 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.
Risk For Hypoglycemia With Concomitant Use Of
The risk for serious hypoglycemia is increased when
Saxenda is used in combination with insulin secretagogues (for example,
sulfonylureas) in patients with type 2 diabetes mellitus. Therefore, patients
may require a lower dose of sulfonylurea (or other concomitantly administered
insulin secretagogues) in this setting [see DOSAGE AND ADMINISTRATION and
ADVERSE REACTIONS]. Saxenda should not be used in patients taking
Saxenda can lower blood glucose [see CLINICAL
PHARMACOLOGY]. Monitor blood glucose parameters prior to starting Saxenda
and during Saxenda treatment in patients with type 2 diabetes. If needed,
adjust coadministered anti-diabetic drugs based on glucose monitoring results
and risk of hypoglycemia.
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
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.
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.
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]. 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].
There have been reports of serious hypersensitivity
reactions (e.g., anaphylactic reactions and angioedema) in patients treated
with liraglutide [see CONTRAINDICATIONS and ADVERSE REACTIONS].
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.
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 reported suicidal
ideation; one of these Saxenda-treated patients attempted suicide. 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.
Patient Counseling Information
FDA-Approved Medication Guide
Advise the patient to read the FDA-approved patient
labeling (Medication Guide and Instructions for Use).
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 patients to discontinue Saxenda if they have not
achieved 4% weight loss by 16 weeks of treatment.
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
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
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
Hypoglycemia In Patients With Type 2 Diabetes Mellitus On
Educate patients on the signs and symptoms of
hypoglycemia. Advise patients with type 2 diabetes mellitus on glycemic
lowering therapy to report signs and/or symptoms of hypoglycemia to their
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
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.
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
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.
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
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.
Use In Specific Populations
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
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
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%,
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
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
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 treatedwith 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.
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.
In lactating rats, liraglutide was present unchanged in
milk at concentrations approximately 50% of maternal plasma concentrations.
Safety and effectiveness of Saxenda have not been
established in pediatric patients. Saxenda is not recommended for use in
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
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 and ADVERSE REACTIONS].
Saxenda should be used with caution in this patient population [see CLINICAL
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].
Saxenda slows gastric emptying. Saxenda has not been
studied in patients with pre-existing gastroparesis.