b'RYBELSUS (semaglutide) tablets in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renalTable 2. Hypoglycemia Adverse Reactions in Placebo-Controlled Trials InPharmacologically mediated reductions in maternal body weight gain and food consump-Rx Only function when initiating or escalating doses of RYBELSUS in patients reporting severePatients with Type 2 Diabetes Mellitus tion were observed at all dose levels. Early pregnancy losses and increased incidences of adverse gastrointestinal reactions. Hypersensitivity: Serious hypersensitivity reactionsminor visceral (kidney, liver) and skeletal (sternebra) fetal abnormalities were observed at BRIEF SUMMARY: Please consult package insert for full prescribing(e.g., anaphylaxis, angioedema) have been reported in patients treated with RYBELSUS.Placebo RYBELSUS7 mg RYBELSUS14 mg 0.0025 mg/kg/day, at clinically relevant exposures. In an embryofetal development study information. If hypersensitivity reactions occur, discontinue use of RYBELSUS; treat promptly perMonotherapy in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg WARNING: RISK OF THYROID C-CELL TUMORS: In rodents, semaglutidestandard of care, and monitor until signs and symptoms resolve. RYBELSUS is contrain- (26 weeks) N=178 N=175 N=175 twice weekly (1.9-, 9.9-, and 29-fold the MRHD) were administered throughout organogen-causesdose-dependentandtreatment-duration-dependentthyroiddicated in patients with a prior serious hypersensitivity reaction to semaglutide or to any of Severe* 0% 1% 0% esis, from Gestation Day 16 to 50. Pharmacologically mediated, marked initial maternal C-cell tumors at clinically relevant exposures. It is unknown whetherPlasma glucose body weight loss and reductions in body weight gain and food consumption coincidedthe excipients in RYBELSUS . [see Adverse Reactions]. Anaphylaxis and angioedema have1% 0% 0% with the occurrence of sporadic abnormalities (vertebra, sternebra, ribs) at 0.075 mg/kg RYBELSUScauses thyroid C-cell tumors, including medullary thyroidbeen reported with GLP-1 receptor agonists. Use caution in a patient with a history of ang-io 54 mg/dL twice weekly (9X human exposure). In a pre- and postnatal development study in preg-carcinoma (MTC), in humans as human relevance of semaglutide-inducededema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whetherAdd-on to metformin and/or sulfonylurea, basal insulin alone or metforminnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice rodent thyroid C-cell tumors has not been determined [see Warnings andsuch patients will be predisposed to anaphylaxis with RYBELSUS. Acute Gallbladderin combination with basal insulin in patients with moderate renalweekly (1.3-, 6.4-, and 14-fold the MRHD) were administered from Gestation Day 16 to Precautions]. RYBELSUS is contraindicated in patients with a personalDisease: Acute events of gallbladder disease such as cholelithiasis or cholecystitis haveimpairment 140. Pharmacologically mediated marked initial maternal body weight loss and reductions or family history of MTC or in patients with Multiple Endocrine Neoplasiabeen reported in GLP-1 receptor agonist trials and postmarketing. In placebo-controlled (26 weeks) N=161N=163 in body weight gain and food consumption coincided with an increase in early pregnancy syndrometype2(MEN2)[seeContraindications].Counselpatientstrials, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg. Choleli- losses and led to delivery of slightly smaller offspring at 0.075 mg/kg twice weekly (6X regarding the potential risk for MTC with the use of RYBELSUS and informthiasis was not reported in RYBELSUS 14 mg or placebo-treated patients. If cholelithiasis Severe* 0%0% human exposure). Salcaprozate sodium (SNAC), an absorption enhancer in RYBELSUS, is suspected, gallbladder studies and appropriate clinical follow-up are indicated [see crosses the placenta and reaches fetal tissues in rats. In a pre- and postnatal development them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia,Plasma glucose 3%6%dyspnea, persistent hoarseness). Routine monitoring of serum calcitoninAdverse Reactions]. 54 mg/dL study in pregnant Sprague Dawley rats, SNAC was administered orally at 1,000 mg/kg/or using thyroid ultrasound is of uncertain value for early detection of MTCADVERSE REACTIONS: The following serious adverse reactions are described below orAdd-on to insulin with or without metformin day (exposure levels were not measured) on Gestation Day 7 through lactation day 20. An in patients treated with RYBELSUS [see Contraindications and Warningselsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and (52 weeks) N=184 N=181 N=181 increase in gestation length, an increase in the number of stillbirths and a decrease in pup and Precautions]. Precautions]; Pancreatitis [see Warnings and Precautions]; Diabetic Retinopathy Compli-Severe* 1% 0% 1% viability were observed. Lactation: Risk Summary: There are no data on the presencecations [see Warnings and Precautions]; Hypoglycemia with Concomitant Use of Insulin of semaglutide in human milk, the effects on the breastfed infant, or the effects on milk Plasma glucoseINDICATIONS AND USAGE: RYBELSUSis indicated as an adjunct to diet and exerciseSecretagogues or Insulin [see Warnings and Precautions]; Acute Kidney Injury [see Warn- 54 mg/dL 32% 26% 30% production. Semaglutide was present in the milk of lactating rats. SNAC and/or its metabo-to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use:ings and Precautions]; Hypersensitivity [see Warnings and Precautions]; Acute Gallbladderlites concentrated in the milk of lactating rats. When a substance is present in animal milk, RYBELSUS has not been studied in patients with a history of pancreatitis. Consider otherDisease [see Warnings and Precautions]. Clinical Trials Experience: Because clinical*Severe hypoglycemia adverse reactions are episodes requiring the assistance of another person. it is likely that the substance will be present in human milk (see Data). There are no data antidiabetic therapies in patients with a history of pancreatitis [see Warnings and Precau- trials are conducted under widely varying conditions, adverse reaction rates observed inHypoglycemia was more frequent when RYBELSUS was used in combination with insulinon the presence of SNAC in human milk. Since the activity of UGT2B7, an enzyme involved tions]. RYBELSUS is not indicated for use in patients with type 1 diabetes mellitus. the clinical trials of a drug cannot be directly compared to rates in the clinical trials ofsecretagogues (e.g., sulfonylureas) or insulin. Increases in Amylase and Lipase: In placebo- in SNAC clearance, is lower in infants compared to adults, higher SNAC plasma levelsmay occur in neonates and infants. Because of the unknown potential for serious adverse CONTRAINDICATIONS: RYBELSUS is contraindicated in patients with: A personal oranother drug and may not reflect the rates observed in practice. Pool of Placebo-Controlledcontrolled trials, patients exposed to RYBELSUS7 mg and 14 mg had a mean increasereactions in the breastfed infant due to the possible accumulation of SNAC from breast-family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endo- Trials: The data in Table 1 are derived from 2 placebo-controlled trials in adult patients withfrom baseline in amylase of 10% and 13%, respectively, and lipase of 30% and 34%,feeding and because there are alternative formulations of semaglutide that can be used crine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions]. A prior serioustype 2 diabetes. These data reflect exposure of 1071 patients to RYBELSUS with a meanrespectively. These changes were not observed in placebo-treated patients. Cholelithiasis:during lactation, advise patients that breastfeeding is not recommended during treatment hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS. Seriousduration of exposure of 41.8 weeks. The mean age of patients was 58 years, 3.9% wereIn placebo-controlled trials, cholelithiasis was reported in 1% of patients treated withwith RYBELSUS. Data: In lactating rats, semaglutide was detected in milk at levels 3-12 RYBELSUS 7 mg. Cholelithiasis was not reported in RYBELSUS 14 mg or placebo-hypersensitivity reactions including anaphylaxis and angioedema have been reported with75 years or older and 52% were male. In these trials, 63% were White, 6% were Black or fold lower than in maternal plasma. SNAC and/or its metabolites were detected in milk of RYBELSUS [see Warnings and Precautions]. African American, and 27% were Asian; 19% identified as Hispanic or Latino ethnicity. Attreated patients. Increases in Heart Rate: In placebo-controlled trials, RYBELSUS7 mglactating rats following a single maternal administration on lactation day 10. Mean levels of baseline, patients had type 2 diabetes for an average of 9.4 years and had a mean HbA 1cofand 14 mg resulted in a mean increase in heart rate of 1 to 3 beats per minute. There wasSNAC and/or its metabolites in milk were approximately 2-12 fold higher than in maternal WARNINGS AND PRECAUTIONS: Risk of Thyroid C-Cell Tumors: In mice and8.1%. At baseline, 20.1% of the population reported retinopathy. Baseline estimated renalno change in heart rate in placebo-treated patients. Postmarketing Experience: Theplasma. Females and Males of Reproductive Potential: Discontinue RYBELSUS rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase2 following adverse reactions have been reported during post-approval use of semaglutide, function was normal (eGFR 90 mL/min/1.73m) in 66.2%, mildly impaired (eGFR 60 to in women at least 2 months before a planned pregnancy due to the long washout period for in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime expo- 2 2 the active ingredient of RYBELSUS . Because these reactions are reported voluntarily fromsemaglutide [see Use in Specific Populations]. Pediatric Use: The safety and effective-sure at clinically relevant plasma exposures. It is unknown whether RYBELSUS causes90 mL/min/1.73m) in 32.4% and moderately impaired (eGFR 30 to 60 mL/min/1.73m) ina population of uncertain size, it is not always possible to reliably estimate their frequencyness of RYBELSUS have not been established in pediatric patients.Geriatric Use: In the thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human1.4% of patients. Pool of Placebo- and Active-Controlled Trials: The occurrence of adverseor establish a causal relationship to drug exposure. Gastrointestinal: ileus; Hypersensitivity:pool of glycemic control trials, 1229 (30%) RYBELSUS-treated patients were 65 years of relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined.reactions was also evaluated in a larger pool of adult patients with type 2 diabetes partici- anaphylaxis,angioedema,rash,urticaria;Hepatobiliary:cholecystitis,cholelithiasisage and over and 199 (5%) RYBELSUS-treated patients were 75 years of age and over. pating in 9 placebo- and active-controlled trials. In this pool, 4116 patients with type 2Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have requiring cholecystectomy In PIONEER 6, the cardiovascular outcomes trial, 891 (56%) RYBELSUS -treated patients been reported in the postmarketing period; the data in these reports are insufficient todiabetes were treated with RYBELSUSfor a mean duration of 59.8 weeks. The mean ageDRUG INTERACTIONS: Concomitant Use with an Insulin Secretagogue (e.g.,were 65 years of age and over and 200 (13%) RYBELSUS-treated patients were 75 years of patients was 58 years, 5% were 75 years or older and 55% were male. In these trials, establish or exclude a causal relationship between MTC and GLP-1 receptor agonist useSulfonylurea) or with Insulin: RYBELSUSstimulates insulin release in the presenceof age and over. No overall differences in safety or effectiveness for RYBELSUS have been in humans. RYBELSUS is contraindicated in patients with a personal or family history65% were White, 6% were Black or African American, and 24% were Asian; 15% identifiedof elevated blood glucose concentrations. Patients receiving RYBELSUS in combina- observed between patients 65 years of age and older and younger adult patients. Renal of MTC or in patients with MEN 2. Counsel patients regarding the potential risk foras Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average oftion with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increasedImpairment: The safety and effectiveness of RYBELSUS was evaluated in a 26-week8.8 years and had a mean HbA 1cof 8.2%. At baseline, 16.6% of the population reportedMTC with the use of RYBELSUSand inform them of symptoms of thyroid tumors (e.g.,2 riskofhypoglycemia,includingseverehypoglycemia.WheninitiatingRYBELSUS ,clinical study that included 324 patients with moderate renal impairment (eGFR 30 to 59 retinopathy. Baseline estimated renal function was normal (eGFR 90 mL/min/1.73m) in2a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring2 consider reducing the dose of concomitantly administered insulin secretagogue (such asmL/min/1.73m ). In patients with renal impairment including end-stage renal disease 65.9%, mildly impaired (eGFR 60 to 90 mL/min/1.73m) in 28.5%, and moderately impaired(ESRD), no clinically relevant change in semaglutide pharmacokinetics (PK) was observed. of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection2 sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precau- of MTC in patients treated with RYBELSUS. Such monitoring may increase the risk of(eGFR 30 to 60 mL/min/1.73m) in 5.4% of the patients. Common Adverse Reactions: Tabletions and Adverse Reactions]. Oral Medications: RYBELSUS causes a delay of gastricNo dose adjustment of RYBELSUSis recommended for patients with renal impairment. 1 shows common adverse reactions, excluding hypoglycemia, associated with the use ofemptying, and thereby has the potential to impact the absorption of other oral medications.Hepatic Impairment: In a study in subjects with different degrees of hepatic impairment, unnecessary procedures, due to the low test specificity for serum calcitonin and a highRYBELSUS in adult patients with type 2 diabetes in the pool of placebo-controlled trials.no clinically relevant change in semaglutide pharmacokinetics (PK) was observed. No dose background incidence of thyroid disease. Significantly elevated serum calcitonin value may Levothyroxine exposure was increased 33% (90% CI: 125-142) when administered withThese adverse reactions occurred more commonly on RYBELSUSthan on placebo andRYBELSUS in a drug interaction study. When coadministering oral medications instructadjustment of RYBELSUSis recommended for patients with hepatic impairment.indicate MTC and patients with MTC usually have calcitonin values 50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated.occurred in at least 5% of patients treated with RYBELSUS . patients to closely follow RYBELSUSadministration instructions. Consider increasedOVERDOSAGE: In the event of overdose, appropriate supportive treatment should be Patients with thyroid nodules noted on physical examination or neck imaging should alsoTable 1. Adverse Reactions in Placebo-Controlled Trials Reported in 5% ofclinical or laboratory monitoring for medications that have a narrow therapeutic index orinitiated according to the patients clinical signs and symptoms. A prolonged period of that require clinical monitoring. observation and treatment for these symptoms may be necessary, taking into account the be further evaluated. Pancreatitis: In glycemic control trials, pancreatitis was reportedRYBELSUS-Treated Patients with Type 2 Diabetes Mellitus as a serious adverse event in 6 RYBELSUS-treated patients (0.1 events per 100 patientUSE IN SPECIFIC POPULATIONS: Pregnancy: Risk Summary: Available data withlong half-life of RYBELSUSof approximately 1 week.Adverse Reaction PlaceboRYBELSUS7mgRYBELSUS14mgyears) versus 1 in comparator-treated patients (0.1 events per 100 patient years). After(N=362) % (N=356) % (N=356) % RYBELSUSuse in pregnant women are insufficient to evaluate for a drug-associated risk initiation of RYBELSUS, observe patients carefully for signs and symptoms of pancreatitisNausea 6 11 20 of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are (including persistent severe abdominal pain, sometimes radiating to the back and whichclinical considerations regarding the risks of poorly controlled diabetes in pregnancy (see may or may not be accompanied by vomiting). If pancreatitis is suspected, RYBELSUSAbdominal Pain 4 10 11 Clinical Considerations). Based on animal reproduction studies, there may be potential should be discontinued and appropriate management initiated; if confirmed, RYBELSUSDiarrhea4 9 10 risks to the fetus from exposure to RYBELSUS during pregnancy. RYBELSUS should be should not be restarted. Diabetic Retinopathy Complications: In a pooled analysisDecreased appetite1 6 9 used during pregnancy only if the potential benefit justifies the potential risk to the fetus. of glycemic control trials with RYBELSUS, patients reported diabetic retinopathy relatedVomiting 3 6 8 In pregnant rats administered semaglutide during organogenesis, embryofetal mortality, adverse reactions during the trial (4.2% with RYBELSUS and 3.8% with comparator). Instructural abnormalities and alterations to growth occurred at maternal exposures below a 2-year cardiovascular outcomes trial with semaglutide injection involving patients withConstipation 2 6 5 the maximum recommended human dose (MRHD) based on AUC. In rabbits and cyno-type 2 diabetes and high cardiovascular risk, diabetic retinopathy complications (whichIn the pool of placebo- and active-controlled trials, the types and frequency of commonmolgusmonkeysadministeredsemaglutideduringorganogenesis,earlypregnancy was a 4 component adjudicated endpoint) occurred in patients treated with semaglutideadverse reactions, excluding hypoglycemia, were similar to those listed in Table 1. losses and structural abnormalities were observed at exposure below the MRHD (rabbit) injection (3.0%) compared to placebo (1.8%). The absolute risk increase for diabetic reti- Gastrointestinal Adverse Reactions: In the pool of placebo-controlled trials, gastrointestinaland 10-fold the MRHD (monkey). These findings coincided with a marked maternal body nopathy complications was larger among patients with a history of diabetic retinopathyadverse reactions occurred more frequently among patients receiving RYBELSUS thanweight loss in both animal species (see Data). The estimated background risk of major at baseline (semaglutide injection 8.2%, placebo 5.2%) than among patients without aplacebo (placebo 21%, RYBELSUS 7 mg 32%, RYBELSUS 14 mg 41%). The majoritybirth defects is 610% in women with pre-gestational diabetes with an HbA 1c7 and has been reported to be as high as 2025% in women with a HbA10. In the U.S. generalMore detailed information is available upon request. known history of diabetic retinopathy (semaglutide injection 0.7%, placebo 0.4%). Rapidof reports of nausea, vomiting, and/or diarrhea occurred during dose escalation. More1cimprovement in glucose control has been associated with a temporary worsening ofpatients receiving RYBELSUS 7 mg (4%) and RYBELSUS 14 mg (8%) discontinuedpopulation, the estimated background risk of major birth defects and miscarriage in clini- For information about RYBELSUS contact:cally recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations:Novo Nordisk Inc., 800 Scudders Mill Road, Plainsboro, NJ 08536, 1-833-457-7455diabetic retinopathy. The effect of long-term glycemic control with semaglutide on diabetictreatment due to gastrointestinal adverse reactions than patients receiving placebo (1%).Disease associated maternal and fetal risk: Poorly controlled diabetes during pregnancy retinopathy complications has not been studied. Patients with a history of diabetic reti- In addition to the reactions in Table 1, the following gastrointestinal adverse reactions withincreases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abor- Date of Issue: 01/2023; Version: 5nopathy should be monitored for progression of diabetic retinopathy. Hypoglycemiaa frequency of 5% were associated with RYBELSUS (frequencies listed, respectively,tions, preterm delivery, and delivery complications. Poorly controlled diabetes increasesManufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmarkwith Concomitant Use of Insulin Secretagogues or Insulin: Patients receivingas placebo; 7 mg; 14 mg): abdominal distension (1%, 2%, 3%), dyspepsia (0.6%, 3%,the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data:RYBELSUS and OZEMPIC are registered trademarks of Novo Nordisk A/S. RYBELSUS in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin0.6%), eructation (0%, 0.6%, 2%), flatulence (0%, 2%, 1%), gastroesophageal refluxAnimal Data: In a combined fertility and embryofetal development study in rats, subcuta - PATENT INFORMATION:may have an increased risk of hypoglycemia, including severe hypoglycemia [see Adversedisease (0.3%, 2%, 2%), and gastritis (0.8%, 2%, 2%). Other Adverse Reactions: Pancre- neous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.2-, 0.7-, and 2.1-fold the MRHD) were Reactions and Drug Interactions]. The risk of hypoglycemia may be lowered by a reductionatitis: In the pool of placebo- and active-controlled trials with RYBELSUS, pancreatitisadministered to males for 4 weeks prior to and throughout mating and to females for 2http://www.novonordisk-us.com/products/product-patents.htmlin the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) orwas reported as a serious adverse event in 6 RYBELSUS-treated patients (0.1 events perweeks prior to mating, and throughout organogenesis to Gestation Day 17. In parental 2023 Novo NordiskUS22RYB010751/2023insulin. Inform patients using these concomitant medications of the risk of hypoglycemia100 patient years) versus 1 in comparator-treated patients (0.1 events per 100 patientanimals, pharmacologically mediated reductions in body weight gain and food consump-and educate them on the signs and symptoms of hypoglycemia. Acute Kidney Injury:years). Diabetic Retinopathy Complications: In the pool of placebo- and active-controlledtion were observed at all dose levels. In the offspring, reduced growth and fetuses with There have been postmarketing reports of acute kidney injury and worsening of chronictrials with RYBELSUS, patients reported diabetic retinopathy related adverse reactionsvisceral (heart blood vessels) and skeletal (cranial bones, vertebra, ribs) abnormalities were renal failure, which may sometimes require hemodialysis, in patients treated with GLP-1during the trial (4.2% with RYBELSUSand 3.8% with comparator). Hypoglycemia: Table 2observed at the human exposure. In an embryofetal development study in pregnant rabbits, receptor agonists, including semaglutide. Some of these events have been reported insummarizes the incidence of hypoglycemia by various definitions in the placebo-controlledsubcutaneous doses of 0.0010, 0.0025 or 0.0075 mg/kg/day (0.06-, 0.6-, and 4.4-fold patients without known underlying renal disease. A majority of the reported events occurredtrials. the MRHD) were administered throughout organogenesis from Gestation Day 6 to 19.'