Tirzepatide (Monograph)

Brand names: Mounjaro, Zepbound
Drug class: Incretin Mimetics

Medically reviewed by Drugs.com on Nov 20, 2023. Written by ASHP.

Introduction

Dual glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide 1 (GLP-1) receptor agonist.

Uses for Tirzepatide

Type 2 Diabetes

Used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

There are 2 preparations of tirzepatide commercially available; Mounjaro is specifically FDA-labeled for use in diabetes mellitus.

Not studied in patients with a history of pancreatitis.

Not indicated for use in patients with type 1 diabetes.

Guidelines support use of tirzepatide in patients with type 2 diabetes whose treatment goals warrant use of agents with very high glucose-lowering and/or weight loss efficacy.

Weight Management

Used as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults who are obese (pretreatment body mass index [BMI] ≥30 kg/m²) or, in adults who are overweight (pretreatment BMI ≥27 kg/m²) and who have at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea, cardiovascular disease).

There are 2 preparations of tirzepatide commercially available; Zepbound is specifically FDA-labeled for use in chronic weight management.

Has been shown to substantially decrease body weight in patients with obesity with or without diabetes.

Do not use in combination with any other tirzepatide-containing products or any other GLP-1 receptor agonist. Safety and efficacy of tirzepatide in combination with other products used to promote weight loss not established.

Not studied in patients with a history of pancreatitis.

Clinical practice guidelines recommend that patients with excess body weight and associated health risks be treated for obesity. Essential component of therapy is a comprehensive lifestyle intervention; may consider pharmacologic therapy as an adjunct in patients who fail to achieve or sustain clinically meaningful weight loss (generally defined as loss of >4–5% of total body weight) with behavioral modification alone. Evaluate response to drug therapy after 3–4 months; if clinically meaningful weight loss not achieved, consider new treatment plan because patient is likely not responding to the drug.

Related/similar drugs

metformin, Mounjaro, semaglutide, Trulicity, phentermine, Wegovy, Lantus

Tirzepatide Dosage and Administration

General

Pretreatment Screening

• If used for weight management, select patients for treatment based on BMI.

• In patients with type 2 diabetes mellitus receiving tirzepatide for chronic weight management, monitor blood glucose prior to initiating therapy.

Patient Monitoring

• Periodically monitor blood glucose and glycosylated hemoglobin (HbA_1c) to determine therapeutic response in patients with type 2 diabetes mellitus.

• Monitor for signs and symptoms of thyroid tumors, including a mass in the neck, dysphagia, dyspnea, and persistent hoarseness.

• Monitor for signs and symptoms of pancreatitis such as persistent severe abdominal pain with or without vomiting.

• For patients with pre-existing renal impairment reporting severe GI adverse reactions, monitor renal function when initiating or escalating doses of tirzepatide.

• For patients with a history of diabetic retinopathy, monitor for progression of retinopathy.

• Monitor for signs and symptoms of hypoglycemia, particularly in patients receiving concomitant therapy with insulin or an insulin secretagogue.

• Monitor patients with a history of diabetic retinopathy for progression of diabetic retinopathy while receiving tirzepatide.

• Monitor for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.

Administration

Sub-Q Administration

Administer via sub-Q injection once weekly with or without meals.

Tirzepatide for type 2 diabetes (Mounjaro) is available in pre-filled single-dose pens or single-dose vials in the following strengths per 0.5 mL: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg. Tirzepatide for weight management (Zepbound) is available in pre-filled single-dose pens in the following strengths per 0.5 mL: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg.

Tirzepatide is a clear, colorless to slightly yellow solution; do not use if particulate matter or discoloration is seen.

Train patients and/or caregivers on proper injection technique. Inject sub-Q into the abdomen, thigh, or upper arm. Rotate injection sites with each dose.

Instruct patients using the single-dose vial of Mounjaro to use an appropriate syringe for administration (e.g., a 1 mL syringe capable of measuring a 0.5 mL dose). When using with insulin, administer as separate injections; do not mix. Injections of tirzepatide and insulin can be given in the same body region but injections should not be adjacent to one other.

If a dose is missed, administer as soon as possible within 4 days (96 hours) after the missed dose; then, resume the regular once weekly dosing schedule. If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. May change day of weekly administration, if necessary, as long as the time between the 2 doses is at least 3 days (72 hours).

Dosage

Adults

Type 2 Diabetes

Sub-Q

2.5 mg once weekly initially; increase to 5 mg once weekly after 4 weeks.

If needed, may further increase dosage in 2.5 mg increments after at least 4 weeks on the current dosage; maximum of 15 mg once weekly.

Chronic Weight Management

Sub-Q

2.5 mg once weekly initially; increase to 5 mg once weekly after 4 weeks.

If needed, may further increase dosage in 2.5 mg increments after at least 4 weeks on the current dosage.

Recommended maintenance dosage in adults is 5 mg, 10 mg, or 15 mg once weekly; consider treatment response and tolerability when selecting appropriate maintenance dosage. Maximum recommended dosage is 15 mg once weekly.

Special Populations

Hepatic Impairment

No dosage adjustment required.

Renal Impairment

No dosage adjustment required.

Geriatric Use

No specific dosage recommendations at this time.

Cautions for Tirzepatide

Contraindications

• Personal or family history of medullary thyroid carcinoma (MTC) or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).

• Known serious hypersensitivity to tirzepatide or any excipients.

Warnings/Precautions

Risk of Thyroid C-Cell Tumors

Causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors in rats at clinically relevant exposures. Unknown whether tirzepatide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. (See Boxed Warning.)

Contraindicated in patients with a personal or family history of MTC or in patients with MEN 2.

Counsel patients regarding potential risk of MTC 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 thyroid ultrasound is of uncertain value for early MTC detection in patients receiving tirzepatide.

Risks During General Anesthesia and Deep Sedation

GLP-1 agonists are associated with adverse GI effects such as nausea, vomiting, and delayed gastric emptying.

Delayed gastric emptying from GLP-1 agonists can increase the risk of regurgitation and pulmonary aspiration of gastric contents during general anesthesia and deep sedation.

Given these concerns, the American Society of Anesthesiologists (ASA) Task Force on Preoperative Fasting has issued a consensus-based guidance for management of GLP-1 receptor agonists prior to elective surgery. The task force suggests that for patients on daily GLP-1 agonist dosing (irrespective of indication, dose, or type of surgery), consider holding the drug on the day of procedure/surgery. For patients on weekly dosing (irrespective of indication, dose, or type of surgery), consider holding the GLP-1 agonist a week prior to procedure/surgery. If GLP-1 agonists prescribed for diabetes management are held for longer than the dosing schedule, consider consulting an endocrinologist for bridging the antidiabetic therapy to avoid hyperglycemia.

For patients requiring urgent or emergent procedures, the task force states to proceed and treat the patient as ‘full stomach’ and manage accordingly.

Pancreatitis

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, observed in patients treated with glucagon-like peptide 1 (GLP-1) receptor agonists.

Not studied in patients with a prior history of pancreatitis. Unknown if the risk of pancreatitis is increased in such patients.

After initiation of tirzepatide, observe patients carefully for signs and symptoms of pancreatitis (e.g., persistent severe abdominal pain that sometimes radiates to the back; may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue tirzepatide and initiate appropriate management.

Hypoglycemia

Tirzepatide lowers blood glucose and can cause hypoglycemia.

Increased risk of hypoglycemia, including severe hypoglycemia, in patients receiving tirzepatide in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin.

Risk of hypoglycemia may be lowered by reducing the dose of the insulin secretagogue or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on signs and symptoms of hypoglycemia.

Hypersensitivity Reactions

Serious hypersensitivity reactions reported with tirzepatide (e.g., anaphylaxis, angioedema). If hypersensitivity reactions occur, discontinue use of tirzepatide; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previous serious hypersensitivity reaction to tirzepatide or any excipients in the formulation.

Anaphylaxis and angioedema reported with other GLP-1 receptor agonists. Use caution in patients with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist; unknown whether such patients will be predisposed to these reactions with tirzepatide.

Acute Kidney Injury

Tirzepatide is associated with GI adverse reactions (e.g., nausea, vomiting, diarrhea); these events may lead to dehydration, which could cause acute kidney injury if severe. Acute kidney injury and worsening of chronic renal failure, sometimes requiring hemodialysis, documented in postmarketing reports. Some events reported in patients without known underlying renal disease; most events occurred in patients who experienced nausea, vomiting, diarrhea, or dehydration.

Monitor renal function when initiating or escalating doses of tirzepatide in patients with renal impairment reporting severe GI adverse reactions.

Severe GI Disease

Use of tirzepatide associated with GI adverse reactions, sometimes severe.

Not studied in patients with severe GI disease, including severe gastroparesis; use in such patients not recommended.

Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy

Rapid improvement in glucose control has been associated with temporary worsening of diabetic retinopathy.

Tirzepatide not 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 of diabetic retinopathy.

Acute Gallbladder Disease

Acute events of gallbladder disease such as cholelithiasis or cholecystitis reported. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.

Suicidality

Suicidal behavior and ideation reported with other weight management products.

Monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.

If a patient experiences suicidal thoughts or behaviors while receiving semaglutide, discontinue the drug. Avoid tirzepatide in patients with a history of suicidal attempts or active suicidal ideation.

Immunogenicity

Anti-tirzepatide antibody formation reported during tirzepatide therapy. Anti-tirzepatide antibodies did not impact pharmacokinetics or effectiveness of tirzepatide; however, patients who developed anti-tirzepatide antibodies were more likely to experience hypersensitivity reactions or injection site reactions.

Specific Populations

Pregnancy

Available data with tirzepatide use in pregnant women are insufficient to inform a drug-associated 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. Tirzepatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

No data on the presence of tirzepatide in animal or human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for tirzepatide and any potential adverse effects on the breast-fed infant from tirzepatide or from the underlying maternal condition.

Females and Males of Reproductive Potential

Tirzepatide may reduce efficacy of oral hormonal contraceptives due to delayed gastric emptying. 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 tirzepatide initiation and 4 weeks after each dose escalation.

Pediatric Use

Safety and effectiveness not established in pediatric patients (<18 years of age).

Geriatric Use

No overall differences in safety or efficacy observed between older patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment

Hepatic impairment (mild, moderate, or severe) does not impact pharmacokinetics of tirzepatide.

Renal Impairment

Renal impairment, including end-stage renal disease, does not impact pharmacokinetics of tirzepatide. Monitor renal function when initiating or escalating doses of tirzepatide in patients with renal impairment reporting severe adverse GI reactions.

Common Adverse Effects

Adverse reactions (≥5%) in patients receiving tirzepatide for diabetes mellitus: nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, abdominal pain.

Adverse reactions (≥5%) in patients receiving tirzepatide for chronic weight management: nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, injection site reactions, fatigue, hypersensitivity reactions, eructation, hair loss, gastroesophageal reflux disease.

Drug Interactions

Low potential to inhibit or induce CYP enzymes or to inhibit drug transporters.

Orally Administered Drugs

Tirzepatide delays gastric emptying and may impact absorption of concomitantly administered oral medications. Use caution when oral medications are administered concomitantly with tirzepatide. Monitor patients taking oral medications dependent on threshold concentrations for efficacy and those with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with tirzepatide.

Specific Drugs

Tirzepatide Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability after sub-Q administration: 80%.

Exposure increases in dose-proportional manner.

Time to maximum plasma concentration: 8–72 hours.

Steady-state concentrations achieved after 4 weeks of once weekly administration.

Distribution

Plasma Protein Binding

99% bound to plasma albumin.

Elimination

Metabolism

Metabolized by proteolytic cleavage of the peptide backbone, beta oxidation of the C20 fatty diacid moiety, and amide hydrolysis.

Elimination Route

Metabolites excreted in urine and feces; intact tirzepatide not observed in urine or feces.

Half-Life

5 days.

Stability

Storage

Parenteral

Injection for Sub-Q Use

2–8°C. Store in original carton to protect from light; do not freeze.

May store vials and pens unrefrigerated at temperatures not exceeding 30°C for up to 21 days.

Actions

• A 39-amino-acid modified peptide based on the glucose-dependent insulinotropoic polypeptide (GIP) sequence with a C20 fatty diacid moiety that enables albumin binding and prolongs half-life.

• A dual GIP receptor and glucagon-like peptide 1 (GLP-1) receptor agonist.

• Selectively binds to and activates both GIP and GLP-1 receptors (targets for native GIP and GLP-1).

• Enhances first- and second-phase insulin secretion in a glucose-dependent manner.

• Reduces glucagon levels in a glucose-dependent manner.

• Increases insulin sensitivity and delays gastric emptying.

Advice to Patients

• Inform patients that tirzepatide causes thyroid C-cell tumors in rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, persistent hoarseness, dysphagia, or dyspnea) to their healthcare provider.

• Inform patients of the potential risk for pancreatitis. Instruct patients to discontinue tirzepatide promptly and contact their healthcare provider if pancreatitis is suspected (severe abdominal pain that may radiate to the back; may or may not be accompanied by vomiting).

• Inform patients that the risk of hypoglycemia is increased when tirzepatide is used with an insulin secretagogue (such as a sulfonylurea) or insulin. Educate patients on the signs and symptoms of hypoglycemia.

• Inform patients that serious hypersensitivity reactions have been reported with use of tirzepatide. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking tirzepatide and seek medical advice promptly if such symptoms occur.

• Advise patients treated with tirzepatide of the potential risk of dehydration due to GI adverse reactions and take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs.

• Inform patients of the potential risk of severe GI adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent GI symptoms.

• Inform patients to contact their healthcare provider if changes in vision are experienced during treatment with tirzepatide.

• Inform patients of the risk of acute gallbladder disease. Instruct patients to contact their healthcare provider for appropriate clinical follow-up if gallbladder disease is suspected.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Advise a pregnant woman of the potential risk to a fetus.

• Use of tirzepatide may reduce the efficacy of oral hormonal contraceptives. 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 tirzepatide initiation and for 4 weeks after each dose escalation with tirzepatide.

• Instruct patients how to prepare and administer the correct dose of tirzepatide and assess their ability to inject subcutaneously to ensure the proper administration of tirzepatide. 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).

• Advise patients to report emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Inform patients that if they experience suicidal thoughts or behaviors, they should stop taking the drug.

• Inform patients that if a dose is missed, it should be administered as soon as possible within 4 days after the missed dose. If more than 4 days have passed, the missed dose should be skipped and the next dose should be administered on the regularly scheduled day. In each case, inform patients to resume their regular once weekly dosing schedule.

• Advise patient to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other cautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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