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Zepbound is the first and only pharmaceutical treatment approved for moderate-to-severe OSA in adults with obesity in combination with a reduced-calorie diet and increased physical activity.1

Clinical Data: Obstructive Sleep Apnea (OSA)

Zepbound is the first and only pharmaceutical treatment approved for moderate-to-severe OSA in adults with obesity in combination with a reduced-calorie diet and increased physical activity.1

Clinical Data: Obstructive Sleep Apnea (OSA)

Efficacy Cardiometabolic Parameters Safety Study Designs

In SURMOUNT-OSA,

Adults taking Zepbound achieved significant reductions in AHI1

With significant percentage reductions in AHI at week 521

Study 1: 50.7% reduction in AHI from baseline in adults taking Zepbound MTD vs -3.0% with placebo.1

Study 2: 58.7% reduction in AHI from baseline in adults taking Zepbound MTD vs -2.5% with placebo.1

PRIMARY ENDPOINT: CHANGE IN AHI FROM BASELINE TO WEEK 52 (EVENTS/h)1,2

Treatment and placebo included a reduced-calorie diet and increased physical activity.2

aP<0.001 for superiority of Zepbound vs placebo, controlled for type I error.1
bKey secondary endpoint.2

Studied in adults with moderate-to-severe OSA with a BMI ≥30 kg/m2 randomized to receive Zepbound MTD (10 mg or 15 mg) or placebo.2

Study 1 (not on PAP therapy): Participants (n=234) who were unable or unwilling to use PAP therapy. Participants must not have used PAP for at least 4 weeks at the time of screening.1-3

Study 2 (on PAP therapy): Participants (n=235) were on PAP therapy for at least 3 consecutive months at the time of screening and planned to continue PAP therapy during the study. Participants in Study 2 suspended PAP use for 7 days before the scheduled PSGs.1-3

Data shown are least squares mean. Least squares mean at week 52 from ANCOVA adjusted for baseline values and other stratification factors with multiple imputation of missing data are also shown for week 52. For change in AHI from randomization to week 52 data are derived from a mixed-model-for-repeated-measures analysis for the mITT population, and no explicit imputations were performed for missing data. mITT population included randomly assigned participants who are exposed to at least 1 dose of study treatment. Two participants in Study 2 were randomized but did not receive study drug.2,4,5

AHI=apnea-hypopnea index; ANCOVA=analysis of covariance; BMI=body mass index; MI=multiple imputation; mITT=modified intent-to-treat; MTD=maximum tolerated dose; OSA=obstructive sleep apnea; PAP=positive airway pressure; PSG=polysomnography.

See SURMOUNT-OSA design

Select Important Safety Information

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.

In SURMOUNT-OSA,

Up to half of adults taking Zepbound achieved the criteria for OSA disease resolution1

Disease resolution is defined as AHI <5 or AHI 5-14 without excessive sleepiness measured by ESS ≤101

% OF ADULTS WITH AHI <5 OR AHI 5-14 AND ESS ≤10 AT WEEK 521,2

Treatment and placebo included a reduced-calorie diet and increased physical activity.2

aP<0.001 for superiority of Zepbound vs placebo, controlled for type I error.1

Studied over 52 weeks in adults with moderate-to-severe OSA with a BMI ≥30 kg/m2 randomized to receive Zepbound MTD (10 mg or 15 mg) or placebo.2

Disease resolution is also characterized as remission or mild non-symptomatic OSA.1

Study 1 (not on PAP therapy): Participants (n=234) who were unable or unwilling to use PAP therapy. Participants must not have used PAP for at least 4 weeks at the time of screening.1-3

Study 2 (on PAP therapy): Participants (n=235) were on PAP therapy for at least 3 consecutive months at the time of screening and planned to continue PAP therapy during the study. Participants in Study 2 suspended PAP use for 7 days before the scheduled PSGs.1-3

mITT population included randomly assigned participants who are exposed to at least 1 dose of study intervention; two participants in Study 2 were randomized but did not receive study drug.1

AHI=apnea-hypopnea index; BMI=body mass index; ESS=Epworth Sleepiness Scale; mITT=modified intent-to-treat; MTD=maximum tolerated dose; OSA=obstructive sleep apnea; PAP=positive airway pressure; PSG=polysomnography.

See SURMOUNT-OSA design

Select Important Safety Information

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.

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In SURMOUNT-OSA,

Adults taking Zepbound experienced significant reductions in hypoxic burden1a

CHANGE IN SLEEP APNEA-SPECIFIC HYPOXIC BURDEN FROM BASELINE TO WEEK 521,2,a

Treatment and placebo included a reduced-calorie diet and increased physical activity.2

aSASHB is a metric derived from PSG that quantifies the frequency, duration, and depth of oxygen desaturation associated with respiratory events.2

bP<0.001 for superiority of Zepbound vs placebo, controlled for type I error.1

Studied in adults with moderate-to-severe OSA with a BMI ≥30 kg/m2 randomized to receive Zepbound MTD (10 mg or 15 mg) or placebo.2

Study 1 (not on PAP therapy): Participants (n=234) who were unable or unwilling to use PAP therapy. Participants must not have used PAP for at least 4 weeks at the time of screening.1-3

Study 2 (on PAP therapy): Participants (n=235) were on PAP therapy for at least 3 consecutive months at the time of screening and planned to continue PAP therapy during the study. Participants in Study 2 suspended PAP use for 7 days before the scheduled PSGs.1-3

mITT population includes randomly assigned participants who were exposed to at least 1 dose of study intervention. Data represent change in sleep apnea-specific hypoxic burden from week 0 to 52. Least-squares mean from ANCOVA adjusted for baseline values and other stratification factors, with multiple imputation by treatment for missing data at week 52.1

ANCOVA=analysis of covariance; BMI=body mass index; mITT=modified intent-to-treat; MTD=maximum tolerated dose; OSA=obstructive sleep apnea; PAP=positive airway pressure; PSG=polysomnography; SASHB=sleep apnea-specific hypoxic burden.

See SURMOUNT-OSA design

Select Important Safety Information

Severe Gastrointestinal Adverse Reactions: Use of Zepbound has been associated with gastrointestinal adverse reactions, sometimes severe. In a pool of two Zepbound clinical trials (SURMOUNT-1 and SURMOUNT-2), 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%). Similar rates of severe gastrointestinal adverse reactions were observed in Zepbound clinical trials for weight reduction and in Zepbound clinical trials for obstructive sleep apnea (OSA). Zepbound has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

In SURMOUNT-OSA,

Adults taking Zepbound achieved significant reductions in body weight1

SECONDARY ENDPOINT: PERCENTAGE CHANGE IN BODY WEIGHT OVER TIME FROM BASELINE TO WEEK 521,2,6,a

Treatment and placebo included a reduced-calorie diet and increased physical activity.2

aGraph represents EE; numbers indicate TRE.6

bP<0.001 for superiority of Zepbound vs placebo, controlled for type I error.1

Studied in adults with moderate-to-severe OSA with a BMI ≥30 kg/m2 randomized to receive Zepbound MTD (10 mg or 15 mg) or placebo.2

Study 1 (not on PAP therapy): Participants (n=234) who were unable or unwilling to use PAP therapy. Participants must not have used PAP for at least 4 weeks at the time of screening.1-3

Study 2 (on PAP therapy): Participants (n=235) were on PAP therapy for at least 3 consecutive months at the time of screening and planned to continue PAP therapy during the study. Participants in Study 2 suspended PAP use for 7 days before the scheduled PSGs.1-3

Data shown are least squares mean. Least-squares mean from ANCOVA adjusted for baseline values and other stratification factors, with multiple imputation by treatment for missing data at Week 52. For percent change in body weight from randomization to week 52, data are derived from a mixed-model-for-repeated- measures analysis for the mITT population, and no explicit imputations were performed for missing data. mITT population included randomly assigned participants who are exposed to at least 1 dose of study treatment. Two participants in Study 2 were randomized but did not receive the study drug.2,4,5

ANCOVA=analysis of covariance; BMI=body mass index; EE=efficacy estimand; mITT=modified intent-to-treat; MTD=maximum tolerated dose; OSA=obstructive sleep apnea; PAP=positive airway pressure; PSG=polysomnography; TRE=treatment regimen estimand.

See SURMOUNT-OSA design

Select Important Safety Information

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.

In SURMOUNT-OSA Study 1,

Adults taking Zepbound achieved improvements in cardiometabolic parameters1

SECONDARY ENDPOINTS: CHANGES IN CARDIOMETABOLIC PARAMETERS FROM BASELINE1,2,7,8

Treatment and placebo included a reduced-calorie diet and increased physical activity.2

Zepbound is not indicated for hypertension or dyslipidemia.

aP<0.001 for superiority of Zepbound vs placebo, controlled for type I error.2
bP<0.05 for superiority of Zepbound vs placebo, controlled for type I error.2
cSecondary endpoint, not adjusted for multiplicity.2,7
dBP was assessed at Week 48 because PAP withdrawal at Week 52 may confound BP assessment.2,7,8
eLeast-squares mean from ANCOVA adjusted for baseline values and stratification factors, with multiple imputation for missing data at Week 52.8
fBaseline value is the geometric mean.8
gLeast-squares mean from mixed model for repeated measures adjusted for baseline value and stratification factors.8

Studied in adults with moderate-to-severe OSA with a BMI ≥30 kg/m2 randomized to receive Zepbound MTD (10 mg or 15 mg) or placebo.2

Study 1 (not on PAP therapy): Participants (n=234) who were unable or unwilling to use PAP therapy. Participants must not have used PAP for at least 4 weeks at the time of screening.2,3

Randomly assigned participants who are exposed to at least 1 dose of study intervention; two participants in Study 2 were randomized but did not receive study drug.8

ANCOVA=analysis of covariance;BMI=body mass index; HDL=high-density lipoprotein; hsCRP=high-sensitivity C-reactive protein; mITT=modified intent-to-treat; MTD=maximum tolerated dose; OSA=obstructive sleep apnea; PAP=positive airway pressure.

See SURMOUNT-OSA design

Select Important Safety Information

Acute Gallbladder Disease: Treatment with Zepbound and GLP-1 receptor agonists is associated with an increased occurrence of acute gallbladder disease. In a pool of two clinical trials of Zepbound (SURMOUNT-1 and SURMOUNT-2), 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. Similar rates of cholelithiasis were reported in Zepbound clinical trials for weight reduction and in Zepbound trials for OSA. If cholecystitis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.

In SURMOUNT-OSA Study 2,

Adults taking Zepbound achieved improvements in cardiometabolic parameters1

SECONDARY ENDPOINTS: CHANGES IN CARDIOMETABOLIC PARAMETERS FROM BASELINE1,2,7,8

Treatment and placebo included a reduced-calorie diet and increased physical activity.2

Zepbound is not indicated for hypertension or dyslipidemia.

aP<0.001 for superiority of Zepbound vs placebo, controlled for type I error.2
bSecondary endpoint, not controlled for type I error.2,7
cBP was assessed at Week 48 because PAP withdrawal at Week 52 may confound BP assessment.2,7,8
dLeast-squares mean from ANCOVA adjusted for baseline values and stratification factors, with multiple imputation for missing data at Week 52.8
eBaseline value is the geometric mean.8
fLeast-squares mean from mixed model for repeated measures adjusted for baseline value and stratification factors.8

Studied in adults with moderate-to-severe OSA with a BMI ≥30 kg/m2 randomized to receive Zepbound MTD (10 mg or 15 mg) or placebo.2

Study 2 (on PAP therapy): Participants (n=235) were on PAP therapy for at least 3 consecutive months at the time of screening and planned to continue PAP therapy during the study. Participants in Study 2 suspended PAP use for 7 days before the scheduled PSGs.2,3

Randomly assigned participants who are exposed to at least 1 dose of study intervention; two participants in Study 2 were randomized but did not receive study drug.8

ANCOVA=analysis of covariance; BMI=body mass index; HDL=high-density lipoprotein; hsCRP=high-sensitivity C-reactive protein; mITT=modified intent-to-treat; MTD=maximum tolerated dose; OSA=obstructive sleep apnea; PAP=positive airway pressure; PSG=polysomnography.

See SURMOUNT-OSA design

Select Important Safety Information

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 a pool of two Zepbound clinical trials (SURMOUNT-1 and SURMOUNT-2), 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). The exposure-adjusted incidence rate for treatment-emergent adjudication-confirmed pancreatitis in the pooled clinical studies for OSA was 0.84 patients per 100 years for Zepbound and 0 for placebo-treated patients. 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. Continuation of Zepbound after a confirmed diagnosis of pancreatitis should be individually determined in the clinical judgment of a patient’s health care provider.

Adverse reactions in SURMOUNT-OSA

Adverse Reactions Occurring in ≥5% of Adults Treated With Zepbound and More Frequently Than Placebo in Either Study1

Treatment and placebo included a reduced-calorie diet and increased physical activity.2

Studied in adults with moderate-to-severe OSA with a BMI ≥30 kg/m2 randomized to receive Zepbound MTD (10 mg or 15 mg) or placebo.1

Study 1 (not on PAP therapy): Participants (n=234) who were unable or unwilling to use PAP therapy. Participants must not have used PAP for at least 4 weeks at the time of screening.1-3

Study 2 (on PAP therapy): Participants (n=235) were on PAP therapy for at least 3 consecutive months at the time of screening and planned to continue PAP therapy during the study. Participants in Study 2 suspended PAP use for 7 days before the scheduled PSGs.1-3

Use of Zepbound has been associated with gastrointestinal adverse reactions, sometimes severe. In a pool of two Zepbound clinical trials (SURMOUNT-1 and SURMOUNT-2), 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%). Similar rates of severe gastrointestinal adverse reactions were observed in Zepbound clinical trials for weight reduction and Zepbound clinical trials for obstructive sleep apnea (OSA). Zepbound has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.2

BMI=body mass index; MTD=maximum tolerated dose; OSA=obstructive sleep apnea; PAP=positive airway pressure; PSG=polysomnography.

See SURMOUNT-OSA design

Select Important Safety Information

Hypersensitivity Reactions: There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) in patients treated with tirzepatide. In a pool of two Zepbound clinical trials (SURMOUNT-1 and SURMOUNT-2), 0.1% of Zepbound-treated patients had severe hypersensitivity reactions compared to no placebo-treated patients. Similar rates of severe hypersensitivity reactions were observed in Zepbound clinical trials for weight reduction and in Zepbound trials for OSA. 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.

Treatment discontinuation rates from the SURMOUNT- OSA trial1

TREATMENT DISCONTINUATION RATES1

Treatment and placebo included a reduced-calorie diet and increased physical activity.2

OSA=obstructive sleep apnea.

Select Important Safety Information

Hypoglycemia: Zepbound lowers blood glucose and can cause hypoglycemia. In a trial of patients with type 2 diabetes mellitus and BMI ≥27 kg/m2 (Study 2), 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. Hypoglycemia has also been associated with Zepbound and GLP-1 receptor agonists in adults without type 2 diabetes mellitus. 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 insulin or sulfonylurea (or other oncomitantly administered insulin secretagogue).

SURMOUNT-OSA study design

2 studies evaluating the effect of Zepbound in adults with moderate-to-severe OSA and obesity1,2

The SURMOUNT-OSA program included two 52-week phase 3, randomized, double-blind, placebo-controlled studies to evaluate the efficacy and safety of Zepbound at the maximum tolerated dose (10 mg or 15 mg) vs placebo as an adjunct to a reduced-calorie diet and increased physical activity. Primary endpoint of both studies was the change in the apnea-hypopnea index (AHI) from baseline.1,2

Participants had moderate-to-severe OSA (AHI ≥15 events/h) and obesity (BMI ≥30 kg/m2) without type 1 or type 2 diabetes.1,2

The participant population was composed of ~70% male adults.2

  • Study 1 (not on PAP therapy): Participants (n=234) who were unable or unwilling to use PAP therapy. Participants must not have used PAP for at least 4 weeks at the time of screening.1-3
  • Study 2 (on PAP therapy): Participants (n=235) were on PAP therapy for at least 3 consecutive months at the time of screening and planned to continue PAP therapy during the study.1-3*

*Participants in Study 2 suspended PAP use for 7 days before the scheduled PSGs and Patient-Reported Outcome (PRO) assessments.2

AHI=apnea-hypopnea index; BMI=body mass index; OSA=obstructive sleep apnea; PAP=positive airway pressure; PSG=polysomnography.

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References

  1. Zepbound. Prescribing Information. Lilly USA, LLC.
  2. Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N Engl J Med. 2024;391(13):1193-1205. doi:10.1056/NEJMoa2404881
  3. Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N Engl J Med. 2024; (suppl append). doi:10.1056/NEJMoa2404881
  4. Data on File. DOF-ZP-US-0028. Lilly USA, LLC.
  5. Data on File. DOF-ZP-US-0029. Lilly USA, LLC.
  6. Data on File. DOF-ZP-US-0027. Lilly USA, LLC.
  7. Malhotra A, Bednarik J, Chakladar S, et al. Tirzepatide for the treatment of obstructive sleep apnea: Rationale, design, and sample baseline characteristics of the SURMOUNT -OSA phase 3 trial. Contemporary Clinical Trials. 2024;141:107516. doi.org/10.1016/j.cct.2024.107516
  8. Data on File. DOF-ZP-US-0042. Lilly USA, LLC.
  9. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216. doi:10.1056/NEJMoa2206038
  10. Garvey WT, Frias JP, Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023;402(10402):613-626. doi:10.1016/S0140-6736(23)01200-X
  11. Data on File. DOF-ZP-US-0001. Lilly USA, LLC.
  12. Data on File. DOF-ZP-US-0005. Lilly USA, LLC.

Important Safety Information for Zepbound® (tirzepatide) injection

Warning:

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 Adverse Reactions: Use of Zepbound has been associated with gastrointestinal adverse reactions, sometimes severe. In a pool of two Zepbound clinical trials (SURMOUNT-1 and SURMOUNT-2), 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%). Similar rates of severe gastrointestinal adverse reactions were observed in Zepbound clinical trials for weight reduction and in Zepbound clinical trials for obstructive sleep apnea (OSA). 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 a pool of two clinical trials of Zepbound (SURMOUNT-1 and SURMOUNT-2), 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. Similar rates of cholelithiasis were reported in Zepbound clinical trials for weight reduction and in Zepbound trials for OSA. 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 a pool of two Zepbound clinical trials (SURMOUNT-1 and SURMOUNT-2), 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). The exposure-adjusted incidence rate for treatment-emergent adjudication-confirmed pancreatitis in the pooled clinical studies for OSA was 0.84 patients per 100 years for Zepbound and 0 for placebo-treated patients. 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. Continuation of Zepbound after a confirmed diagnosis of pancreatitis should be individually determined in the clinical judgment of a patient’s health care provider.

Hypersensitivity Reactions: There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) in patients treated with tirzepatide. In a pool of two Zepbound clinical trials (SURMOUNT-1 and SURMOUNT-2), 0.1% of Zepbound-treated patients had severe hypersensitivity reactions compared to no placebo-treated patients. Similar rates of severe hypersensitivity reactions were observed in Zepbound clinical trials for weight reduction and in Zepbound trials for OSA. 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 (Study 2), 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. Hypoglycemia has also been associated with Zepbound and GLP-1 receptor agonists in adults without type 2 diabetes mellitus. 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 insulin or sulfonylurea (or other concomitantly administered insulin secretagogue).

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 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.

Pulmonary Aspiration During General Anesthesia or Deep Sedation: Zepbound delays gastric emptying. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking Zepbound, including whether modifying preoperative fasting recommendations or temporarily discontinuing Zepbound could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking Zepbound.

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 or insulin secretagogues (e.g., sulfonylureas) 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.

Please see accompanying Prescribing Information, including Boxed Warning about possible thyroid tumors, including thyroid cancer, and Medication Guide.

Please see Instructions for Use.

Zepbound is available as a 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg and 15 mg injection.

ZP HCP ISI 20DEC2024

INDICATIONS

Zepbound is indicated in combination with a reduced-calorie diet and increased physical activity:

  • to reduce excess body weight and maintain weight reduction long term in adults with obesity or adults with overweight in the presence of at least one weight-related comorbid condition.
  • to treat moderate-to-severe obstructive sleep apnea (OSA) in adults with obesity.

Limitations of Use

Zepbound contains tirzepatide. Coadministration with other tirzepatide-containing products or with any glucagon-like peptide-1 (GLP-1) receptor agonist is not recommended.