b'Add-on to metformin and/or sulfonylurea, basal insulin alone or metforminmediated reductions in maternal body weight gain and food consumption were observed at in combination with basal insulin in patients with moderate renalall dose levels. Early pregnancy losses and increased incidences of minor visceral (kidney, impairment liver) and skeletal (sternebra) fetal abnormalities were observed at 0.0025 mg/kg/day,(26 weeks) N=161N=163 at clinically relevant exposures. In an embryofetal development study in pregnant cyno-molgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (1.9-,Severe* 0%0% 9.9-, and 29-fold the MRHD) were administered throughout organogenesis, from Gesta- 3%6% tion Day 16 to 50. Pharmacologically mediated, marked initial maternal body weight loss Plasma glucose54 mg/dL and reductions in body weight gain and food consumption coincided with the occurrence Add-on to insulin with or without metformin 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(52 weeks) N=184 N=181 N=181 monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (1.3-, 6.4-,Severe* 1% 0% 1% and 14-fold the MRHD) were administered from Gestation Day 16 to 140. Pharmacologi- 32% 26% 30% cally mediated marked initial maternal body weight loss and reductions in body weight Plasma glucose gain and food consumption coincided with an increase in early pregnancy losses and led 54 mg/dL to delivery of slightly smaller offspring at 0.075 mg/kg twice weekly (6X human expo-*Severe hypoglycemia adverse reactions are episodes requiring the assistance of another person. sure). Salcaprozate sodium (SNAC), an absorption enhancer in RYBELSUS, crosses the Hypoglycemia was more frequent when RYBELSUS was used in combination withplacenta and reaches fetal tissues in rats. In a pre- and postnatal development study in insulin secretagogues (e.g., sulfonylureas) or insulin. Increases in Amylase and Lipase:pregnant Sprague Dawley rats, SNAC was administered orally at 1,000 mg/kg/day (expo-In placebo-controlled trials, patients exposed to RYBELSUS 7 mg and 14 mg had a meansure levels were not measured) on Gestation Day 7 through lactation day 20. An increase in increase from baseline in amylase of 10% and 13%, respectively, and lipase of 30% andgestation length, an increase in the number of stillbirths and a decrease in pup viability were 34%, respectively. These changes were not observed in placebo-treated patients. Chole- observed. Lactation: Risk Summary: There are no data on the presence of semaglutide lithiasis: In placebo-controlled trials, cholelithiasis was reported in 1% of patients treatedin human milk, the effects on the breastfed infant, or the effects on milk production. Sema-with RYBELSUS 7 mg. Cholelithiasis was not reported in RYBELSUS 14 mg or placebo- glutide was present in the milk of lactating rats. SNAC and/or its metabolites concentrated treated patients. Increases in Heart Rate: In placebo-controlled trials, RYBELSUS 7 mgin the milk of lactating rats. When a substance is present in animal milk, it is likely that the and 14 mg resulted in a mean increase in heart rate of 2 to 3 beats per minute. Theresubstance will be present in human milk (see Data). There are no data on the presence of was no change in heart rate in placebo-treated patients. Immunogenicity: ConsistentSNAC in human milk. Since the activity of UGT2B7, an enzyme involved in SNAC clear-with the potentially immunogenic properties of protein and peptide pharmaceuticals,ance, is lower in infants compared to adults, higher SNAC plasma levels may occur in patients treated with RYBELSUS may develop anti-semaglutide antibodies. The detectionneonates and infants. Because of the unknown potential for serious adverse reactions in of antibody formation is highly dependent on the sensitivity and specificity of the assay.the breastfed infant due to the possible accumulation of SNAC from breastfeeding and because there are alternative formulations of semaglutide that can be used during lactation, Additionally, the observed incidence of antibody (including neutralizing antibody) positivityadvise patients that breastfeeding is not recommended during treatment with RYBELSUS. in an assay may be influenced by several factors including assay methodology, sampleData: In lactating rats, semaglutide was detected in milk at levels 3-12 fold lower than handling, timing of sample collection, concomitant medications, and underlying disease.in maternal plasma. SNAC and/or its metabolites were detected in milk of lactating rats For these reasons, the incidence of antibodies to semaglutide in the studies describedfollowing a single maternal administration on lactation day 10. Mean levels of SNAC and/below cannot be directly compared with the incidence of antibodies in other studies oror its metabolites in milk were approximately 2-12 fold higher than in maternal plasma. to other products. Across the placebo- and active-controlled glycemic control trials withFemales and Males of Reproductive Potential: Discontinue RYBELSUS in women antibody measurements, 14 (0.5%) RYBELSUS-treated patients developed anti-drugat least 2 months before a planned pregnancy due to the long washout period for semaglu-antibodies (ADAs) to the active ingredient in RYBELSUS(i.e., semaglutide). Of the 14tide [see Use in Specific Populations]. Pediatric Use: Safety and efficacy of RYBELSUS semaglutide-treated patients that developed semaglutide ADAs, 7 patients (0.2% of thehave not been established in pediatric patients (younger than 18 years). Geriatric Use: In overall population) developed antibodies cross-reacting with native GLP-1. The neutral- the pool of glycemic control trials, 1229 (29.9%) RYBELSUS-treated patients were 65 years izing activity of the antibodies is uncertain at this time. of age and over and 199 (4.8%) RYBELSUS-treated patients were 75 years of age and over. DRUGINTERACTIONS:ConcomitantUsewithanInsulinSecretagogueIn PIONEER 6, the cardiovascular outcomes trial, 691 (43.4%) RYBELSUS-treated patients (e.g., Sulfonylurea) or with Insulin: The risk of hypoglycemia is increased whenwere 65 years of age and over and 196 (12.3%) RYBELSUS-treated patients were 75 years RYBELSUS is used in combination with insulin secretagogues (e.g., sulfonylureas) orof age and over. No overall differences in safety or efficacy were detected between these insulin. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylureapatients and younger patients, but greater sensitivity of some older individuals cannot be (or other concomitantly administered insulin secretagogues) or insulin [see Warnings andruled out. Renal Impairment: The safety and efficacy of RYBELSUS was evaluated in a Precautions]. Oral Medications: RYBELSUS causes a delay of gastric emptying, and26-week clinical study that included 324 patients with moderate renal impairment (eGFR 30 thereby has the potential to impact the absorption of other oral medications. Levothyroxineto 59 mL/min/1.73m 2 ). In patients with renal impairment including end-stage renal disease exposure was increased 33% (90% CI: 125-142) when administered with RYBELSUS in a(ESRD), no clinically relevant change in semaglutide pharmacokinetics (PK) was observed. drug interaction study. When coadministering oral medications instruct patients to closelyNo dose adjustment of RYBELSUS is recommended for patients with renal impairment. follow RYBELSUS administration instructions. Consider increased clinical or laboratoryHepatic Impairment: In a study in subjects with different degrees of hepatic impairment, monitoring for medications that have a narrow therapeutic index or that require clinicalno clinically relevant change in semaglutide pharmacokinetics (PK) was observed. No dose monitoring. adjustment of RYBELSUS is recommended for patients with hepatic impairment.USE IN SPECIFIC POPULATIONS: Pregnancy: Risk Summary: Available data withOVERDOSAGE: In the event of overdose, appropriate supportive treatment should be RYBELSUS use in pregnant women are insufficient to evaluate for a drug-associated riskinitiated according to the patients clinical signs and symptoms. A prolonged period of of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There areobservation and treatment for these symptoms may be necessary, taking into account the clinical considerations regarding the risks of poorly controlled diabetes in pregnancy (seelong half-life of RYBELSUS of approximately 1 week.Clinical Considerations). Based on animal reproduction studies, there may be potential risks to the fetus from exposure to RYBELSUS during pregnancy. RYBELSUS 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). The estimated background risk of major birth defects is 610% in women with pre-gestational diabetes with an HbA 1c7 and has been reportedMore detailed information is available upon request. to be as high as 2025% in women with a HbA 1c10. In the U.S. general population, theFor information about RYBELSUS contact: Novo Nordisk Inc., 800 Scudders Mill Road, estimated background risk of major birth defects and miscarriage in clinically recognizedPlainsboro, NJ 08536, 1-833-457-7455pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations: Disease asso- Date of Issue: January 2020 ciated maternal and fetal risk: Poorly controlled diabetes during pregnancy increases theVersion: 2maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal riskManufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmarkfor major birth defects, stillbirth, and macrosomia related morbidity. Data: Animal Data:RYBELSUS and OZEMPIC are registered trademarks of Novo Nordisk A/S. In a combined fertility and embryofetal development study in rats, subcutaneous dosesPATENT INFORMATION:of 0.01, 0.03 and 0.09 mg/kg/day (0.2-, 0.7-, and 2.1-fold the MRHD) were administeredhttp://www.novonordisk-us.com/products/product-patents.htmlto males for 4 weeks prior to and throughout mating and to females for 2 weeks prior to 2020 Novo NordiskUS20RYB000792/2020mating, and throughout organogenesis to Gestation Day 17. In parental animals, pharma-cologically 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 6 to 19. Pharmacologically'