b'96OZEMPIC (semaglutide) injection theseconcomitantmedicationsoftheriskofhypoglycemiaandeducatethemreceiving OZEMPIC 2 mg (34.0%) vs OZEMPIC 1 mg (30.8%). In addition to theadministered semaglutide during organogenesis, embryofetal mortality, structural Rx Only on the signs and symptoms of hypoglycemia. Acute Kidney Injury: There havereactions in Table 1, the following gastrointestinal adverse reactions with a frequencyabnormalities and alterations to growth occurred at maternal clinical exposure based been postmarketing reports of acute kidney injury and worsening of chronic renalof 5% were associated with OZEMPIC (frequencies listed, respectively, as: placebo;on AUC. In rabbits and cynomolgus monkeys administered semaglutide during BRIEF SUMMARY: Please consult package insert for full prescribinginformation. failure, which may sometimes require hemodialysis, in patients treated with GLP-10.5 mg; 1 mg): dyspepsia (1.9%, 3.5%, 2.7%), eructation (0%, 2.7%, 1.1%), flatulenceorganogenesis, early pregnancy losses or structural abnormalities were observed at receptor agonists. Some of these events have been reported in patients without known(0.8%, 0.4%, 1.5%), gastroesophageal reflux disease (0%, 1.9%, 1.5%), and gastritisclinical exposure (rabbit) and 2-fold the MRHD (monkey). These findings coincided WARNING: RISK OF THYROID C-CELL TUMORS: In rodents, semaglutideunderlying renal disease. A majority of the reported events occurred in patients who(0.8%, 0.8%, 0.4%). Other Adverse Reactions: Hypoglycemia: Table 2 summarizeswith a marked maternal body weight loss in both animal species (see Data). In the had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal functionthe incidence of events related to hypoglycemia by various definitions in the placebo- U.S.generalpopulation,theestimatedbackgroundriskofmajorbirthdefects causes dose-dependent and treatment-duration-dependent thyroidwheninitiatingorescalatingdosesofOZEMPICinpatientsreportingseverecontrolled trials. and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, C-cell tumors at clinically relevant exposures. It is unknown whether OZEMPIC causes thyroid C-cell tumors, including medullary thyroidadversegastrointestinalreactions.Hypersensitivity:SerioushypersensitivityTable 2. Hypoglycemia Adverse Reactions in Placebo-Controlled Trialsrespectively. The estimated background risk of major birth defects is 6 to 10% in reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated withwomen with pre-gestational diabetes with a peri-conceptional HbA7 and has been carcinoma (MTC), in humans as human relevance of semaglutide- in Patients with Type 2 Diabetes Mellitus 1cOZEMPIC . If hypersensitivity reactions occur, discontinue use of OZEMPIC ; treatreported to be as high as 20 to 25% in women with a peri-conceptional HbA 10. The induced rodent thyroid C-cell tumors has not been determined [see1cpromptly per standard of care, and monitor until signs and symptoms resolve. Do notOZEMPIC OZEMPIC estimated background risk of miscarriage for the indicated population is unknown. Warnings and Precautions]. OZEMPIC is contraindicated in patientswith a personal or family history of MTC or in patients with Multipleuse in patients with a previous hypersensitivity to OZEMPIC[see ContraindicationsPlacebo 0.5 mg 1 mg ClinicalConsiderations:Disease-AssociatedMaternaland/orEmbryo/fetalRisk: Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications].and Adverse Reactions]. Anaphylaxis and angioedema have been reported with otherMonotherapyHypoglycemia and hyperglycemia occur more frequently during pregnancy in patients Counsel patients regarding the potential risk for MTC with the useGLP-1 receptor agonists. Use caution in a patient with a history of angioedema or(30 weeks) N=129 N=127 N=130 with pre-gestational diabetes. Poorly controlled diabetes during pregnancy increases of OZEMPIC and inform them of symptoms of thyroid tumors (e.g.anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such the maternal risk for diabetic ketoacidosis, pre- eclampsia, spontaneous abortions, a mass in the neck, dysphagia, dyspnea, persistent hoarseness).patients will be predisposed to anaphylaxis with OZEMPIC. Acute GallbladderSevere 0% 0% 0% preterm delivery, and delivery complications. Poorly controlled diabetes increases Routine monitoring of serum calcitonin or using thyroid ultrasound isDisease: Acute events of gallbladder disease such as cholelithiasis or cholecystitisDocumented symptomatic (70mg/dL glucose threshold) 0% 1.6% 3.8% the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. of uncertain value for early detection of MTC in patients treated withhave been reported in GLP-1 receptor agonist trials and postmarketing. In placebo- Severe or Blood Glucose Confirmed SymptomaticData: Animal Data: In a combined fertility and embryofetal development study in rats, OZEMPIC [see Contraindications and Warnings and Precautions]. controlled trials, cholelithiasis was reported in 1.5% and 0.4% of patients-treated with(56mg/dL glucose threshold)1.6% 0% 0% subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.06-, 0.2-, and 0.6-fold the OZEMPIC 0.5 mg and 1 mg, respectively. Cholelithiasis was not reported in placebo- Add-on to Basal Insulin with or without Metformin MRHD) were administered to males for 4 weeks prior to and throughout mating and INDICATIONS AND USAGE: OZEMPIC is indicated: as an adjunct to diet andtreated patients. If cholelithiasis is suspected, gallbladder studies and appropriate(30 weeks) N=132 N=132 N=131 to females for 2 weeks prior to mating, and throughout organogenesis to Gestation exercise to improve glycemic control in adults with type 2 diabetes mellitus; toclinical follow-up are indicated.Day 17. In parental animals, pharmacologically mediated reductions in body weight reduce the risk of major adverse cardiovascular events (cardiovascular death, non- ADVERSE REACTIONS: The following serious adverse reactions are describedSevere0% 0% 1.5% gain and food consumption were observed at all dose levels. In the offspring, reduced fatal myocardial infarction or non-fatal stroke) in adults with type 2 diabetes mellitusbelow or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [seeDocumented symptomatic (70mg/dL glucose threshold) 15.2% 16.7% 29.8% growth and fetuses with visceral (heart blood vessels) and skeletal (cranial bones, and established cardiovascular disease. Limitations of Use: OZEMPIC has not beenWarnings and Precautions]; Pancreatitis [see Warnings and Precautions]; DiabeticSevere or Blood Glucose Confirmed Symptomaticvertebra, ribs) abnormalities were observed at the human exposure. In an embryofetal studied in patients with a history of pancreatitis. Consider other antidiabetic therapiesRetinopathy Complications[seeWarningsandPrecautions];Hypoglycemiawith(56mg/dL glucose threshold)5.3% 8.3% 10.7% development study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025 or in patients with a history of pancreatitis [see Warnings and Precautions]. OZEMPICConcomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions]; 0.0075 mg/kg/day (0.02-, 0.2-, and 1.2-fold the MRHD) were administered throughout Severe hypoglycemia adverse reactions are episodes requiring the assistance of another person.organogenesis from Gestation Day 6 to 19. Pharmacologically mediated reductions in is not indicated for use in patients with type 1 diabetes mellitus. Acute Kidney Injury [see Warnings and Precautions]; Hypersensitivity [see Warnings andPrecautions];AcuteGallbladderDisease [see Warnings and Precautions] .Hypoglycemia was more frequent when OZEMPICwas used in combination withmaternal body weight gain and food consumption were observed at all dose levels. CONTRAINDICATIONS: OZEMPICis contraindicated in patients with: A personala sulfonylurea [see Warnings and Precautions]. Severe hypoglycemia occurred inEarly pregnancy losses and increased incidences of minor visceral (kidney, liver) or family history of medullary thyroid carcinoma (MTC) or in patients with MultipleClinical Trials Experience: Because clinical trials are conducted under widely0.8% and 1.2% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, wasand skeletal (sternebra) fetal abnormalities were observed at 0.0025 mg/kg/day, Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions];varying conditions, adverse reaction rates observed in the clinical trials of a drugco-administeredwithasulfonylurea.Documentedsymptomatichypoglycemiaat clinically relevant exposures. In an embryofetal development study in pregnant A serious hypersensitivity reaction to semaglutide or to any of the excipients incannot be directly compared to rates in the clinical trials of another drug and may cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice OZEMPIC. Serious hypersensitivity reactions including anaphylaxis and angio- not reflect the rates observed in practice. Pool of Placebo-Controlled Trials: The dataoccurred in 17.3% and 24.4% of patients when OZEMPIC0.5 mg and 1 mg,weekly (0.5-, 3-, and 8-fold the MRHD) were administered throughout organogenesis, edema have been reported with OZEMPIC [see Warnings and Precautions]. in Table 1 are derived from 2 placebo-controlled trials (1 monotherapy trial and 1respectively, was co-administered with a sulfonylurea. Severe or blood glucosefrom Gestation Day 16 to 50. Pharmacologically mediated, marked initial maternal confirmed symptomatic hypoglycemia occurred in 6.5% and 10.4% of patients when trial in combination with basal insulin) in patients with type 2 diabetes. These dataWARNINGS AND PRECAUTIONS: Risk of Thyroid C-Cell Tumors: In micereflect exposure of 521 patients to OZEMPIC and a mean duration of exposure toOZEMPIC0.5 mg and 1 mg, respectively, was co-administered with a sulfonylurea.body weight loss and reductions in body weight gain and food consumption coincided and rats, semaglutide caused a dose-dependent and treatment-duration-dependentOZEMPIC of 32.9 weeks. Across the treatment arms, the mean age of patients wasInjection Site Reactions: In placebo-controlled trials, injection site reactions (e.g.,with the occurrence of sporadic abnormalities (vertebra, sternebra, ribs) at 0.075 increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after56 years, 3.4% were 75 years or older and 55% were male. In these trials 71% wereinjection-site discomfort, erythema) were reported in 0.2% of OZEMPIC-treatedmg/kg twice weekly (3X human exposure). In a pre- and postnatal development lifetime exposure at clinically relevant plasma exposures. It is unknown whetherWhite, 7% were Black or African American, and 19% were Asian; 21% identified aspatients. Increases in Amylase and Lipase: In placebo-controlled trials, patientsstudy in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and OZEMPIC causes thyroid C-cell tumors, including medullary thyroid carcinomaHispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an averageexposed to OZEMPIChad a mean increase from baseline in amylase of 13% and lipase 0.15 mg/kg twice weekly (0.3-, 2-, and 4-fold the MRHD) were administered from (MTC),inhumansashumanrelevanceofsemaglutide-inducedrodentthyroidof 8.8 years and had a mean HbA 1cof 8.2%. At baseline, 8.9% of the populationof 22%. These changes were not observed in placebo-treated patients. Cholelithiasis:Gestation Day 16 to 140. Pharmacologically mediated marked initial maternal body C-cell tumors has not been determined. Cases of MTC in patients treated withreported retinopathy. Baseline estimated renal function was normal (eGFR 90 mL/ In placebo-controlled trials, cholelithiasis was reported in 1.5% and 0.4% of patients- weight loss and reductions in body weight gain and food consumption coincided with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketingmin/1.73m 2 ) in 57.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 35.9%treated with OZEMPIC 0.5 mg and 1 mg, respectively. Cholelithiasis was notan increase in early pregnancy losses and led to delivery of slightly smaller offspring period; the data in these reports are insufficient to establish or exclude a causaland moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 6.9% of patients. Poolreported in placebo-treated patients. Increases in Heart Rate: In placebo-controlledat 0.075 mg/kg twice weekly (2X human exposure). Lactation: Risk Summary: relationship between MTC and GLP-1 receptor agonist use in humans. OZEMPICof Placebo- and Active-Controlled Trials: The occurrence of adverse reactions wastrials, OZEMPIC 0.5 mg and 1 mg resulted in a mean increase in heart rate of 2 to 3There are no data on the presence of semaglutide in human milk, the effects on the is contraindicated in patients with a personal or family history of MTC or in patientsalso evaluated in a larger pool of patients with type 2 diabetes participating in 7beats per minute. There was a mean decrease in heart rate of 0.3 beats per minute inbreastfed infant, or the effects on milk production. Semaglutide was present in the milk with MEN 2. Counsel patients regarding the potential risk for MTC with the use ofplacebo- and active-controlled glycemic control trials including two trials in Japaneseplacebo-treated patients. Fatigue, Dysgeusia and Dizziness: Other adverse reactionsof lactating rats, however, due to species-specific differences in lactation physiology, OZEMPIC and inform them of symptoms of thyroid tumors (e.g., a mass in the neck,patients evaluating the use of OZEMPIC as monotherapy and add-on therapy to oralwith a frequency of 0.4% were associated with OZEMPIC include fatigue, dysgeusiathe clinical relevance of these data are not clear (see Data). The developmental dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitoninmedications or insulin. In this pool, a total of 3150 patients with type 2 diabetes wereanddizziness. Immunogenicity: Consistent with the potentially immunogenicand health benefits of breastfeeding should be considered along with the mothers or using thyroid ultrasound is of uncertain value for early detection of MTC in patients properties of protein and peptide pharmaceuticals, patients treated with OZEMPICclinical need for OZEMPIC and any potential adverse effects on the breastfed infant treated with OZEMPIC. Such monitoring may increase the risk of unnecessarytreated with OZEMPICfor a mean duration of 44.9 weeks. Across the treatment arms,may develop anti-semaglutide antibodies. The detection of antibody formation isfrom OZEMPIC or from the underlying maternal condition. Data: In lactating rats, procedures, due to the low test specificity for serum calcitonin and a high backgroundthe mean age of patients was 57 years, 3.2% were 75 years or older and 57% werehighly dependent on the sensitivity and specificity of the assay. Additionally, thesemaglutide was detected in milk at levels 3-12 fold lower than in maternal plasma. incidence of thyroid disease. Significantly elevated serum calcitonin value maymale. In these trials, 60% were White, 6% were Black or African American, and 31%observed incidence of antibody (including neutralizing antibody) positivity in anFemalesandMalesofReproductivePotential:DiscontinueOZEMPIC were Asian; 16% identified as Hispanic or Latino ethnicity. At baseline, patients had indicate MTC and patients with MTC usually have calcitonin values 50 ng/L. If1c assay may be influenced by several factors including assay methodology, samplein women at least 2 months before a planned pregnancy due to the long washout serum calcitonin is measured and found to be elevated, the patient should be furthertype 2 diabetes for an average of 8.2 years and had a mean HbA of 8.2%. At baseline,handling, timing of sample collection, concomitant medications, and underlyingperiod for semaglutide [see Use in Specific Populations]. Pediatric Use: Safety and 7.8% of the population reported retinopathy. Baseline estimated renal function wasevaluated. Patients with thyroid nodules noted on physical examination or necknormal (eGFR 90 mL/min/1.73m 2 ) in 63.1%, mildly impaired (eGFR 60 to 90 mL/ disease. For these reasons, the incidence of antibodies to semaglutide in the studiesefficacy of OZEMPIChave not been established in pediatric patients (younger than imaging should also be further evaluated. Pancreatitis: In glycemic control trials,2 2 describedbelowcannotbedirectlycomparedwiththeincidenceofantibodies18 years). Geriatric Use: In the pool of placebo- and active-controlled glycemic acute pancreatitis was confirmed by adjudication in 7 OZEMPIC-treated patients (0.3min/1.73m ) in 34.3%, and moderately impaired (eGFR 30 to 60 mL/min/1.73m) inin other studies or to other products. Across the placebo- and active-controlledcontrol trials, 744 (23.6%) OZEMPIC-treated patients were 65 years of age and over2.5% of the patients. Common Adverse Reactions: Table 1 shows common adversecases per 100 patient years) versus 3 in comparator-treated patients (0.2 cases per glycemic control trials, 32 (1.0%) OZEMPIC-treated patients developed anti-drugand 102 OZEMPIC -treated patients (3.2%) patients were 75 years of age and over. 100 patient years). One case of chronic pancreatitis was confirmed in an OZEMPIC- reactions, excluding hypoglycemia, associated with the use of OZEMPICin theantibodies (ADAs) to the active ingredient in OZEMPIC (i.e., semaglutide). Of the 32In SUSTAIN 6, the cardiovascular outcome trial, 788 (48.0%) OZEMPIC-treated pool of placebo-controlled trials. These adverse reactions occurred more commonlytreated patient. In a 2-year trial, acute pancreatitis was confirmed by adjudication in 8on OZEMPIC than on placebo and occurred in at least 5% of patients treated withsemaglutide-treated patients that developed semaglutide ADAs, 19 patients (0.6% ofpatients were 65 years of age and over and 157 OZEMPIC -treated patients (9.6%) OZEMPIC-treated patients (0.27 cases per 100 patient years) and 10 placebo-treatedOZEMPIC. the overall population) developed antibodies cross-reacting with native GLP-1. The inpatients were 75 years of age and over. No overall differences in safety or efficacy were patients (0.33 cases per 100 patient years), both on a background of standard of care.vitro neutralizing activity of the antibodies is uncertain at this time. Postmarketingdetected between these patients and younger patients, but greater sensitivity of someTable 1. Adverse Reactions in Placebo-Controlled Trials Reported inolder individuals cannot be ruled out. Renal Impairment: No dose adjustment of After initiation of OZEMPIC , observe patients carefully for signs and symptoms of Experience: The following adverse reactions have been reported during post- pancreatitis (including persistent severe abdominal pain, sometimes radiating to5% of OZEMPIC -Treated Patients with Type 2 Diabetes Mellitus approval use of semaglutide, the active ingredient of OZEMPIC. Because theseOZEMPICis recommended for patients with renal impairment. In subjects with renal the back and which may or may not be accompanied by vomiting). If pancreatitisPlacebo OZEMPIC 0.5 mg OZEMPIC 1 mg reactions are reported voluntarily from a population of uncertain size, it is not alwaysimpairment including end-stage renal disease (ESRD), no clinically relevant change insemaglutide pharmacokinetics (PK) was observed. Hepatic Impairment: No dose issuspected,OZEMPICshould be discontinued and appropriate managementAdverse Reaction (N=262) % (N=260) % (N=261) % possible to reliably estimate their frequency or establish a causal relationship to druginitiated; if confirmed, OZEMPIC should not be restarted. Diabetic RetinopathyNausea 6.1 15.820.3exposure. Hypersensitivity: anaphylaxis, angioedema, rash, urticaria; Hepatobiliary:adjustment of OZEMPICis recommended for patients with hepatic impairment. In a Complications: In a 2-year trial involving patients with type 2 diabetes and highcholecystitis, cholecystectomy. study in subjects with different degrees of hepatic impairment, no clinically relevant cardiovascular risk, more events of diabetic retinopathy complications occurred inVomiting 2.35.09.2change in semaglutide pharmacokinetics (PK) was observed.DRUG INTERACTIONS: Concomitant Use with an Insulin Secretagogue patients treated with OZEMPIC(3.0%) compared to placebo (1.8%). The absoluteDiarrhea 1.98.58.8(e.g.,Sulfonylurea)orwithInsulin: When initiating OZEMPIC,considerOVERDOSAGE: In the event of overdose, appropriate supportive treatment should be risk increase for diabetic retinopathy complications was larger among patients withAbdominal pain 4.6 7.3 5.7 initiated according to the patients clinical signs and symptoms. A prolonged period of a history of diabetic retinopathy at baseline (OZEMPIC 8.2%, placebo 5.2%) thanreducing the dose of concomitantly administered insulin secretagogue (such asobservation and treatment for these symptoms may be necessary, taking into accountConstipation 1.55.03.1sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings andamong patients without a known history of diabetic retinopathy (OZEMPIC0.7%,Precautions and Adverse Reactions]. OralMedications: OZEMPIC causes athe long half-life of OZEMPICof approximately 1 week.placebo 0.4%). Rapid improvement in glucose control has been associated with aIn the pool of placebo- and active-controlled trials and in the 2-year cardiovasculardelay of gastric emptying, and thereby has the potential to impact the absorptionMore detailed information is available upon request. temporaryworseningofdiabeticretinopathy.Theeffectoflong-termglycemicoutcomes trial, the types and frequency of common adverse reactions, excludingof concomitantly administered oral medications. In clinical pharmacology trials,For information about OZEMPIC contact: Novo Nordisk Inc.,control with semaglutide on diabetic retinopathy complications has not been studied.hypoglycemia, were similar to those listed in Table 1. In a clinical trial with 959 Patients with a history of diabetic retinopathy should be monitored for progressionpatients treated with OZEMPIC 1 mg or OZEMPIC 2 mg once weekly as add-on tosemaglutide did not affect the absorption of orally administered medications to800 Scudders Mill Road, Plainsboro, NJ 08536, 1-888-693-6742 any clinically relevant degree. Nonetheless, caution should be exercised when oral of diabetic retinopathy. Never Share an OZEMPICPen Between Patients:metformin with or without sulfonylurea treatment for 40 weeks, no new safety signals Date of Issue: 10/2022 OZEMPIC pens must never be shared between patients, even if the needle iswere identified. Gastrointestinal Adverse Reactions: In the pool of placebo-controlledmedications are concomitantly administered with OZEMPIC . Version: 8changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.trials, gastrointestinal adverse reactions occurred more frequently among patientsUSE IN SPECIFIC POPULATIONS: Pregnancy: Risk Summary: There are limitedManufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, DenmarkHypoglycemiawithConcomitantUseofInsulinSecretagoguesorreceiving OZEMPIC than placebo (placebo 15.3%, OZEMPIC 0.5 mg 32.7%,data with semaglutide use in pregnant women to inform a drug-associated risk forOZEMPIC and NovoFine are registered trademarks of Insulin: Patients receiving OZEMPIC in combination with an insulin secretagogueOZEMPIC 1 mg 36.4%). The majority of reports of nausea, vomiting, and/or diarrheaadverse developmental outcomes. There are clinical considerations regarding theNovoNordisk A/S. (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, includingoccurred during dose escalation. More patients receiving OZEMPIC 0.5 mg (3.1%)risks of poorly controlled diabetes in pregnancy (see Clinical Considerations). Based severe hypoglycemia [see Adverse Reactions and Drug Interactions]. The risk ofand OZEMPIC 1 mg (3.8%) discontinued treatment due to gastrointestinal adverseon animal reproduction studies, there may be potential risks to the fetus from exposurePATENT INFORMATION: to semaglutide during pregnancy. OZEMPIC should be used during pregnancyhttp://www.novonordisk-us.com/products/product-patents.htmlhypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or otherreactions than patients receiving placebo (0.4%). In the trial with OZEMPIC 1 mg andonly if the potential benefit justifies the potential risk to the fetus. In pregnant rats 2022 Novo NordiskUS22OZM0114611/2022concomitantly administered insulin secretagogue) or insulin. Inform patients using2 mg, gastrointestinal adverse reactions occurred more frequently among patients'