OZEMPIC

and OZEMPIC tablets, for oral use, contain semaglutide, a GLP-1 receptor agonist.

The peptide backbone is produced by yeast fermentation.

The main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid.

Furthermore, semaglutide is modified in position to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4).

A minor modification was made in position to ensure the attachment of only one fatty di-acid.

The molecular formula is

C 187 H 291 N 45 O and the molecular weight is 4113.58 g/mol.

Structural formula

Semaglutide is a white to almost white hygroscopic powder.

RYBELSUS tablets contain 3 mg, 7 mg or 14 mg of semaglutide and the following inactive ingredients: magnesium stearate, microcrystalline cellulose, povidone and salcaprozate sodium (SNAC).

OZEMPIC tablets contain 1.5 mg, 4 mg or 9 mg of semaglutide and the following inactive ingredients: magnesium stearate and SNAC. structural_formula.

This medicine is used to treat type II diabetes together with a healthy diet, and exercise.

It is used after other drugs fail to control blood sugar levels.

The drug is used with caution and under the supervision of the doctor in the following cases: history of pancreatic infections, where the complications of the drug are that it increases the risk of pancreatic infection.

Low-skinned diet.

Hepatitis or kidney disease.

Diabetes neural neural disorder.

Intestinal disorders and digestive problems.

Diseases of diarrhoea.

It should be noted that the semagluteide drug increases suicidal thoughts, so caution must be exercised when it is used for persons with depression, and those using psychiatric treatments.

Smiglute for pregnant women is not recommended for use during pregnancy.

A recent study has stated that it may increase the chances of contracting pregnancy complications, such as early birth, so some doctors prefer to stop using it at least two months before the attempt to have a baby.

Smiglutide for the infant, although studies have not shown that this drug may be transmitted through breast milk, but it is not recommended that it be avoided without consulting a doctor during the breastfeeding period.

Mechanism of Action Semaglutide is a

GLP-1 analogue with 94% sequence homology to human GLP-1.

Semaglutide acts as a

GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1.

GLP-1 is a physiological hormone that has multiple actions on glucose, mediated by the GLP-1 receptors.

The principal mechanism of protraction resulting in the long half-life of semaglutide is albumin binding, which results in decreased renal clearance and protection from metabolic degradation.

Furthermore, semaglutide is stabilized against degradation by the DPP-4 enzyme.

Semaglutide reduces blood glucose through a mechanism where it stimulates insulin secretion and lowers glucagon secretion, both in a glucose-dependent manner.

Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited.

The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. 12.2 Pharmacodynamics The pharmacodynamic evaluations described below were in patients with type 2 diabetes mellitus who received once-weekly subcutaneous injections of placebo or semaglutide injection over 12 weeks (semaglutide injection-treated patients were started on lower dosages and then titrated up to 1 mg once weekly).

RYBELSUS and

OZEMPIC tablets are not approved for subcutaneous use.

Semaglutide reduces fasting and postprandial glucose concentrations.

In patients with type 2 diabetes mellitus, treatment with semaglutide injection 1 mg resulted in reductions in glucose in terms of absolute change from baseline and relative reduction compared to placebo of 29 mg/dL (22%) for fasting glucose, 74 mg/dL (36%) for 2-hour postprandial glucose and 30 mg/dL (22%) for mean 24-hour glucose concentration.

Both first.

• and second-phase insulin secretion are increased in patients with type 2 diabetes mellitus treated with semaglutide compared with placebo.

Semaglutide lowers the fasting and postprandial glucagon concentrations.

Glucose dependent insulin and glucagon secretion

Semaglutide lowers high blood glucose concentrations by stimulating insulin secretion and lowering glucagon secretion in a glucose-dependent manner.

During induced hypoglycemia, semaglutide did not alter the counter regulatory responses of increased glucagon compared to placebo and did not impair the decrease of C-peptide in patients with type 2 diabetes mellitus.

Gastric emptying

Semaglutide causes a delay of early postprandial gastric emptying, thereby reducing the rate at which glucose appears in the circulation postprandially.

The effect of subcutaneously administered semaglutide on cardiac repolarization was tested in a thorough QTc trial.

At an average exposure level 4-fold higher than that of the maximum recommended dose of semaglutide tablets, semaglutide does not prolong QTc intervals to any clinically relevant extent. 12.3 Pharmacokinetics Semaglutide estimated mean steady-state concentration was 6.7 nmol/L and 14.6 nmol/L following once daily oral administration of 7 mg and 14 mg of RYBELSUS, respectively, in patients with type 2 diabetes mellitus.

Semaglutide exposures increased in a dose-proportional manner.

Steady-state exposure was achieved following to 5 weeks of semaglutide tablets oral administration.

Absorption RYBELSUS and OZEMPIC tablets are co-formulated with SNAC which facilitates the absorption of semaglutide after oral administration.

The absorption of semaglutide predominantly occurs in the stomach.

• 0.4% to 1% after oral administration of 3 mg, 7 mg and 14 mg of RYBELSUS.

• 1% to 2% after oral administration of 1.5 mg, 4 mg and 9 mg of OZEMPIC tablets.

Semaglutide maximum concentration was reached approximately 1-hour after oral administration of semaglutide tablets.

There were no clinically significant differences observed in the mean steady state AUC 0-24h,SS and C max,SS between the 3 mg, 7 mg and 14 mg doses of RYBELSUS and the 1.5 mg, 4 mg and 9 mg doses of OZEMPIC tablets, respectively, in a clinical study conducted in healthy subjects.

Effect of Volume and Timing of Water Consumption: Single oral doses of semaglutide tablets were administered with 50 mL or 240 mL of water after an 8-hour overnight fast and a continued fast of 4 hours post-dose in healthy subjects.

Semaglutide absorption (i.e., area under the curve (AUC) and peak concentrations (C max ) were higher following dosing with 50 mL water compared to that of 240 mL water.

For 10 days, healthy subjects received semaglutide tablets once daily doses orally with 50 mL or 120 mL of water under fasting conditions with post-dose fasting period of 15, 30, 60 or 120 minutes.

In this study, semaglutide absorption (i.e., AUC and C max ) was higher after a longer post-dose fasting period.

There were no clinically significant differences in semaglutide absorption with administration of 50 mL or 120 mL of water.

Semaglutide absolute volume of distribution is approximately 8 L in patients with type 2 diabetes.

Semaglutide is >99% bound to plasma albumin.

Semaglutide elimination half-life is approximately one week with an absolute clearance of approximately 0.04 L/hour in patients with type 2 diabetes.

Semaglutide is present in the circulation for about five weeks after the last semaglutide tablet dose.

The primary route of elimination for semaglutide is metabolism following proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid side chain.

The primary excretion routes of semaglutide-related material are via the urine and feces.

Approximately 3% of the absorbed dose is excreted in the urine as intact semaglutide.

No clinically significant differences in semaglutide pharmacokinetics were observed based on age (≥18 years old), sex, race (White, Asian or Black or African American), ethnicity, body weight (40 to 188 kg), upper GI disease (i.e., chronic gastritis and/or gastroesophageal reflux disease), hepatic impairment (i.e., mild, moderate, severe based on the Child-Pugh system) and renal impairment (i.e., mild, moderate, severe, end staged renal disease).

Drug Interaction Studies Clinical Studies and Model-Informed Approaches: The delay of gastric emptying with semaglutide may influence the absorption of concomitantly administered oral drugs.

Trials were conducted to study the potential effect of semaglutide on the absorption of oral drugs taken with semaglutide administered orally at steady-state exposure.

Total thyroxine (i.e., adjusted for endogenous levels) AUC was increased by 33% following administration of a single dose of levothyroxine 600 mcg concomitantly administered with semaglutide tablets.

Maximum exposure (C max ) was unchanged.

No clinically significant differences in semaglutide pharmacokinetics were observed when used concomitantly with omeprazole.

No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with semaglutide: lisinopril, S-warfarin, R-warfarin, metformin, digoxin, ethinyl estradiol, levonorgestrel, furosemide or rosuvastatin.

Semaglutide has very low potential to inhibit or induce CYP enzymes, and to inhibit drug transporters. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.

Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of semaglutide or of other semaglutide products.

During the 26.

• to 78-week treatment periods in 5 clinical trials in adults with type 2 diabetes mellitus and 1 clinical trial in Japanese adults with type 2 diabetes mellitus, 14/2,924 (0.5%) of semaglutide tablet-treated patients developed anti-semaglutide antibodies.

Of these 14 semaglutide tablet -treated patients, 7 patients (0.2% of the total semaglutide tablet-treated study population) developed antibodies that cross-reacted with native GLP-1.

No identified clinically significant effect of anti-semaglutide antibodies on pharmacokinetics of semaglutide tablets was observed.

There is insufficient information to characterize the effects of anti-semaglutide antibodies on pharmacodynamics, safety or effectiveness of semaglutide.

The uterus is used in the form of subcutaneous injection, containing effective biomaggotide, which is used in: controlling blood sugar levels in the case of type II diabetes patients, together with dietary dietary and exercise; helping Ozmbek needle to reduce the cumulative blood sugar ratio significantly; reducing the risk of major cardiovascular diseases, such as heart attack, stroke, or death in adults with type II diabetes and heart disease; ummbc to deflate when the ozmbek needle starts to function; the method of using the acmbex needle damage or embroidery damage to the uterus is used in the case of the ribbite; the umbr is taken from the other venomous, so it is recommended to avoid using the drug except after the remission of the second type, as it helps to reduce the umbb or tumb of the tumm during the period of its use.

It should be noted that the umbek needle damage has some damage and side effects, as a defrogates, so as a pumpile is used in the same way as a pap.

• Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin.

• Pulmonary Aspiration During General Anesthesia or Deep Sedation Most common adverse reactions (incidence ≥5%) are nausea, abdominal pain, diarrhea, decreased appetite, vomiting and constipation.

To report SUSPECTED ADVERSE

REACTIONS, contact Novo Nordisk Inc.fda.gov/medwatch. 6.1 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

OZEMPIC tablets (1.5 mg, 4 mg and 9 mg strengths) and RYBELSUS (3 mg, 7, mg and 14 mg strengths) has been established as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus based on adequate and well-controlled studies of RYBELSUS in adult patients with type 2 diabetes mellitus.

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 are derived from 2 placebo-controlled trials in adult patients with type 2 diabetes mellitus.

These data reflect exposure of 1,071 patients to semaglutide tablets (3 mg, 7, mg or 14 mg orally once daily) with a mean duration of exposure of 41.8 weeks.

The mean age of patients was 58 years, 3.9% were 75 years or older and 52% were male.

In these trials, 63% were White, 6% were Black or African American and 27% were Asian; 19% identified as Hispanic or Latino ethnicity.

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.

Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 66.2%, mildly impaired (eGFR to 90 mL/min/1.73m 2 ) in 32.4% and moderately impaired (eGFR to 60 mL/min/1.73m 2 ) in 1.4% of patients.

Pool of

• 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.

The mean age of patients was 58 years, 5% were 75 years or older and 55% were male.

In these trials, 65% were White, 6% were Black or African American and 24% were Asian; 15% identified as Hispanic or Latino ethnicity.

At baseline, patients had type 2 diabetes mellitus for an average of 8.8 years and had a mean HbA 1c of 8.2%.

At baseline, 16.6% of the population reported retinopathy.

Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 65.9%, mildly impaired (eGFR to 90 mL/min/1.73m 2 ) in 28.5% and moderately impaired (eGFR to 60 mL/min/1.73m 2 ) in 5.4% of the patients.

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.

Reported in ≥5% of Semaglutide Tablets-Treated Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=362) % Semaglutide Tablets 7 mg (N=356) % Semaglutide Tablets 14 mg (N=356) % Nausea 6 11 20 Abdominal Pain 4 10 11 Diarrhea 4 9 10 Decreased appetite 1 6 9 Vomiting 3 6 8 Constipation 2 6 5 In the pool of placebo.

• and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 2.

In a 4-year CV outcomes trial (Trial 7), 4,825 patients were randomized to semaglutide tablets for a median follow-up of 49.6 months and 4,825 patients were randomized to placebo for a median follow-up of 49.4 months.

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.

In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients who received semaglutide tablets than placebo: semaglutide tablets 14 mg once daily (41%), semaglutide tablets 7 mg once daily (32%) and placebo (21%), including severe reactions (semaglutide tablets 14 mg 2.0%, semaglutide tablets 7 mg 0.6%, placebo 0.3%).

The majority of reports of nausea, vomiting and/or diarrhea occurred during dose escalation.

A greater percentage of patients who received semaglutide tablets 14 mg once daily (8%) and semaglutide tablets 7 mg once daily (4%) discontinued treatment due to gastrointestinal adverse reactions than patients who received placebo (1%).

In addition to the reactions in

Table 2, the following gastrointestinal adverse reactions with a frequency of <5% occurred in semaglutide tablets -treated patients (frequencies listed, respectively, as 14 mg once daily, 7 mg once daily and placebo): abdominal distension (3%, 2% and 1%), dyspepsia (0.6%, 3%, 0.6%), eructation (2%, 0.6%, 0%,), flatulence (1%, 2%, 0%), gastroesophageal reflux disease (2%, 2%, 0.3%) and gastritis (2%, 2%, 0.8%).

In the pool of placebo.

• and active-controlled trials with semaglutide tablets, pancreatitis was reported as a serious adverse event in 6 semaglutide tablets -treated patients (0.1 events per 100 patient years) versus in comparator-treated patients (<0.1 events per 100 patient years).

• 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).

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 Placebo Semaglutide Tablets 7 mg Semaglutide Tablets 14 mg Monotherapy (26 weeks) N=178 N=175 N=175 Severe* 0% 1% 0% Plasma glucose <54 mg/dL 1% 0% 0% Add-on to metformin and/or sulfonylurea, basal insulin alone or metformin in combination with basal insulin in patients with moderate renal impairment (26 weeks) N=161.

• N=163 Severe* 0%.

• 0% Plasma glucose <54 mg/dL 3%.

• 6% Add-on to insulin with or without metformin (52 weeks) N=184 N=181 N=181 Severe 1% 0% 1% Plasma glucose <54 mg/dL 32% 26% 30% “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.

In placebo-controlled trials, patients exposed to semaglutide tablets 7 mg and 14 mg tablets had a mean increase from baseline in amylase of 10% and 13%, respectively and lipase of 30% and 34%, respectively.

These changes were not observed in placebo-treated patients.

In placebo-controlled trials to improve glycemic control, cholelithiasis was reported in 1% of patients treated with semaglutide tablets 7 mg. In a 4-year CV outcomes trial (Trial 7), cholelithiasis was reported in 1.1% of patients treated with semaglutide 14 mg tablets and in 0.9% of placebo-treated patients.

In Trial 7, cholecystitis was reported in 1.1% of patients treated with semaglutide14 mg tablets and in 0.7% of placebo-treated patients.

In placebo-controlled trials, semaglutide tablets 7 mg and 14 mg tablets resulted in a mean increase in heart rate of to 3 beats per minute.

There was no change in heart rate in placebo-treated patients. 6.2 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.

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 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.

• 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.