Ozempic Drug Information

• RYBELSUS and OZEMPIC tablets are indicated:
• As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
• To reduce the risk of major adverse cardiovascular (CV) events (CV death, non-fatal myocardial infarction or non-fatal stroke) in adults with type 2 diabetes mellitus who are at high risk for these events. RYBELSUS and OZEMPIC tablets are glucagon-like peptide-1 (GLP-1) receptor agonists indicated:
• To reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus who are at high risk for these events.

Important Administration Instructions • RYBELSUS and OZEMPIC tablets are not substitutable on a mg-to-mg basis. • Take one RYBELSUS or OZEMPIC tablet orally once daily on an empty stomach in the morning with water (up to 4 ounces of water). Do not take RYBELSUS or OZEMPIC tablets with other liquids besides water. • Do not take more than one tablet per day. • Swallow tablets whole. Do not split, crush, chew or dissolve in any solution. • After taking RYBELSUS or OZEMPIC tablets, wait at least 30 minutes before eating food, drinking beverages or taking other oral medications. • If a dose is missed, skip the missed dose and take the next dose the following day.

Recommended Starting, Escalation and Maintenance Dosage of RYBELSUS and OZEMPIC Tablets RYBELSUS: Recommended Dosage Follow the RYBELSUS starting, escalation, and maintenance dosage described below to reduce the risk of gastrointestinal (GI) adverse reactions: • Starting Dosage (Initiation Phase) (Days 1 to 30): The recommended starting dosage is 3 mg orally once daily (this dosage is not effective for glycemic control). • Escalation and Maintenance Dosage (Days 31 and beyond): o Days 31 to 60: Increase the dosage to 7 mg orally once daily. o On Day 61 or thereafter, if: ▪ No additional glycemic control is needed, maintain the dosage at 7 mg orally once daily. ▪ Additional glycemic control is needed, increase the dosage to 14 mg orally once daily.

Switching Between RYBELSUS and OZEMPIC Tablets •

Do not switch between RYBELSUS and OZEMPIC tablets during the initiation phase (Days 1 to 30). • After 30 days of RYBELSUS or OZEMPIC tablet treatment (after the initiation phase), patients may switch between RYBELSUS and OZEMPIC tablet products (see Table 1 ). • When switching between RYBELSUS and OZEMPIC tablets, initiate the other semaglutide tablet product the day after discontinuing the previous semaglutide tablet product. Table 1. Switching Between Escalation or Maintenance Dosage of

Switching from OZEMPIC Injection to RYBELSUS or OZEMPIC Tablets Switching from OZEMPIC Injection to RYBELSUS Tablets • Patients taking the 0.5 mg dose of OZEMPIC injection may switch to RYBELSUS tablets. • One week after discontinuing 0.5 mg of subcutaneous OZEMPIC injection, start 7 mg or 14 mg of RYBELSUS orally once daily.

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. Below is a display of the safety results of the adequate and well-controlled studies of RYBELSUS (referred to below as semaglutide tablets) in adult patients with type 2 diabetes mellitus. Pool of Placebo-Controlled Trials The data in Table 2 are derived from 2 placebo-controlled trials in adult patients with type 2 diabetes mellitus.

At baseline, patients had type 2 mellitus diabetes for an average of 9.4 years and had a mean HbA 1c of 8.1%. At baseline, 20.1% of the population reported retinopathy. Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of adult patients with type 2 diabetes mellitus participating in 9 placebo- and active-controlled trials.

In this pool, 4,116 patients with type 2 diabetes mellitus were treated with semaglutide tablets for a mean duration of 59.8 weeks. At baseline, 16.6% of the population reported retinopathy. Common Adverse Reactions Table 2 shows common adverse reactions, excluding hypoglycemia, associated with the use of semaglutide tablets in adult patients with type 2 diabetes mellitus in the pool of placebo-controlled trials.

These adverse reactions occurred more commonly on semaglutide tablets than on placebo and occurred in at least 5% of patients treated with semaglutide tablets. Table 2. Safety data collection was limited to serious adverse events (including death), adverse events leading to discontinuation, and adverse events of special interest.

Study drug was permanently discontinued due to an adverse event in 15.5% of semaglutide tablets-treated patients and 11.6% of placebo-treated patients. Additional information from this trial is included in subsequent sections below, when relevant. The majority of reports of nausea, vomiting and/or diarrhea occurred during dose escalation.

Diabetic Retinopathy Complications: In the pool of placebo- and active-controlled trials with semaglutide tablets, patients reported diabetic retinopathy related adverse reactions during the trial (4.2% with semaglutide tablets and 3.8% with comparator). Hypoglycemia: Table 3 summarizes the incidence of hypoglycemia by various definitions in the placebo-controlled trials. Table 3.

Hypoglycemia Adverse Reactions in Placebo-Controlled Trials in Patients with Type 2 Diabetes Mellitus “Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person. Hypoglycemia was more frequent when semaglutide tablets were used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. These changes were not observed in placebo-treated patients.

Cholelithiasis: In placebo-controlled trials to improve glycemic control, cholelithiasis was reported in 1% of patients treated with semaglutide tablets 7 mg. In Trial 7, cholecystitis was reported in 1.1% of patients treated with semaglutide14 mg tablets and in 0.7% of placebo-treated patients. There was no change in heart rate in placebo-treated patients.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient in RYBELSUS and OZEMPIC tablets. 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: acute pancreatitis and necrotizing pancreatitis, sometimes resulting in death; ileus, intestinal obstruction, severe constipation including fecal impaction • Hypersensitivity: anaphylaxis, angioedema, rash, urticaria • Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy • Nervous system disorders: dizziness, dysesthesia, dysgeusia, headache • Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation • Renal: acute kidney injury • Skin and Subcutaneous Tissue: alopecia

Concomitant Use with an Insulin

Secretagogue (e.g., Sulfonylurea) or with Insulin Semaglutide stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving RYBELSUS or OZEMPIC tablets in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating RYBELSUS or OZEMPIC tablets, consider reducing the dosage of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia.

Other Oral Drugs

Semaglutide cause a delay of gastric emptying and thereby has the potential to impact the absorption of other oral drugs. Levothyroxine exposure was increased when administered with semaglutide tablets in a drug interaction study. When using RYBELSUS or OZEMPIC tablets concomitantly with other oral drugs that have a narrow therapeutic index or that require clinical monitoring, consider increased clinical or laboratory monitoring.

Pregnancy Risk Summary Available data with semaglutide use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy (see Clinical Considerations ). Based on animal reproduction studies, there may be potential risks to the fetus from exposure to semaglutide during pregnancy.

RYBELSUS or OZEMPIC tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant rats administered semaglutide during organogenesis, embryofetal mortality, structural abnormalities and alterations to growth occurred at maternal exposures below the maximum recommended human dose (MRHD) based on AUC. In rabbits and cynomolgus monkeys administered semaglutide during organogenesis, early pregnancy losses and structural abnormalities were observed at exposure below the MRHD (rabbit) and ≥10-fold the MRHD (monkey).

These findings coincided with a marked maternal body weight loss in both animal species (see Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Disease Associated Maternal and Fetal Risk: Poorly controlled diabetes during pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications.

Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth and macrosomia related morbidity. In parental animals, pharmacologically mediated reductions in body weight gain and food consumption were observed at all dose levels. In the offspring, reduced growth and fetuses with visceral (heart blood vessels) and skeletal (cranial bones, vertebra, ribs) abnormalities were observed at the human exposure.

Early pregnancy losses and increased incidences of minor visceral (kidney, liver) and skeletal (sternebra) fetal abnormalities were observed at ≥0.0025 mg/kg/day, at clinically relevant exposures. Pharmacologically mediated, marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with the occurrence of sporadic abnormalities (vertebra, sternebra, ribs) at ≥0.075 mg/kg twice weekly (≥9X human exposure). Pharmacologically mediated marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with an increase in early pregnancy losses and led to delivery of slightly smaller offspring at ≥0.075 mg/kg twice weekly (≥6X human exposure).

Salcaprozate sodium (SNAC), an absorption enhancer in RYBELSUS and OZEMPIC tablets, crosses the placenta and reaches fetal tissues in rats. In a pre- and postnatal development study in pregnant Sprague Dawley rats, SNAC was administered orally at 1,000 mg/kg/day (exposure levels were not measured) on Gestation Day 7 through Lactation Day 20. An increase in gestation length, an increase in the number of stillbirths and a decrease in pup viability were observed.

Pediatric Use The safety and effectiveness of RYBELSUS and OZEMPIC tablets have not been established in pediatric patients.

• RYBELSUS and OZEMPIC tablets are 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).
• A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS or OZEMPIC tablets. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with semaglutide tablets.
• Personal or family history of MTC or in patients with MEN 2 syndrome type 2
• Prior serious hypersensitivity reaction to semaglutide or any of the excipients in OZEMPIC

In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the long half-life of semaglutide of approximately 1 week.