OZEMPIC

Semaglutide is a glucagon-like peptide 1 (GLP-1) analog used to manage type 2 diabetes along with lifestyle changes, such as dietary restrictions and increased physical activity. 1, 15 Other members of this drug class include Exenatide and Liraglutide.

Semaglutide was developed by Novo Nordisk and approved by the FDA for subcutaneous injection in December 2017.

The tablet formulation was approved for oral administration in September 2019.

Semaglutide works by binding to and activating the GLP-1 receptor, thereby stimulating insulin secretion and reducing blood glucose.

The subcutaneous injection is administered once weekly and the tablet is administered once a day. Semaglutide offers a competitive advantage over other drugs used to manage diabetes, which may require several daily doses.

Clinical trials have determined that this drug reduces glycosylated hemoglobin (HbA1c) levels and reduces body weight, proving to be effective for patients with type 2 diabetes.

In June 2021, semaglutide was approved by the FDA for chronic weight management in adults with general obesity or overweight who have at least one weight-related condition, marking semaglutide as the first approved drug for such use since 2014.

The use of semaglutide in weight management is also approved by Health Canada and the EMA.

On May 31, 2023, the FDA issued a warning regarding the use of compounded semaglutide after receiving adverse event reports.

The use of salt forms of semaglutide, including semaglutide sodium and semaglutide acetate, has not been proven to be safe or effective.

On August 15, 2025, the FDA granted Accelerated Approval for the treatment of metabolic-associated steatohepatitis (MASH) in adults with moderate-to-advanced fibrosis 28.

Semaglutide is always intended to be used with a reduced calorie diet and increased physical activity.

It is indicated to improve glycemic control in adults diagnosed with type 2 diabetes mellitus. 14, 15 However, semaglutide is not a suitable first-line drug for diabetes that has not been controlled by diet and exercise.

In addition, it has not been studied in patients with pancreatitis.

Semaglutide is not intended for use in patients with type 1 diabetes or to treat diabetic ketoacidosis.

Semaglutide (available as both an injection and an oral tablet)is indicated for chronic weight management in adults with obesity or overweight with at least one weight-related condition (such as high blood pressure, type 2 diabetes, or high cholesterol). 18, 21.

Semaglutide it is also indicated for chronic weight management in pediatric patients aged 12 years and older with an initial BMI at the 95th percentile or greater for age and sex. 22, 29 Semaglutide is also used to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with established cardiovascular disease and either obesity or overweight.

It is additionally indicated to reduce the risk of sustained eGFR decline, end-stage kidney disease, and cardiovascular death in adults with type 2 diabetes mellitus and chronic kidney disease.

Semaglutide is also indicated to reduce the risk of non-fatal myocardial infarction in adults with established cardiovascular disease and BMI equal to or greater than 27 kg/m². 27.

In August 2025, the FDA expanded its use by granting accelerated approval for semaglutide in the treatment of metabolic-associated steatohepatitis (MASH) in adults with moderate-to-advanced liver fibrosis

Semaglutide reduces

HbA1c, systolic blood pressure, and body weight.

After 12 weeks of treatment, semaglutide decreased fasting and postprandial glucose by increasing insulin production and decreasing glucagon secretion (which is normally associated with increases in blood sugar).

Semaglutide also lowers fasting triglycerides and

VLDL cholesterol, exerting beneficial effects on cardiovascular health. 5, 12 Semaglutide has been shown to cause medullary thyroid cell carcinoma in rodents.

While its clinical relevance to humans is unknown, the FDA advises not to administer this drug in those with a personal or family history of medullary thyroid carcinoma.

Semaglutide also poses a risk of pancreatitis and dehydration.

Patients must be adequately hydrated while on semaglutide and are advised to seek medical attention immediately in cases of abdominal pain radiating to the back.

Because this drug delays gastric emptying, it is important to monitor for the efficacy or adverse effects of other drugs that are administered Oral.

Cmax of semaglutide was 10.9 nmol/L, with AUC of 3123.4 nmol h/L and a Tmax of 56 h in one clinical trial, achieved within 1-3 days. 4, 15 The absolute bioavailability is 89%.

Steady-state concentration of the oral tablet is achieved in 4-5 weeks.

Average steady state concentrations of semaglutide are the mean steady state concentrations after dosing at 0.5 mg to 1 mg range from 16 nmol/L to 30 nmol/L.

The volume of distribution of semaglutide is 8 L to 9.4 L. It crosses the placenta in rats. 4, 15.

Semaglutide is cleaved at the peptide backbone, followed by β‐oxidation of the fatty acid chain.

Naturally occurring

GLP‐1 is quickly metabolized by dipeptidyl peptidase‐4 (DPP‐4) and other enzymes, which is ubiquitous in human tissues.

Chemical structure modifications render semaglutide less susceptible to enzymatic degradation by gastrointestinal DPP‐4 enzymes.

It is slowly and extensively metabolized, with about 83% of the administered dose measured in the plasma as unchanged drug.

Neural endopeptidase (NEP) is another enzyme that metabolizes this drug.

DPP-4 inactivates semaglutide, truncating the N-terminal segment while NEP hydrolyzes peptide bondsSix different metabolites of semaglutide have been identified in human plasma.

The major metabolite, named P3, accounts for about 7.7% of an ingested dose.

Hover over products below to view reaction partners Semaglutide P3 semaglutide U7 semaglutide U6 semaglutide.

This drug is mainly cleared by the kidneys, and is found excreted in both the urine and feces.

The main elimination route is the urine by corresponding to 53% of an ingested radiolabeled dose, with 18.6% found in the feces.

A smaller amount of 3.2% was found to be exhaled.

Hepatic impairment does not appear to affect the clearance of this drug and dose adjustments are not required in patients with decreased liver function.

One of the major properties of semaglutide is its long half-life of 168 h.

The long half-life is attributed to its albumin binding.

This lowers the renal clearance and protects semaglutide from metabolic breakdown. 14, 15.

The clearance rate of semaglutide is 0.039 L/h according to one clinical study.

On the

FDA label, semaglutide clearance is reported to be about 0.05 L/h in patients with type 2 diabetes mellitus.

Improve decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

View sample adverse effects data in our new Data Library! See the data Improve decision support & research outcomes with our structured adverse effects data.

Overdoses of up to 4 mg in one ingestion have been reported, with nausea being the most commonly reported symptom.

All patients in clinical trials who experienced an overdose recovered fully.

Appropriate supportive care should be given according and dictated by the patient's condition.

Prolonged observation and treatment may be required, as the half-life of this drug is about one week.

There is no antidote to an overdose with semaglutide.

• 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.

• RYBELSUS and OZEMPIC tablets are not substitutable on a mg-to-mg basis.

• Take RYBELSUS or OZEMPIC tablets orally once daily on an empty stomach in the morning with water (up to 4 ounces of water); do not take with other liquids besides water.

• 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.

• See the Full Prescribing Information for instructions on switching between RYBELSUS and OZEMPIC tablets and from OZEMPIC injections to RYBELSUS or OZEMPIC tablets.

Starting, Escalation and Maintenance Dosage of RYBELSUS and OZEMPIC Tablets RYBELSUS.

• Day to 30: Recommended starting dosage is 3 mg orally once daily for 30 days (this dosage is not effective for glycemic control).

• Days to 60: Increase the dosage to 7 mg orally once daily.

• On Day 61 or thereafter, if: o No additional glycemic control is needed, maintain the dosage at 7 mg orally once daily. o Additional glycemic control is needed, increase the dosage to 14 mg orally once daily.

• Day to 30: Recommended starting dosage is 1.5 mg orally once daily for 30 days (this dosage is not effective for glycemic control).

• Days to 60: Increase the dosage to 4 mg orally once daily.

• On Day 61 or thereafter, if: o No additional glycemic control is needed, maintain the dosage at 4 mg orally once daily. o Additional glycemic control is needed, increase the dosage to 9 mg orally once daily. 2.1 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.

• If a dose is missed, skip the missed dose and take the next dose the following day. 2.2 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 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 and beyond) : o Days 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.

Recommended Dosage Follow the OZEMPIC tablets starting, escalation, and maintenance dosage described below to reduce the risk of GI adverse reactions:

• Starting Dosage (Initiation Phase) (Days 1 through 30) : The recommended starting dosage is 1.5 mg orally once daily (this dosage is not effective for glycemic control).

• Escalation and Maintenance Dosage (Days and beyond) : o Days to 60: Increase the dosage to 4 mg orally once daily. o On Day 61 or thereafter, if: ▪ No additional glycemic control is needed, maintain the dosage at 4 mg orally once daily. ▪ Additional glycemic control is needed, increase the dosage to 9 mg orally once daily. 2.3 Switching Between RYBELSUS and OZEMPIC Tablets.

• Do not switch between RYBELSUS and OZEMPIC tablets during the initiation phase (Days to 30) .

• After 30 days of RYBELSUS or OZEMPIC tablet treatment (after the initiation phase) , patients may switch between RYBELSUS and OZEMPIC tablet products.

• 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 RYBELSUS and OZEMPIC Tablets RYBELSUS OZEMPIC Tablets 7 mg orally once daily 4 mg orally once daily 14 mg orally once daily 9 mg orally once daily 2.4 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.

• Patients taking the 0.5 mg dose of OZEMPIC injection may switch to OZEMPIC tablets.

• One week after discontinuing 0.5 mg of subcutaneous OZEMPIC injection, start 4 mg or 9 mg of OZEMPIC tablets orally once daily.

RYBELSUS strengths are available as follows

Tablet Strength Description Package Configuration NDC Number 3 mg White to light yellow, oval shaped debossed with “3” on one side and “novo” on the other side Bottle of 30 tablets 0169-4303-30 7 mg White to light yellow, oval shaped debossed with “7” on one side and “novo” on the other side Bottle of 30 tablets 0169-4307-30 14 mg White to light yellow, oval shaped debossed with “14” on one side and “novo” on the other side Bottle of 30 tablets 0169-4314-30 OZEMPIC tablet strengths are available as follows: Tablet Strength Description Package Configuration NDC Number 1.5 mg White to light yellow, round shaped debossed with “1.5” on one side and “novo” on the other side Bottle of 30 tablets 0169-1715-30 4 mg White to light yellow, round shaped debossed with “4” on one side and “novo” on the other side Bottle of 30 tablets 0169-1704-30 9 mg White to light yellow, round shaped debossed with “9” on one side and “novo” on the other side Bottle of 30 tablets 0169-1709-30 Storage and Handling Store RYBELSUS and OZEMPIC tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Store and dispense in the original bottle.

Store tablets in the original bottle until use to protect tablets from moisture.

Store product in a dry place away from moisture.

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.

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.

The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with an HbA 1c >7 and has been reported to be as high as 20% to 25% in women with an HbA 1c >10.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, 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 a combined fertility and embryofetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.2-, 0.7 - and 2.1-fold the MRHD) were administered to males for 4 weeks prior to and throughout mating and to females for 2 weeks prior to mating, and throughout organogenesis to Gestation Day 17.

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.

In an embryofetal development study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025 or 0.0075 mg/kg/day (0.06-, 0.6 - and 4.4-fold the MRHD) were administered throughout organogenesis from Gestation Day to 19.

Pharmacologically mediated reductions in maternal body weight gain and food consumption were observed at all dose levels.

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.

In an embryofetal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075 and 0.15 mg/kg twice weekly (1.9-, 9.9 - and 29-fold the MRHD) were administered throughout organogenesis, from Gestation Day to 50.

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).

In a pre.

• and postnatal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075 and 0.15 mg/kg twice weekly (1.3-, 6.4 - and 14-fold the MRHD) were administered from Gestation Day to 140.

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.

• 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.

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

In the pool of glycemic control trials, 1,229 (30%) patients treated with semaglutide tablets were 65 years of age and over and 199 (5%) patients treated with semaglutide tablets were 75 years of age and over.

In Trial 8, one of the CV outcomes trials, 891 (56%) patients treated with semaglutide tablets were 65 years of age and over and 200 (13%) patients treated with semaglutide tablets were 75 years of age and over.

No overall differences in safety or effectiveness for semaglutide tablets have been observed between patients 65 years of age and older and younger adult patients.