Source: FDA, National Drug Code (US) Revision Year: 2023
ZEPBOUND is contraindicated in patients with:
In rats, tirzepatide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) in a 2-year study at clinically relevant plasma exposures [see Nonclinical Toxicology (13.1)]. It is unknown whether ZEPBOUND causes thyroid C-cell tumors, including 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 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. 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.
Use of ZEPBOUND has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions 6.1]. 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%). ZEPBOUND has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.
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 [see Adverse Reactions (6.1)].
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.
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% 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, 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.
After initiation of ZEPBOUND, observe patients carefully 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.
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 [see Contraindications (4) and Adverse Reactions (6.2)].
Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with GLP-1 receptor agonists. Use caution in patients with a history of angioedema or anaphylaxis with a GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with ZEPBOUND.
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%). There is also increased risk of hypoglycemia in patients treated with tirzepatide in combination with insulin [see Drug Interactions (7.1)].
Hypoglycemia has also been associated with ZEPBOUND and GLP-1 receptor agonists in adults without type 2 diabetes mellitus [see Adverse Reactions (6.1)].
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.
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 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.
The following serious adverse reactions are described below or elsewhere in the prescribing information:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
ZEPBOUND was evaluated for safety in 2 randomized, double-blind, placebo-controlled trials that included 2519 adult patients with overweight or obesity treated with ZEPBOUND for up to 72 weeks and a 4-week off drug follow-up period [see Clinical Studies (14.1)]. The mean age of patients was 47 years and 37% were male. The population was 72% White, 12% Asian, 8% Black or African American, and 7% American Indian or Alaska Native; 51% identified as Hispanic or Latino ethnicity. Baseline characteristics included an average BMI of 37.4 kg/m2, 29% with a BMI ≥40 kg/m2, 41% with hypertension, 37% with dyslipidemia, 25% with type 2 diabetes mellitus, 7% with obstructive sleep apnea, and 4% with cardiovascular disease.
Across both trials, 4.8%, 6.3%, and 6.7% of patients treated with 5 mg, 10 mg, and 15 mg of ZEPBOUND, respectively, permanently discontinued treatment as a result of adverse reactions compared to 3.4% of patients treated with placebo. The majority of patients who discontinued ZEPBOUND due to adverse reactions did so during the first few months of treatment due to gastrointestinal adverse reactions.
Table 2 shows common adverse reactions associated with the use of ZEPBOUND in the placebo-controlled trials for chronic weight management. These adverse reactions occurred more commonly with ZEPBOUND than with placebo and occurred in at least 2% of patients treated with ZEPBOUND.
Table 2. Adverse Reactions (≥2% and Greater than Placebo) in ZEPBOUND-Treated Adults with Obesity or Overweight for Chronic Weight Management:</>
| Adverse Reaction | Placebo (N=958) % | ZEPBOUND 5 mg (N=630) % | ZEPBOUND 10 mg (N=948) % | ZEPBOUND 15 mg (N=941) % |
| Nausea | 8 | 25 | 29 | 28 |
| Diarrhea a | 8 | 19 | 21 | 23 |
| Vomiting | 2 | 8 | 11 | 13 |
| Constipation b | 5 | 17 | 14 | 11 |
| Abdominal Pain c | 5 | 9 | 9 | 10 |
| Dyspepsia | 4 | 9 | 9 | 10 |
| Injection Site Reactions d | 2 | 6 | 8 | 8 |
| Fatigue e | 3 | 5 | 6 | 7 |
| Hypersensitivity Reactions | 3 | 5 | 5 | 5 |
| Eructation | 1 | 4 | 5 | 5 |
| Hair Loss | 1 | 5 | 4 | 5 |
| Gastroesophageal Reflux Disease | 2 | 4 | 4 | 5 |
| Flatulence | 2 | 3 | 3 | 4 |
| Abdominal Distension | 2 | 3 | 3 | 4 |
| Dizziness | 2 | 4 | 5 | 4 |
| Hypotension f | 0 | 1 | 1 | 2 |
a Includes diarrhea, frequent bowel movements.
b Includes constipation, feces hard.
c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness.
d Includes multiple related adverse event terms, such as injection site bruising, injection site erythema, injection site pruritus, injection site pain, injection site rash, injection site reaction.
e Includes asthenia, fatigue, lethargy, malaise.
f Includes blood pressure decreased, hypotension, orthostatic hypotension.
In ZEPBOUND clinical trials, gastrointestinal adverse reactions occurred more frequently among patients receiving ZEPBOUND (5 mg 56%, 10 mg 56%, 15 mg 56%) than placebo (30%). More patients receiving ZEPBOUND 5 mg (1.9%), ZEPBOUND 10 mg (3.3%), and ZEPBOUND 15 mg (4.3%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.5%). The majority of nausea, vomiting, and/or diarrhea events occurred during dose escalation and decreased over time.
In ZEPBOUND clinical trials, hypotension occurred more frequently among patients taking ZEPBOUND (1.6%) than patients taking placebo (0.1%). Hypotension was more frequently seen in ZEPBOUND-treated patients on concomitant antihypertensive therapy (2.2%) compared to ZEPBOUND-treated patients not on antihypertensive therapy (1.2%). Hypotension also occurred in association with gastrointestinal adverse events and dehydration.
In ZEPBOUND clinical trials, immediate hypersensitivity reactions (within one day after drug administration) occurred in 2.1% of ZEPBOUND-treated patients compared to 0.4% of placebo-treated patients, while non-immediate hypersensitivity reactions occurred in 3.5% of ZEPBOUND-treated patients compared to 2.7% of placebo-treated patients. Among ZEPBOUND-treated patients, hypersensitivity reactions were more frequent in those with anti-tirzepatide antibodies (6.2%) compared to those who did not develop anti-tirzepatide antibodies (3%) [see Clinical Pharmacology (12.6)]. The majority of the hypersensitivity reactions in trials were skin reactions (e.g., rash, itching).
In ZEPBOUND-treated patients in clinical trials, injection site reactions were more frequent in those with anti-tirzepatide antibodies (11.3%) compared to those who did not develop anti-tirzepatide antibodies (1%) [see Clinical Pharmacology (12.6)].
Hair loss adverse reactions in ZEPBOUND-treated patients were associated with weight reduction. In ZEPBOUND clinical trials, hair loss was reported more frequently in female than male patients in the ZEPBOUND (7.1% female versus 0.5% male) and placebo (1.3% female versus 0% male) treatment groups. No ZEPBOUND-treated patients and one placebo-treated patient discontinued study treatment due to hair loss.
In clinical trials, acute kidney injury was reported in 0.5% of ZEPBOUND-treated patients compared to 0.2% of placebo-treated patients.
In clinical trials of ZEPBOUND, cholelithiasis was reported in 1.1% of ZEPBOUND-treated patients and 1% 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.
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 a trial of ZEPBOUND in adults with obesity/overweight without type 2 diabetes mellitus, there was no systematic capturing of hypoglycemia, but plasma glucose <54 mg/dL was reported in 0.3% of ZEPBOUND-treated patients versus no placebo-treated patients.
In ZEPBOUND clinical trials, treatment with ZEPBOUND resulted in a mean increase in heart rate of 1 to 3 beats per minute compared to no increase in placebo-treated patients.
In clinical trials, treatment with ZEPBOUND resulted in mean increases from baseline in serum pancreatic amylase concentrations of 20% to 25% and serum lipase concentrations of 28% to 35%, compared to mean increases from baseline in pancreatic amylase of 2.1% and serum lipase of 5.8% in placebo-treated patients. The clinical significance of elevations in amylase or lipase with ZEPBOUND is unknown in the absence of other signs and symptoms of pancreatitis.
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the trials described below with the incidence of anti-drug antibodies in other trials.
During the 72-week treatment period with anti-drug antibodies (ADA) sampling in the chronic weight management studies [see Clinical Studies (14)], 64.5% (1591/2467) of ZEPBOUND-treated patients developed anti-tirzepatide antibodies. In these trials, anti-tirzepatide antibody formation in 40% and 16.5% of ZEPBOUND-treated patients showed cross-reactivity to native GIP or native GLP-1, respectively.
Of the ZEPBOUND-treated patients, 2.8% and 2.7% developed neutralizing antibodies against tirzepatide activity on the GIP or GLP-1 receptors, respectively, and 0.8% and 0.1% developed neutralizing antibodies against native GIP or GLP-1, respectively.
There was no identified clinically significant effect of anti-tirzepatide antibodies on pharmacokinetics or effectiveness of ZEPBOUND. More ZEPBOUND-treated patients who developed anti-tirzepatide antibodies experienced hypersensitivity reactions or injection site reactions than those who did not develop these antibodies [see Adverse Reactions (6.1)].
The following adverse reactions have been reported during post-approval use of tirzepatide, the active ingredient in ZEPBOUND. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.
Hypersensitivity: anaphylaxis, angioedema
Gastrointestinal: ileus
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 [see Warnings and Precautions (5.7)].
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.
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. Hormonal contraceptives that are not administered orally should not be affected [see Use in Specific Populations (8.3) and Clinical Pharmacology (12.2, 12.3)].
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).
Weight loss offers no benefit to a pregnant patient and may cause fetal harm. Advise pregnant patients that weight loss is not recommended during pregnancy and to discontinue ZEPBOUND when a pregnancy is recognized (see Clinical Considerations). 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.
In pregnant rats administered tirzepatide during organogenesis, fetal growth reductions and fetal abnormalities occurred at clinical exposure in maternal rats based on AUC. In rabbits administered tirzepatide during organogenesis, fetal growth reductions were observed at clinically relevant exposures based on AUC. These adverse embryo/fetal effects in animals coincided with pharmacological effects on maternal weight and food consumption (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is increased when compared to the general population. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those with obesity or overweight, due to the obligatory weight gain that occurs in maternal tissues during pregnancy.
In pregnant rats given twice weekly subcutaneous doses of 0.02, 0.1, and 0.5 mg/kg tirzepatide (0.03-, 0.07-, and 0.5-fold the maximum recommended human dose (MRHD) of 15 mg once weekly based on AUC) during organogenesis, increased incidences of external, visceral, and skeletal malformations, increased incidences of visceral and skeletal developmental variations, and decreased fetal weights coincided with pharmacologically-mediated reductions in maternal body weights and food consumption at 0.5 mg/kg. In pregnant rabbits given once weekly subcutaneous doses of 0.01, 0.03, or 0.1 mg/kg tirzepatide (0.01-, 0.06-, and 0.2-fold the MRHD) during organogenesis, pharmacologically mediated effects on the gastrointestinal system resulting in maternal mortality or abortion in a few rabbits occurred at all dose levels. Reduced fetal weights associated with decreased maternal food consumption and body weights were observed at 0.1 mg/kg. In a pre- and post-natal study in rats administered subcutaneous doses of 0.02, 0.10, or 0.25 mg/kg tirzepatide twice weekly from implantation through lactation, F1 pups from F0 maternal rats given 0.25 mg/kg tirzepatide had statistically significant lower mean body weight when compared to controls from post-natal day 7 through post-natal day 126 for males and post-natal day 56 for females.
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.
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 [see Drug Interactions (7.2) and Clinical Pharmacology (12.2, 12.3)].
The safety and effectiveness of ZEPBOUND have not been established in pediatric patients less than 18 years of age.
In ZEPBOUND clinical trials, 226 (9%) ZEPBOUND-treated patients were 65 years of age or older, and 13 (0.5%) ZEPBOUND-treated patients were 75 years of age or older at baseline.
No overall differences in safety or effectiveness of ZEPBOUND have been observed between patients 65 years of age and older and younger adult patients.
No dosage adjustment of ZEPBOUND is recommended for patients with renal impairment. In subjects with renal impairment including end-stage renal disease (ESRD), no change in tirzepatide pharmacokinetics (PK) was observed [see Clinical Pharmacology (12.3)]. Monitor renal function in patients reporting adverse reactions to ZEPBOUND that could lead to volume depletion [see Warnings and Precautions (5.3)].
No dosage adjustment of ZEPBOUND is recommended for patients with hepatic impairment. In a clinical pharmacology study in subjects with varying degrees of hepatic impairment, no change in tirzepatide PK was observed [see Clinical Pharmacology (12.3)].
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