Mounjaro Side Effects: Rare but Serious Adverse Events

Which serious reactions does the Mounjaro label warn about?

The warnings section of the Mounjaro label covers acute pancreatitis, hypoglycemia with insulin secretagogues or insulin, hypersensitivity reactions, acute kidney injury due to volume depletion, severe gastrointestinal reactions, diabetic retinopathy complications, acute gallbladder disease, and pulmonary aspiration during general anesthesia or deep sedation [1]. Only one of them, thyroid C-cell tumors, carries a boxed warning [1].

Most of what patients actually report is gastrointestinal and common rather than serious. In SURPASS-2, a 40-week open-label trial of 1,879 adults with type 2 diabetes on metformin, nausea was reported by 17% to 22% of tirzepatide-treated patients versus 18% with semaglutide 1 mg, diarrhea by 13% to 16% versus 12%, and vomiting by 6% to 10% versus 8% [2]. The reactions described below are the label's serious ones.

The label reports its adverse reaction data from two placebo-controlled adult trials in type 2 diabetes (SURPASS-1 and SURPASS-5), with 718 patients on Mounjaro and a mean exposure of 36.6 weeks, plus a seven-trial pool of 5,119 adults treated for a mean of 48.1 weeks; it also draws on animal findings and postmarketing reports [1]. The label states that adverse reaction rates from different trials cannot be compared directly [1].

Thyroid C-cell tumors: the boxed warning

In a 2-year study, both sexes of rats given tirzepatide developed dose-dependent and treatment-duration-dependent thyroid C-cell tumors, adenomas and carcinomas, at clinically relevant plasma exposures [1]. The label says it is unknown whether Mounjaro causes thyroid C-cell tumors, including medullary thyroid carcinoma, in humans, because the human relevance of the rodent finding has not been determined [1].

Mounjaro is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or with Multiple Endocrine Neoplasia syndrome type 2 [1]. The label directs that patients be counseled about the potential MTC risk and about symptoms of thyroid tumors: a mass in the neck, dysphagia, dyspnea, or persistent hoarseness [1]. Routine serum calcitonin monitoring or thyroid ultrasound is of uncertain value for early detection, the label says, since calcitonin testing has low specificity and background thyroid disease is common [1].

Acute pancreatitis

The label warns that acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists or with Mounjaro [1]. Signs may include persistent or severe abdominal pain, sometimes radiating to the back, with or without nausea or vomiting [1]. The label's instruction is that if pancreatitis is suspected, Mounjaro should be discontinued and appropriate management started [1].

Gallbladder disease

Acute gallbladder disease, covering cholelithiasis, biliary colic and cholecystectomy, was reported by 0.6% of Mounjaro-treated adults and 0% of placebo-treated adults in the label's placebo-controlled trials [1]. If gallstones are suspected, the label says gallbladder studies and clinical follow-up are indicated [1].

Acute kidney injury from dehydration

The label describes postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists or Mounjaro [1]. The majority of those events occurred in patients who had gastrointestinal adverse reactions leading to dehydration, such as nausea, vomiting or diarrhea [1]. The label says to monitor renal function in patients reporting reactions that could lead to volume depletion, especially during starting and dose escalation [1]. Separately, the label states that no dose adjustment is needed for renal or hepatic impairment [1].

Severe gastrointestinal reactions

In placebo-controlled adult trials, severe gastrointestinal reactions were reported in 1.3% of patients on 5 mg, 0.4% on 10 mg, and 1.2% on 15 mg, compared with 0.9% on placebo [1]. Gastrointestinal adverse reactions of any severity occurred in 37.1%, 39.6% and 43.6% of patients on 5, 10 and 15 mg versus 20.4% on placebo, and treatment was discontinued for gastrointestinal reasons in 3.0%, 5.4% and 6.6% versus 0.4% [1]. Most reports of nausea, vomiting and diarrhea occurred during dose escalation and decreased over time [1]. The label states that Mounjaro is not recommended in patients with severe gastroparesis [1].

Severe hypoglycemia with insulin or a sulfonylurea

The Mounjaro label warns that hypoglycemia risk, including severe hypoglycemia, increases when the drug is used with an insulin secretagogue such as a sulfonylurea, or with insulin, and says to consider reducing the dose of the sulfonylurea or insulin when Mounjaro is started [1]. The label also tells prescribers to inform patients on those medicines about the risk and to educate them on the signs and symptoms of hypoglycemia [1].

Serious allergic reactions

The label states that serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with Mounjaro, and that if a reaction occurs the drug should be discontinued, treated promptly per standard of care, and the patient monitored until signs and symptoms resolve [1]. A known serious hypersensitivity to tirzepatide or any excipient in Mounjaro is a contraindication [1]. The label adds caution for patients with a history of angioedema or anaphylaxis to a GLP-1 receptor agonist, since it is unknown whether they are predisposed to the same reactions with Mounjaro [1].

Diabetic retinopathy

The label warns that temporary worsening of diabetic retinopathy has been reported with rapid improvement in glucose control, and says patients with a history of diabetic retinopathy should be monitored for progression [1].

Gastric emptying and anesthesia

Mounjaro delays gastric emptying, and the label warns that pulmonary aspiration has been reported in patients receiving GLP-1 receptor agonists during elective surgery or procedures under general anesthesia or deep sedation [1]. The label instructs patients to inform healthcare providers of any planned surgeries or procedures [1].

Who should not use Mounjaro

The label's contraindications are a personal or family history of medullary thyroid carcinoma, Multiple Endocrine Neoplasia syndrome type 2, and a known serious hypersensitivity to tirzepatide or an excipient [1]. On pregnancy, the label says available human data are insufficient to assess risk, that animal reproduction studies suggest possible fetal harm, and that Mounjaro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [1].