tirzepatide (Rx)

>10%

Blood glucose <54 mg/dL (added to basal insulin) (14-19%)

Nausea (12-18%)

Diarrhea (12-17%)

Decreased appetite (5-11%)

1-10%

Vomiting (5-9%)

Dyspepsia (5-8%)

Constipation (5-7%)

Abdominal pain (5-6%)

Injection site reactions (3.2%)

Hypersensitivity reactions (3.2%)

Severe hypoglycemia (add-on to basal insulin) (1-2%)

<1%

Acute gallbladder disease (0.5%)

Contraindications

Personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2

Known hypersensitivity to tirzepatide or to any of the product components

Cautions

On the basis of findings in rats and mice, may cause thyroid C-cell tumors, including MTC, in humans; human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, observed in patients treated with GLP-1 receptor agonists; after initiating, monitor for signs and symptoms of pancreatitis (eg, persistent severe abdominal pain, which sometimes radiates to the back and may or may not be accompanied by vomiting); if pancreatitis suspected, discontinue and do not restart if confirmed

Rapid improvement in glucose control associated with temporary worsening of diabetic retinopathy; tirzepatide has not been studied in patients with nonproliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema; monitor patients with a history of diabetic retinopathy

Gastrointestinal (GI) adverse reactions, sometimes severe, reported; has not been studied in patients with severe GI disease, including severe gastroparesis, and is not recommended in these patients

Acute gallbladder disease (eg, cholelithiasis, cholecystitis) reported in GLP-1 receptor agonist trials and postmarketing surveillance; if suspected, gallbladder studies and appropriate clinical follow-up are indicated

Kidney injury

• Acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis in patients treated with GLP-1 receptor agonists, has been described
• Most reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration
• Events also reported in patients without known underlying renal disease
• Monitor renal function when initiating or escalating doses in patients reporting severe adverse GI reactions

Hypersensitivity

• Serious hypersensitivity reactions reported with GLP-1 receptor agonists; caution in patients with history of angioedema or anaphylaxis with a GLP-1 receptor agonist
• Unknown whether such patients will be predisposed to these reactions with tirzepatide
• If hypersensitivity reactions occur, discontinue treatment, treat promptly, and monitor until signs and symptoms resolve

Drug interaction overview

• Insulin secretagogues or insulin

  • May require dosage modification
  • Coadministration with insulin secretagogues (eg, sulfonylureas) or insulin may increase risk of hypoglycemia
  • Consider lower dose of secretagogue or insulin to reduce risk of hypoglycemia
  • Inform patients using concomitant medications of risk of hypoglycemia and educate them on signs and symptoms of hypoglycemia

• Oral drugs with narrow therapeutic index

  • Caution/dosage modification
  • Tirzepatide may delay gastric emptying, thereby potentially impacting oral absorption
  • Caution with drugs having a narrow therapeutic index (eg, warfarin)
  • Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or to add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each tirzepatide dose escalation

Pregnancy

Data are insufficient regarding use in pregnant females to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes

On the basis of animal reproduction studies, there may be risks to the fetus from tirzepatide exposure during pregnancy

Use during pregnancy only if potential benefit justifies the potential risk to the fetus

Clinical considerations

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

Contraception

• Tirzepatide may reduce efficacy of oral hormonal contraceptives owing 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 to add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation

Animal studies

• In pregnant rats administered tirzepatide during organogenesis, fetal growth reductions and fetal abnormalities occurred at clinical exposure based on AUC
• In rabbits administered tirzepatide during organogenesis, fetal growth reductions were observed at clinically relevant exposures based on AUC

Lactation

Data are unavailable on presence of drug in animal or human milk, effects on breastfed infants, or effects on milk production

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

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

GIP is an incretin hormone that induces insulin secretion in response to a meal (primarily by hyperosmolarity of glucose in the duodenum) to facilitate the metabolism of carbohydrates, fats, and proteins

GLP-1 receptor agonists increase insulin secretion in the presence of elevated blood glucose, suppress glucagon postprandially, delay gastric emptying to decrease postprandial glucose, and decrease glucagon secretion

Pharmacodynamic effects observed include lower fasting and postprandial glucose concentration, decreased food intake, and reduced body weight

Absorption

Bioavailability: 80%

Peak plasma concentration: 8-72 hr

Steady-state achieved: 4 weeks

Distribution

Protein bound: 99% (primarily to albumin)

Vd: 10.3 L

Metabolism

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

Elimination

Half-life: ~5 days

Clearance: 0.061 L/hr

Excretion: Metabolites via urine and feces

SC Preparation

Inspect visually before use

Solution should appear clear and colorless to slightly yellow; discard if particulate matter or discoloration observed

When using with insulin, administer as separate injections and never mix

May inject tirzepatide and insulin in same body region, but injections should not be adjacent to each other

SC Administration

Administer SC in abdomen, thigh, or upper arm

Rotate injection site with each dose

Administer once weekly, at any time of day, with or without meals

Change day of weekly administration: May be changed, if necessary, as long as time between the 2 doses is at least 3 days (72 hr)

Missed dose

• Within 4 days (96 hr): Administer as soon as possible after missed dose
• >4 days: Skip missed dose and administer next dose on regularly scheduled day
• In each case, patients can resume their regular once weekly dosing schedule

Storage

Refrigerate at 2-8ºC (36-46ºF)

If needed, each single-dose pen can be stored unrefrigerated at temperatures not to exceed 30ºC (86ºF) for up to 21 days

Do not freeze; do use if frozen

Protect from light