Zepbound

• 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 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 ]

  . 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.

  ) and Nonclinical Toxicology (

  13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

  A 2-year carcinogenicity study was conducted with tirzepatide in male and female rats at doses of 0.15, 0.50, and 1.5 mg/kg (0.1-, 0.4-, and 1-fold the MRHD of 15 mg once weekly based on AUC) administered by subcutaneous injection twice weekly. A statistically significant increase in thyroid C-cell adenomas was observed in male rats (≥0.5 mg/kg) and female rats (≥0.15 mg/kg), and a statistically significant increase in thyroid C-cell adenomas and carcinomas combined was observed in male and female rats at all doses examined. In a 6-month carcinogenicity study in rasH2 transgenic mice, tirzepatide at doses of 1, 3, and 10 mg/kg administered by subcutaneous injection twice weekly was not tumorigenic.

  Tirzepatide was not genotoxic in a rat bone marrow micronucleus assay.

  In fertility and early embryonic development studies, male and female rats were administered twice weekly subcutaneous doses of 0.5, 1.5, or 3 mg/kg (0.3-, 1-, and 2-fold and 0.3-, 0.9-, and 2-fold, respectively, the MRHD of 15 mg once weekly based on AUC). No effects of tirzepatide were observed on sperm morphology, mating, fertility, and conception. In female rats, an increase in the number of females with prolonged diestrus and a decrease in the mean number of corpora lutea resulting in a decrease in the mean number of implantation sites and viable embryos was observed at all dose levels. These effects were considered secondary to the pharmacological effects of tirzepatide on food consumption and body weight.

  )].
• 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 CONTRAINDICATIONS

  ZEPBOUND is contraindicated in patients with:

  • A personal or family history of MTC or in patients with MEN 2
    [see Warnings and Precautions ]
    .
  • Known serious hypersensitivity to tirzepatide or any of the excipients in ZEPBOUND. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with tirzepatide
    [see Warnings and Precautions and Adverse Reactions ]
    .

  • Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2
  • Known serious hypersensitivity to tirzepatide or any of the excipients in ZEPBOUND

  )]
  . 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 CONTRAINDICATIONS

  ZEPBOUND is contraindicated in patients with:

  • A personal or family history of MTC or in patients with MEN 2
    [see Warnings and Precautions ]
    .
  • Known serious hypersensitivity to tirzepatide or any of the excipients in ZEPBOUND. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with tirzepatide
    [see Warnings and Precautions and Adverse Reactions ]
    .

  • Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2
  • Known serious hypersensitivity to tirzepatide or any of the excipients in ZEPBOUND

  ) and Warnings and Precautions (

  5.1 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 ]

  . 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.

  )].

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.

• The recommended starting dosage is 2.5 mg injected subcutaneously once weekly for 4 weeks. Increase the dosage in 2.5 mg increments after at least 4 weeks until recommended maintenance dosage is achieved. (
  2.1 Recommended Dose Escalation Schedule

  • The recommended starting dosage of ZEPBOUND for all indications is 2.5 mg injected subcutaneously once weekly for 4 weeks.
  • The 2.5 mg dosage is for treatment initiation and is not approved as a maintenance dosage.
  • Follow the dosage escalation below for all indications to reduce the risk of gastrointestinal adverse reactions
    [see Warnings and Precautions and Adverse Reactions ]
    .
  • After 4 weeks, increase the dosage to 5 mg injected subcutaneously once weekly. The dosage may be increased in 2.5 mg increments, after at least 4 weeks on the current dose
    [see Dosage and Administration ]
    .
  • Consider treatment response and tolerability when selecting the maintenance dosage. If patients do not tolerate a maintenance dosage, consider a lower maintenance dosage.
  )
• Consider treatment response and tolerability when selecting the maintenance dosage. (
  2.1 Recommended Dose Escalation Schedule

  • The recommended starting dosage of ZEPBOUND for all indications is 2.5 mg injected subcutaneously once weekly for 4 weeks.
  • The 2.5 mg dosage is for treatment initiation and is not approved as a maintenance dosage.
  • Follow the dosage escalation below for all indications to reduce the risk of gastrointestinal adverse reactions
    [see Warnings and Precautions and Adverse Reactions ]
    .
  • After 4 weeks, increase the dosage to 5 mg injected subcutaneously once weekly. The dosage may be increased in 2.5 mg increments, after at least 4 weeks on the current dose
    [see Dosage and Administration ]
    .
  • Consider treatment response and tolerability when selecting the maintenance dosage. If patients do not tolerate a maintenance dosage, consider a lower maintenance dosage.
  )

• Weight Reduction and Long-Term Maintenance:
  5 mg, 10 mg, or 15 mg injected subcutaneously once weekly. (
  2.2 Recommended Maintenance and Maximum Dosage

  Recommended Maintenance Dosage

  Weight Reduction and Long-Term Maintenance

  The recommended maintenance dosage is 5 mg, 10 mg, or 15 mg, injected subcutaneously once weekly.

  OSA

  The recommended maintenance dosage is 10 mg or 15 mg injected subcutaneously once weekly.

  Maximum Recommended Dosage

  The maximum dosage of ZEPBOUND for all indications is 15 mg injected subcutaneously once weekly.
  )
• Obstructive Sleep Apnea:
  10 mg or 15 mg injected subcutaneously once weekly. (
  2.2 Recommended Maintenance and Maximum Dosage

  Recommended Maintenance Dosage

  Weight Reduction and Long-Term Maintenance

  The recommended maintenance dosage is 5 mg, 10 mg, or 15 mg, injected subcutaneously once weekly.

  OSA

  The recommended maintenance dosage is 10 mg or 15 mg injected subcutaneously once weekly.

  Maximum Recommended Dosage

  The maximum dosage of ZEPBOUND for all indications is 15 mg injected subcutaneously once weekly.
  )

See full prescribing information for administration instructions. (

Injection: Clear, colorless to slightly yellow solution in pre-filled single-dose pens or single-dose vials, each available in the following strengths:

• 2.5 mg/0.5 mL
• 5 mg/0.5 mL
• 7.5 mg/0.5 mL
• 10 mg/0.5 mL
• 12.5 mg/0.5 mL
• 15 mg/0.5 mL

• Pregnancy:
  May cause fetal harm. When pregnancy is recognized, discontinue ZEPBOUND. (
  8.1 Pregnancy

  Pregnancy Exposure Registry

  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).

  Risk Summary

  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.

  Clinical Considerations

  Disease-Associated Maternal and/or Embryo/Fetal Risk

  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.

  Data

  Animal Data

  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, F₁pups from F₀maternal 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.
  )
• Females of Reproductive Potential:
  Advise females using oral contraceptives to switch to a non-oral contraceptive method or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation. (
  8.3 Females and Males of Reproductive Potential

  Contraception

  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 and Clinical Pharmacology ]

  .
  )