Mounjaro (Tirzepatide)

• In both male and female rats, tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether MOUNJARO 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 both sexes of 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 MOUNJARO 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.

  MOUNJARO 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 MOUNJARO 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 MOUNJARO. 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 males (≥0.5 mg/kg) and females (≥0.15 mg/kg), and a statistically significant increase in thyroid C-cell adenomas and carcinomas combined was observed in males and females 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.

  )].
• MOUNJARO 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

  MOUNJARO is contraindicated in patients with:

  • A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
    [see Warnings and Precautions ]
    .
  • Known serious hypersensitivity to tirzepatide or any of the excipients in MOUNJARO. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with MOUNJARO
    [see Warnings and Precautions ]
    .

  • 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 MOUNJARO

  )]
  . Counsel patients regarding the potential risk for MTC with the use of MOUNJARO 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 MOUNJARO
  [see Contraindications (

  4 CONTRAINDICATIONS

  MOUNJARO is contraindicated in patients with:

  • A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
    [see Warnings and Precautions ]
    .
  • Known serious hypersensitivity to tirzepatide or any of the excipients in MOUNJARO. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with MOUNJARO
    [see Warnings and Precautions ]
    .

  • 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 MOUNJARO

  ) and Warnings and Precautions (

  5.1 Risk of Thyroid C-Cell Tumors

  In both sexes of 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 MOUNJARO 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.

  MOUNJARO 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 MOUNJARO 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 MOUNJARO. 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.

  )].

MOUNJARO^® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

• The recommended starting dosage is 2.5 mg injected subcutaneously once weekly (
  2.1 Dosage

  • The recommended starting dosage of MOUNJARO is 2.5 mg injected subcutaneously once weekly. Follow the dosage escalation below to reduce the risk of gastrointestinal adverse reactions
    [see Warnings and Precautions and Adverse Reactions ]
    . The 2.5 mg dosage is for treatment initiation and is not intended for glycemic control.
  • After 4 weeks, increase the dosage to 5 mg injected subcutaneously once weekly.
  • If additional glycemic control is needed, increase the dosage in 2.5 mg increments after at least 4 weeks on the current dose.
  • The maximum dosage of MOUNJARO is 15 mg injected subcutaneously once weekly.
  • If a dose is missed, instruct patients to administer MOUNJARO as soon as possible within 4 days (96 hours) after the missed dose. If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.
  • The day of weekly administration can be changed, if necessary, as long as the time between the two doses is at least 3 days (72 hours).
  )
• After 4 weeks, increase to 5 mg injected subcutaneously once weekly (
  2.1 Dosage

  • The recommended starting dosage of MOUNJARO is 2.5 mg injected subcutaneously once weekly. Follow the dosage escalation below to reduce the risk of gastrointestinal adverse reactions
    [see Warnings and Precautions and Adverse Reactions ]
    . The 2.5 mg dosage is for treatment initiation and is not intended for glycemic control.
  • After 4 weeks, increase the dosage to 5 mg injected subcutaneously once weekly.
  • If additional glycemic control is needed, increase the dosage in 2.5 mg increments after at least 4 weeks on the current dose.
  • The maximum dosage of MOUNJARO is 15 mg injected subcutaneously once weekly.
  • If a dose is missed, instruct patients to administer MOUNJARO as soon as possible within 4 days (96 hours) after the missed dose. If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.
  • The day of weekly administration can be changed, if necessary, as long as the time between the two doses is at least 3 days (72 hours).
  )
• If additional glycemic control is needed, increase the dosage in 2.5 mg increments after at least 4 weeks on the current dose. (
  2.1 Dosage

  • The recommended starting dosage of MOUNJARO is 2.5 mg injected subcutaneously once weekly. Follow the dosage escalation below to reduce the risk of gastrointestinal adverse reactions
    [see Warnings and Precautions and Adverse Reactions ]
    . The 2.5 mg dosage is for treatment initiation and is not intended for glycemic control.
  • After 4 weeks, increase the dosage to 5 mg injected subcutaneously once weekly.
  • If additional glycemic control is needed, increase the dosage in 2.5 mg increments after at least 4 weeks on the current dose.
  • The maximum dosage of MOUNJARO is 15 mg injected subcutaneously once weekly.
  • If a dose is missed, instruct patients to administer MOUNJARO as soon as possible within 4 days (96 hours) after the missed dose. If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.
  • The day of weekly administration can be changed, if necessary, as long as the time between the two doses is at least 3 days (72 hours).
  )
• The maximum dosage is 15 mg subcutaneously once weekly. (
  2.1 Dosage

  • The recommended starting dosage of MOUNJARO is 2.5 mg injected subcutaneously once weekly. Follow the dosage escalation below to reduce the risk of gastrointestinal adverse reactions
    [see Warnings and Precautions and Adverse Reactions ]
    . The 2.5 mg dosage is for treatment initiation and is not intended for glycemic control.
  • After 4 weeks, increase the dosage to 5 mg injected subcutaneously once weekly.
  • If additional glycemic control is needed, increase the dosage in 2.5 mg increments after at least 4 weeks on the current dose.
  • The maximum dosage of MOUNJARO is 15 mg injected subcutaneously once weekly.
  • If a dose is missed, instruct patients to administer MOUNJARO as soon as possible within 4 days (96 hours) after the missed dose. If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.
  • The day of weekly administration can be changed, if necessary, as long as the time between the two doses is at least 3 days (72 hours).
  )
• Administer once weekly at any time of day, with or without meals. (
  2.2 Important Administration Instructions

  • Prior to initiation, train patients and caregivers on proper injection technique
    [see Instructions for Use]
    .
  • Instruct patients using the single-dose vial to use a syringe appropriate for dose administration (e.g., a 1 mL syringe capable of measuring a 0.5 mL dose).
  • Administer MOUNJARO once weekly, any time of day, with or without meals.
  • Inject MOUNJARO subcutaneously in the abdomen, thigh, or another person should inject in the back of the upper arm.
  • Rotate injection sites with each dose.
  • Inspect MOUNJARO visually before use. It should appear clear and colorless to slightly yellow. Do not use MOUNJARO if particulate matter or discoloration is seen.
  • When using MOUNJARO with insulin, administer as separate injections and never mix. It is acceptable to inject MOUNJARO and insulin in the same body region, but the injections should not be adjacent to each other.
  )
• Inject subcutaneously in the abdomen, thigh, or upper arm. (
  2.2 Important Administration Instructions

  • Prior to initiation, train patients and caregivers on proper injection technique
    [see Instructions for Use]
    .
  • Instruct patients using the single-dose vial to use a syringe appropriate for dose administration (e.g., a 1 mL syringe capable of measuring a 0.5 mL dose).
  • Administer MOUNJARO once weekly, any time of day, with or without meals.
  • Inject MOUNJARO subcutaneously in the abdomen, thigh, or another person should inject in the back of the upper arm.
  • Rotate injection sites with each dose.
  • Inspect MOUNJARO visually before use. It should appear clear and colorless to slightly yellow. Do not use MOUNJARO if particulate matter or discoloration is seen.
  • When using MOUNJARO with insulin, administer as separate injections and never mix. It is acceptable to inject MOUNJARO and insulin in the same body region, but the injections should not be adjacent to each other.
  )
• Rotate injection sites with each dose (
  2.2 Important Administration Instructions

  • Prior to initiation, train patients and caregivers on proper injection technique
    [see Instructions for Use]
    .
  • Instruct patients using the single-dose vial to use a syringe appropriate for dose administration (e.g., a 1 mL syringe capable of measuring a 0.5 mL dose).
  • Administer MOUNJARO once weekly, any time of day, with or without meals.
  • Inject MOUNJARO subcutaneously in the abdomen, thigh, or another person should inject in the back of the upper arm.
  • Rotate injection sites with each dose.
  • Inspect MOUNJARO visually before use. It should appear clear and colorless to slightly yellow. Do not use MOUNJARO if particulate matter or discoloration is seen.
  • When using MOUNJARO with insulin, administer as separate injections and never mix. It is acceptable to inject MOUNJARO and insulin in the same body region, but the injections should not be adjacent to each other.
  )

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:
  Based on animal studies, may cause fetal harm. (
  8.1 Pregnancy

  Risk Summary

  Available data with MOUNJARO use in pregnant women are insufficient to evaluate for a drug-related risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy

  (see Clinical Considerations)

  . Based on animal reproduction studies, there may be risks to the fetus from exposure to tirzepatide during pregnancy. MOUNJARO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

  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 is 6–10% in women with pre-gestational diabetes with an HbA1c >7% and has been reported to be as high as 20–25% in women with an HbA1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. 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

  Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

  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 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 MOUNJARO 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 and for 4 weeks after each dose escalation with MOUNJARO

  [see Drug Interactions and Clinical Pharmacology ].
  )