Tirzepatide

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 [see Warnings and Precautions ( 5.1 ) and Nonclinical Toxicology ( 13.1 )]. 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) [see Contraindications ( 4 )] . 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 [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. In rats, tirzepatide causes thyroid C-cell tumors. It is unknown whether ZEPBOUND causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). 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 of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).

Severe Gastrointestinal Adverse Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. ZEPBOUND is not recommended in patients with severe gastroparesis. ( 5.2 ) Acute Kidney Injury Due to Volume Depletion: Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.3 ) Acute Gallbladder Disease: Has been reported in clinical trials. If cholecystitis is suspected, gallbladder studies and clinical follow-up are indicated. ( 5.4 ) Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, or ZEPBOUND. Discontinue if pancreatitis is suspected. ( 5.5 ) Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported postmarketing with tirzepatide. If suspected, advise patients to promptly seek medical attention and discontinue ZEPBOUND. ( 5.6 ) Hypoglycemia: Concomitant use with insulin or an insulin secretagogue may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing dose of insulin or insulin secretagogue may be necessary. Inform all patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. ( 5.7 ) Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus: Has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema. Monitor patients with a history of diabetic retinopathy for progression. ( 5.8 ) Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.9 ) Never share a ZEPBOUND KwikPen between patients, even if the pen needle is changed. ( 5.10 )

Risk of Thyroid C-Cell Tumors 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.

Severe Gastrointestinal Adverse Reactions Use of ZEPBOUND has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions ( 6 )] . In a pool of two ZEPBOUND clinical trials for weight reduction (Studies 1 and 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%). Similar rates of severe gastrointestinal adverse reactions were observed in ZEPBOUND clinical trials for weight reduction and in ZEPBOUND clinical trials for OSA. Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists. ZEPBOUND is not recommended in patients with severe gastroparesis.

Acute Kidney Injury Due to Volume Depletion There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists, or ZEPBOUND [see Adverse Reactions ( 6.2 )] . The majority of the reported events occurred in patients who experienced gastrointestinal adverse reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions ( 6.1 )] . Monitor renal function in patients reporting adverse reactions to ZEPBOUND that could lead to volume depletion, especially during dosage initiation and escalation of ZEPBOUND.

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 ZEPBOUND clinical trials for weight reduction (Studies 1 and 2), 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. 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 ZEPBOUND [see Adverse Reactions ( 6 )] . After initiation of ZEPBOUND, observe patients carefully for signs and symptoms of acute pancreatitis which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue ZEPBOUND and initiate appropriate management.

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 studies for weight reduction (Studies 1 and 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 [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.

Hypoglycemia ZEPBOUND lowers blood glucose and can cause hypoglycemia. In a trial of patients with type 2 diabetes mellitus and BMI ≥27 kg/m 2 (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 [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 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.

Pulmonary Aspiration During General Anesthesia or Deep Sedation ZEPBOUND delays gastric emptying [see Clinical Pharmacology ( 12.2 )] . 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.

Never Share a ZEPBOUND KwikPen Between Patients Never share ZEPBOUND KwikPen between patients, even if the pen needle is changed. Sharing poses a risk for transmission of blood-borne pathogens.