WARNING: RISK OF THYROID C-CELL
TUMORS
In rats, tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at
clinically relevant exposures. It is unknown whether Zepbound causes thyroid C-cell tumors, including
medullary
thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors
has
not been determined.
Zepbound is contraindicated in patients with a personal or family history of MTC or in patients with
Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC
with
the use of Zepbound 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 Zepbound.
Contraindications:
Zepbound is contraindicated in patients with a personal or family history of MTC or in
patients with MEN
2, and in patients with known serious hypersensitivity to tirzepatide or any of the excipients in Zepbound.
Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with
tirzepatide.
Risk of Thyroid C-cell Tumors: Counsel patients regarding the potential risk for MTC with the
use
of Zepbound 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 Zepbound. Such monitoring may increase the risk of
unnecessary
procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid
disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have
calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be
further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be
further evaluated.
Severe Gastrointestinal Disease: Use of Zepbound has been associated with gastrointestinal
adverse
reactions, sometimes severe. In clinical trials, severe gastrointestinal adverse reactions were reported more
frequently among patients receiving Zepbound (5 mg 1.7%, 10 mg 2.5%, 15 mg 3.1%) than placebo (1.0%). Zepbound
has
not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is
therefore
not recommended in these patients.
Acute Kidney Injury: Use of Zepbound has been associated with acute kidney injury, which can
result
from dehydration due to gastrointestinal adverse reactions to Zepbound, including nausea, vomiting, and
diarrhea. In
patients treated with GLP-1 receptor agonists there have been postmarketing reports of acute kidney injury and
worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events have been
reported in patients without known underlying renal disease. A majority of the reported events occurred in
patients
who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function in patients reporting
adverse
reactions to Zepbound that could lead to volume depletion.
Acute Gallbladder Disease: Treatment with Zepbound and GLP-1 receptor agonists is associated
with
an increased occurrence of acute gallbladder disease. In clinical trials of Zepbound, cholelithiasis was
reported in
1.1% of Zepbound-treated patients and 1.0% of placebo-treated patients, cholecystitis was reported in 0.7% of
Zepbound-treated patients and 0.2% of placebo-treated patients, and cholecystectomy was reported in 0.2% of
Zepbound-treated patients and no placebo-treated patients. Acute gallbladder events were associated with weight
reduction. If cholecystitis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are
indicated.
Acute Pancreatitis: Acute pancreatitis, including fatal and non-fatal hemorrhagic or
necrotizing
pancreatitis, has been observed in patients treated with GLP-1 receptor agonists or tirzepatide. In clinical
trials
of tirzepatide for a different indication, 14 events of acute pancreatitis were confirmed by adjudication in 13
tirzepatide-treated patients (0.23 patients per 100 years of exposure) versus 3 events in 3 comparator-treated
patients (0.11 patients per 100 years of exposure). In Zepbound clinical trials, 0.2% of Zepbound-treated
patients
had acute pancreatitis confirmed by adjudication (0.14 patients per 100 years of exposure) versus 0.2% of
placebo-treated patients (0.15 patients per 100 years of exposure). Zepbound has not been studied in patients
with a
prior history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for
development of pancreatitis on Zepbound. Observe patients for signs and symptoms of pancreatitis, including
persistent severe
abdominal pain sometimes radiating to the back, which may or may not be accompanied by vomiting. If pancreatitis
is
suspected, discontinue Zepbound and initiate appropriate management. If the diagnosis of pancreatitis is
confirmed,
Zepbound should not be restarted.
Hypersensitivity Reactions: There have been postmarketing reports of serious hypersensitivity
reactions (e.g., anaphylaxis, angioedema) in patients treated with tirzepatide. In Zepbound clinical trials,
0.1% of
Zepbound-treated patients had severe hypersensitivity reactions compared to no placebo-treated patients. If
hypersensitivity reactions occur, advise patients to promptly seek medical attention and discontinue use of
Zepbound. Do not use in patients with a previous serious hypersensitivity reaction to tirzepatide or any of the
excipients in Zepbound. Use caution in patients with a history of angioedema or anaphylaxis with a GLP-1
receptor
agonist because it is unknown if such patients will be predisposed to these reactions with Zepbound.
Hypoglycemia: Zepbound lowers blood glucose and can cause hypoglycemia. In a trial of patients
with
type 2 diabetes mellitus and BMI ≥27 kg/m2, hypoglycemia (plasma glucose <54 mg/dL) was reported in
4.2% of Zepbound-treated patients versus 1.3% of placebo-treated patients. In this trial, patients taking
Zepbound
in combination with an insulin secretagogue (e.g., sulfonylurea) had increased risk of hypoglycemia (10.3%)
compared
to Zepbound-treated patients not taking a sulfonylurea (2.1%). Hypoglycemia has also been associated with
Zepbound
and GLP-1 receptor agonists in adults without type 2 diabetes mellitus. There is also increased risk of
hypoglycemia
in patients treated with tirzepatide in combination with insulin. Inform patients of the risk of hypoglycemia
and
educate them on the signs and symptoms of hypoglycemia. In patients with diabetes mellitus, monitor blood
glucose
prior to starting Zepbound and during Zepbound treatment. The risk of hypoglycemia may be lowered by a reduction
in
the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin.
Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus: Rapid
improvement
in glucose control has been associated with a temporary worsening of diabetic retinopathy. Tirzepatide has not
been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative
diabetic retinopathy, or diabetic macular edema. Patients with a history of diabetic retinopathy should be
monitored for progression of diabetic retinopathy.
Suicidal Behavior and Ideation: Suicidal behavior and ideation have been reported in clinical
trials with other chronic weight management products. Monitor patients treated with Zepbound for the emergence
or
worsening of depression, suicidal thoughts or behaviors, and/or any unusual changes in mood or behavior.
Discontinue Zepbound in patients who experience suicidal thoughts or behaviors. Avoid Zepbound in patients with
a
history of suicidal attempts or active suicidal ideation.
Most common adverse reactions: The most common adverse reactions, reported in ≥5% of patients
treated with Zepbound are: nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, injection site
reactions, fatigue, hypersensitivity reactions, eructation, hair loss, and gastroesophageal reflux disease.
Drug Interactions: Zepbound lowers blood glucose. When initiating Zepbound, consider reducing
the
dose of concomitantly administered insulin secretagogues (e.g., sulfonylureas) or insulin to reduce the risk of
hypoglycemia. Zepbound delays gastric emptying and thereby has the potential to impact the absorption of
concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly
administered with Zepbound. Monitor patients on oral medications dependent on threshold concentrations for
efficacy
and those with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with Zepbound.
Pregnancy: Advise pregnant patients that weight loss is not recommended during pregnancy and to
discontinue Zepbound when a pregnancy is recognized. Available data with tirzepatide in pregnant patients are
insufficient to evaluate for a drug-related risk of major birth defects, miscarriage, or other adverse maternal
or
fetal outcomes. Based on animal reproduction studies, there may be risks to the fetus from exposure to
tirzepatide
during pregnancy. There will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed
to
Zepbound (tirzepatide) during pregnancy. Pregnant patients exposed to Zepbound and healthcare providers are
encouraged to contact Eli Lilly and Company at 1-800-LillyRx
(1-800-545-5979).
Lactation: There are no data on the presence of tirzepatide or its metabolites in animal or
human
milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health
benefits of breastfeeding should be considered along with the mother’s clinical need for Zepbound and any
potential adverse effects on the breastfed infant from Zepbound or from the underlying maternal condition.
Females and Males of Reproductive Potential: Use of Zepbound may reduce the efficacy of oral
hormonal contraceptives due to delayed gastric emptying. This delay is largest after the first dose and
diminishes
over time. Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method or
add a
barrier method of contraception, for 4 weeks after initiation with Zepbound and for 4 weeks after each dose
escalation.
Pediatric Use: The safety and effectiveness of Zepbound have not been established in pediatric
patients less than 18 years of age.
Please see accompanying
Prescribing Information, including Boxed Warning about possible thyroid tumors, including thyroid
cancer, and
Medication Guide.
Please see
Instructions for Use for pen and Instructions for Use for vial.
ZP HCP ISI 08NOV2023
