Orforglipron

Weight loss offers no benefit to a pregnant patient and may cause fetal harm. When a pregnancy is recognized, advise the pregnant patient of the risk to a fetus and discontinue orforglipron.

There are no adequate and well-controlled studies of orforglipron during pregnancy. Based on animal reproduction studies, there may be risks to the fetus from exposure to orforglipron during pregnancy.

Imbalances in malformations have been reported in rats and rabbits at low multiples of clinical exposure with GLP-1 receptor agonists active in those species. Orforglipron is not pharmacologically active in rats and rabbits.

In animal reproduction studies, oral administration of orforglipron to pregnant monkeys during organogenesis at doses lower than the maximum recommended human dose (MRHD) did not result in embryofetal effects. Higher dose levels and exposures could not be evaluated in monkeys due to dose limiting effects on body weight.

In a rabbit dose-range finding study, oral administration of orforglipron to pregnant rabbits during organogenesis at exposures 14 times the clinical exposure at the MRHD resulted in external malformations and decreases in fetal and placental weights in the absence of maternal toxicity. In the definitive rabbit study, oral administration of orforglipron to pregnant rabbits during organogenesis at exposures up to 6 times the clinical exposure at the MRHD did not result in embryofetal effects.

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. The estimated background risk of major birth defects and miscarriage for the indicated population is increased when compared to the general population.

There are no data on the presence of orforglipron or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Orforglipron was present in the milk of lactating rats in in vivo testing. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Orforglipron is not recommended for nursing women. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for orforglipron and any potential adverse effects on the breastfed child from orforglipron or from the underlying maternal condition.

Orforglipron is not pharmacologically active in rats or mice. In a 2-year rat carcinogenicity study, orforglipron was non-carcinogenic at oral daily doses of 5, 30, and 200 mg/kg/day resulting in exposures approximately 3, 9, and 26 times the clinical exposure at the MRHD, respectively, based on AUC. In a 26-week study in Tg.RasH2 transgenic mice, orforglipron was non-carcinogenic at oral daily doses of 5, 30, and 200 mg/kg/day. For other GLP-1 receptor agonists that are pharmacologically active in rats, thyroid C-cell hyperplasia, and thyroid C-cell adenoma and carcinoma have been observed at clinically relevant exposures and are considered an on-target class effect. Orforglipron would be expected to have the same on-target class effect if it was pharmacologically active in rats. The human relevance of these findings is unknown.

Orforglipron was not mutagenic or clastogenic in a bacterial reverse mutation test, an in vitro micronucleus test in human lymphoblastoid cells, or in an in vivo bone marrow micronucleus study in rats.

There were no effects on male and female fertility in rats orally administered orforglipron up to 200 mg/kg/day (19 times and 36 times the clinical exposure at the MRHD, respectively, based on AUC).

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of orforglipron has been established 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 based on adequate and well-controlled trials of an investigational orforglipron formulation (Trials 1 and 2), referred to in this section as orforglipron. This section of labeling presents safety data from administration of the investigational orforglipron formulation shown as equivalent dosages of once daily orforglipron.

Adverse Reactions in Patients in Weight Management Clinical Trials

Pool of Two Placebo-Controlled Clinical Trials: orforglipron was evaluated for safety in a pool of two randomized, double-blind, placebo-controlled trials that included 3155 adult patients with obesity or overweight treated with orforglipron once daily for up to 72 weeks and a 2-week off-drug follow-up period (Trial 1 and Trial 2). The mean age of patients was 49 years and 41% were male. The population was 60% White, 25% Asian, 8% Black or African American, and 0.3% American Indian or Alaska Native; 35% identified as Hispanic or Latino ethnicity. At baseline, patients had an average BMI of 36.5 kg/m², 51% with a BMI ≥35 kg/m², 50% with hypertension, 49% with dyslipidemia, 31% with type 2 diabetes, 11% with obstructive sleep apnea, 3% with coronary artery disease, and 3% with cerebrovascular disease.

Across both trials, 8% of patients treated with orforglipron (5.5 mg, 6%; 9 mg, 9%; and 17.2 mg, 10%) once daily permanently discontinued treatment as a result of adverse reactions compared to 3% of patients receiving placebo. The majority of patients (5%) who discontinued orforglipron due to adverse reactions did so due to gastrointestinal adverse reactions.

Common Adverse Reactions

Table 1 shows common adverse reactions associated with the use of once daily orforglipron in the pool of two placebo-controlled trials for weight management (Trials 1 and 2). These adverse reactions occurred more commonly with once daily orforglipron than with placebo and occurred in at least 5% of patients treated with orforglipron.

Table 1. Adverse Reactions Reported in ≥5% of orforglipron-treated Adult Patients with Obesity or Overweight (With or Without Type 2 Diabetes) in Pool of Placebo-Controlled Trials (Trials 1 and 2):

^a Includes other related terms.

Gastrointestinal Adverse Reactions

In a pool of Trials 1 and 2, gastrointestinal adverse reactions occurred more frequently among patients treated with once daily orforglipron 5.5 mg (60%), 9 mg (68%), and 17.2 mg (69%) than placebo (37%). More patients treated with once daily orforglipron 5.5 mg (3%), 9 mg (6%), and 17.2 mg (6%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.7%).

Of the orforglipron-treated patients who reported GI adverse reactions, 60%, 36%, and 4% reported mild or moderate or severe adverse reactions, respectively. The incidence of nausea, vomiting, and diarrhea was higher during the orforglipron dosage escalation period and decreased over time.

Hypoglycemia

In Trial 2, a trial of patients with type 2 diabetes and BMI ≥27 kg/m², hypoglycemia (glucose <54 mg/dL) was reported in 2% of orforglipron-treated patients versus 0.2% of placebo-treated patients. One patient treated with orforglipron 5.5 mg once daily, and no patients receiving placebo reported severe hypoglycemia in Trial 2. In this trial, 7% of patients taking orforglipron in combination with sulfonylurea reported hypoglycemia compared with 0.5% of patients not taking sulfonylurea.

In Trial 1, a trial of orforglipron in adults with BMI ≥27 kg/m² without type 2 diabetes, there was no systematic capturing of hypoglycemia, but glucose <54 mg/dL was reported in 0.6% of orforglipron-treated patients and no placebo-treated patients. No patients in Trial 1 reported severe hypoglycemia.

Other Adverse Reactions

Acute Pancreatitis

In a pool of Trials 1 and 2, 6 events of acute pancreatitis were confirmed by adjudication in 6 orforglipron-treated patients (0.14 patients per 100 years of exposure) versus 2 events in 1 placebo-treated patient (0.04 patients per 100 years of exposure).

Acute Kidney Injury

In a pool of Trials 1 and 2, acute kidney injury was reported in 0.2% of orforglipron-treated patients compared to 0.05% of placebo-treated patients.

Hypotension

In a pool of Trials 1 and 2, hypotension occurred more frequently among patients taking orforglipron (2%) than patients taking placebo (0.5%). Hypotension was more frequently seen in orforglipron-treated patients on concomitant antihypertensive therapy (4%) compared to orforglipron-treated patients not on antihypertensive therapy (1%).

Acute Gallbladder Disease

In a pool of Trials 1 and 2, cholelithiasis was reported in 1% of orforglipron-treated patients and 0.7% of placebo-treated patients, and acute cholecystitis was reported in 0.4% of orforglipron-treated patients and 0.3% of placebo-treated patients.

Tachycardia

In a pool of Trials 1 and 2, tachycardia (tachycardia, heart rate increased, and sinus tachycardia) was reported in 3% of patients treated with orforglipron and 0.9% receiving placebo. Treatment with orforglipron resulted in a mean increase in heart rate of 4 to 5 beats per minute from baseline compared to 0.5 beat per minute with placebo.

Hair Loss

Hair loss adverse reactions in orforglipron-treated patients were associated with weight reduction. In a pool of Trials 1 and 2, hair loss was reported more frequently in female than male patients in the orforglipron (7% female versus 0.9% male) and placebo (3% female versus 0.7% male) treatment groups.

Dizziness

In a pool of Trials 1 and 2, dizziness was reported in 4% of orforglipron-treated patients and 3% of placebo-treated patients.

Dysgeusia

In a pool of Trials 1 and 2, dysgeusia was reported in 0.9% of orforglipron-treated patients and 0.3% of placebo-treated patients.

Dysesthesia

In a pool of Trials 1 and 2, dysesthesia was reported in 0.3% and 1% of patients treated with orforglipron 9 mg, and 17.2 mg, respectively, and 0.1% of patients receiving placebo. No patients taking orforglipron 5.5 mg reported dysesthesia.

Hypersensitivity Reactions

In a pool of Trials 1 and 2, hypersensitivity reactions, including anaphylactic reaction, occurred in 0.5% of orforglipron-treated patients compared to 0.3% of placebo-treated patients.

Laboratory Abnormalities

Amylase and Lipase Increase

In a pool of Trials 1 and 2, treatment with orforglipron resulted in mean increases from baseline in serum pancreatic amylase concentrations of 16% to 20% and serum lipase concentrations of 26% to 31%, compared to mean increases from baseline in serum pancreatic amylase of 3% and serum lipase of 4% in placebo-treated patients. The clinical significance of elevations in amylase or lipase with orforglipron is unknown in the absence of other signs and symptoms of pancreatitis.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of GLP-1 receptor agonists. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders: acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death; ileus, intestinal obstruction, severe constipation including fecal impaction

Hypersensitivity: anaphylaxis, angioedema

Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation

Renal and Urinary Disorders: acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis