semaglutide

1 INDICATIONS AND USAGE WEGOVY is indicated in combination with a reduced calorie diet and increased physical activity:

• to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with established cardiovascular disease and either obesity or overweight.
• to reduce excess body weight and maintain weight reduction long term in: o Adults and pediatric patients aged 12 years and older with obesity o Adults with overweight in the presence of at least one weight-related comorbid condition. Limitations of Use
• WEGOVY contains semaglutide. Coadministration with other semaglutide-containing products or with any other GLP-1 receptor agonist is not recommended. WEGOVY is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated in combination with a reduced calorie diet and increased physical activity:
• to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with established cardiovascular disease and either obesity or overweight .
• to reduce excess body weight and maintain weight reduction long term in: o Adults and pediatric patients aged 12 years and older with obesity o Adults with overweight in the presence of at least one weight-related comorbid condition . Limitations of Use:
• Coadministration with other semaglutide-containing products or with any other GLP-1 receptor agonist is not recommended .

• Administer WEGOVY once weekly as an adjunct to diet and increased physical activity, on the same day each week, at any time of day, with or without meals .
• Inject subcutaneously in the abdomen, thigh or upper arm .
• In patients with type 2 diabetes, monitor blood glucose prior to starting and during WEGOVY treatment .
• Initiate at 0.25 mg once weekly for 4 weeks. Then follow the dosage escalation schedule, titrating every 4 weeks to achieve the maintenance dosage .
• The maintenance dosage of WEGOVY in adults is either 2.4 mg (recommended) or 1.7 mg once weekly .
• The maintenance dosage of WEGOVY in pediatric patients aged 12 years and older is 2.4 mg once weekly .

Important Monitoring and Administration Instructions

• In patients with type 2 diabetes, monitor blood glucose prior to starting WEGOVY and during WEGOVY treatment [see Warnings and Precautions ].
• Prior to initiation of WEGOVY, train patients on proper injection technique. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations.
• Inspect WEGOVY visually prior to each injection. Only use if solution is clear, colorless, and contains no particles.
• Administer WEGOVY in combination with a reduced-calorie diet and increased physical activity.
• Administer WEGOVY once weekly, on the same day each week, at any time of day, with or without meals.
• Inject WEGOVY subcutaneously in the abdomen, thigh, or upper arm. The time of day and the injection site can be changed without dose adjustment.

Recommended Dosage in Adults Dosage Initiation and Escalation

• Initiate WEGOVY with a dosage of 0.25 mg injected subcutaneously once weekly. Then follow the dose escalation schedule presented in Table 1 to minimize gastrointestinal adverse reactions [see Adverse Reactions ] .
• If patients do not tolerate a dose during dosage escalation, consider delaying dosage escalation for 4 weeks. Table 1. Recommended Dosage Regimen for Adults Treatment Weeks Once weekly Subcutaneous Dosage Initiation 1 through 4 0.25 mg Escalation 5 through 8 0.5 mg 9 through 12 1 mg 13 through 16 1.7 mg Maintenance 17 and onward 1.7 mg or 2.4 mg Maintenance Dosage
• The maintenance dosage of WEGOVY in adults is either 2.4 mg (recommended) or 1.7 mg once weekly. Consider treatment response and tolerability when selecting the maintenance dosage [see Clinical Studies ] . 2.3 Recommended Dosage in Pediatric Patients Aged 12 Years and Older Dosage Initiation and Escalation
• Initiate WEGOVY according to the dosage escalation schedule in Table 2 to minimize gastrointestinal adverse reactions [see Adverse Reactions ] .
• If patients do not tolerate a dose during dosage escalation, consider delaying dosage escalation for 4 weeks.
• The 0.25 mg, 0.5 mg, and 1 mg once-weekly dosages are initiation and escalation dosages and are not approved as maintenance dosages. Table 2. Recommended Dosage Regimen for Pediatric Patients Aged 12 Years and Older Treatment Weeks Once weekly Subcutaneous Dosage Initiation 1 through 4 0.25 mg a Escalation 5 through 8 0.5 mg a 9 through 12 1 mg a 13 through 16 1.7 mg b Maintenance 17 and onward 2.4 mg a Not approved as maintenance dosages b See Dosage Modifications for Adverse Reactions Maintenance Dosage
• The maintenance dosage of WEGOVY in pediatric patients aged 12 years and older is 2.4 mg once weekly. Dosage Modifications for Adverse Reactions
• If patients do not tolerate the 2.4 mg once weekly maintenance dosage, the maintenance dosage may be reduced to 1.7 mg once weekly.
• Discontinue WEGOVY if the patient cannot tolerate the 1.7 mg once-weekly dosage.

Recommendations Regarding Missed Dose

• If one dose is missed and the next scheduled dose is more than 2 days away (48 hours), administer WEGOVY as soon as possible. If one dose is missed and the next scheduled dose is less than 2 days away (48 hours), do not administer the dose. Resume dosing on the regularly scheduled day of the week.
• If 2 or more consecutive doses are missed, resume dosing as scheduled or, if needed, reinitiate WEGOVY and follow the dose escalation schedule, which may reduce the occurrence of gastrointestinal symptoms associated with reinitiation of treatment.

12.1 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 regulator of appetite and caloric intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. Animal studies show that semaglutide distributed to and activated neurons in brain regions involved in regulation of food intake. The exact mechanism of cardiovascular risk reduction has not been established.

The following serious adverse reactions are described below or elsewhere in the prescribing information:

• Risk of Thyroid C-Cell Tumors [see Warnings and Precautions ]
• Acute Pancreatitis [see Warnings and Precautions ]
• Acute Gallbladder Disease [see Warnings and Precautions ]
• Hypoglycemia [see Warnings and Precautions ]
• Acute Kidney Injury [see Warnings and Precautions ]
• Hypersensitivity Reactions [see Warnings and Precautions ]
• Diabetic Retinopathy Complications in Patients with Type 2 Diabetes [see Warnings and Precautions ]
• Heart Rate Increase [see Warnings and Precautions ]
• Suicidal Behavior and Ideation [see Warnings and Precautions ] Most common adverse reactions (incidence ≥ 5%) in adults or pediatric patients aged 12 years and older are: nausea, diarrhea, vomiting, constipation, abdominal pain, headache, fatigue, dyspepsia, dizziness, abdominal distension, eructation, hypoglycemia in patients with type 2 diabetes, flatulence, gastroenteritis, gastroesophageal reflux disease, and nasopharyngitis . To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-833-934-6891 or FDA at 1-800-FDA-1088 or www.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 studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in Clinical Trials in Adults with Obesity or Overweight WEGOVY 2.4 mg Subcutaneous Weekly Dosage WEGOVY was evaluated for safety in 3 randomized, double-blind, placebo-controlled trials that included 2,116 adult patients with obesity or overweight treated with 2.4 mg WEGOVY for up to 68 weeks and a 7 week off-drug follow-up period [see Clinical Studies ] . Baseline characteristics included a mean age of 48 years, 71% female, 72% White, 14% Asian, 9% Black or African American, and 5% reported as other or unknown; and 85% were not Hispanic or Latino ethnicity, 13% were Hispanic or Latino ethnicity, and 2% reported as unknown. The baseline characteristics were 42% with hypertension, 19% with type 2 diabetes, 43% with dyslipidemia, 28% with a BMI greater than 40 kg/m 2 , and 4% with cardiovascular disease. In these clinical trials, 6.8% of patients treated with 2.4 mg WEGOVY and 3.2% of patients treated with placebo permanently discontinued treatment as a result of adverse reactions. The most common adverse reactions leading to discontinuation were nausea (1.8% versus 0.2%), vomiting (1.2% versus 0%), and diarrhea (0.7% versus 0.1%) for WEGOVY and placebo, respectively. Adverse reactions reported in clinical trials in adults and greater than or equal to 2% of WEGOVY-treated patients and more frequently than in placebo-treated patients are shown in Table 3. Table 3. Adverse Reactions (≥2% and Greater Than Placebo) in WEGOVY-treated Adults with Obesity or Overweight Placebo N = 1,261 % WEGOVY 2.4 mg N = 2,116 % Nausea 16 44 Diarrhea 16 30 Vomiting 6 24 Constipation 11 24 Abdominal Pain a 10 20 Headache 10 14 Fatigue b 5 11 Dyspepsia 3 9 Dizziness 4 8 Abdominal Distension 5 7 Eructation <1 7 Hypoglycemia in T2DM c 2 6 Flatulence 4 6 Gastroenteritis 4 6 Gastroesophageal Reflux Disease 3 5 Gastritis d 1 4 Gastroenteritis Viral 3 4 Hair Loss 1 3 Dysesthesia e 1 2 a Includes abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain, abdominal tenderness, abdominal discomfort and epigastric discomfort b Includes fatigue and asthenia c Defined as blood glucose <54 mg/dL with or without symptoms of hypoglycemia or severe hypoglycemia (requiring the assistance of another person) in patients with type 2 diabetes not on concomitant insulin (Study 3, WEGOVY N=403, Placebo N=402). See text below for further information regarding hypoglycemia in patients with and without type 2 diabetes. T2DM = type 2 diabetes mellitus d Includes chronic gastritis, gastritis, gastritis erosive, and reflux gastritis e Includes paresthesia, hyperesthesia, burning sensation, allodynia, dysesthesia, skin burning sensation, pain of skin, and sensitive skin In a cardiovascular outcomes trial, 8,803 patients were exposed to WEGOVY for a median of 37.3 months and 8,801 patients were exposed to placebo for a median of 38.6 months [see Clinical Studies ]. Safety data collection was limited to serious adverse events (including death), adverse events leading to discontinuation, and adverse events of special interest. Sixteen percent (16%) of WEGOVY-treated patients and 8% of placebo-treated patients, respectively, discontinued study drug due to an adverse event. Additional information from this trial is included in subsequent sections below when relevant. Adverse Reactions in a Clinical Trial of Pediatric Patients Aged 12 Years and Older with Obesity WEGOVY was evaluated in a 68-week, double-blind, randomized, parallel group, placebo-controlled, multi-center trial in 201 pediatric patients aged 12 years and older with obesity [see Clinical Studies ] . Baseline characteristics included a mean age of 15.4 years; 38% of patients were male; 79% were White, 8% were Black or African American, 2% were Asian, and 11% were of other or unknown race; and 11% were of Hispanic or Latino ethnicity. The mean baseline body weight was 107.5 kg, and mean BMI was 37 kg/m 2 . Table 4 shows adverse reactions reported in greater than or equal to 3% of WEGOVY-treated pediatric patients and more frequently than in the placebo group from a study in pediatric patients aged 12 years and older. Table 4. Adverse Reactions (≥3% and Greater than Placebo) in WEGOVY-Treated Pediatric Patients Aged 12 Years and Older with Obesity Placebo N = 67 % WEGOVY 2.4 mg N = 133 % Nausea 18 42 Vomiting 10 36 Diarrhea 19 22 Headache 16 17 Abdominal Pain 6 15 Nasopharyngitis 10 12 Dizziness 3 8 Gastroenteritis 3 7 Constipation 2 6 Gastroesophageal Reflux Disease 2 4 Sinusitis 2 4 Urinary tract infection 2 4 Ligament sprain 2 4 Anxiety 2 4 Hair Loss 0 4 Cholelithiasis 0 4 Eructation 0 4 Influenza 0 3 Rash 0 3 Urticaria 0 3 Other Adverse Reactions in Adults and/or Pediatric Patients Acute Pancreatitis In WEGOVY clinical trials in adults, acute pancreatitis was confirmed by adjudication in 4 WEGOVY-treated patients (0.2 cases per 100 patient years) versus 1 in placebo-treated patients (less than 0.1 cases per 100 patient years). One additional case of acute pancreatitis was confirmed in a patient treated with WEGOVY in another clinical trial. Acute Gallbladder Disease In WEGOVY clinical trials in adults, cholelithiasis was reported by 1.6% of WEGOVY-treated patients and 0.7% of placebo-treated patients. Cholecystitis was reported by 0.6% of WEGOVY-treated adult patients and 0.2% of placebo-treated patients. In a clinical trial in pediatric patients aged 12 years and older [see Clinical Studies ] , cholelithiasis was reported by 3.8% of WEGOVY-treated patients and 0% placebo-treated patients. Cholecystitis was reported by 0.8% of WEGOVY-treated pediatric patients and 0% placebo-treated patients. Hypoglycemia Patients with Type 2 Diabetes In a trial of adult patients with type 2 diabetes and BMI greater than or equal to 27 kg/m 2 , clinically significant hypoglycemia (defined as a plasma glucose less than 54 mg/dL) was reported in 6.2% of WEGOVY-treated patients versus 2.5% of placebo-treated patients. A higher rate of clinically significant hypoglycemic episodes was reported with WEGOVY (semaglutide 2.4 mg) versus semaglutide 1 mg (10.7 vs. 7.2 episodes per 100 patient years of exposure, respectively); the rate in the placebo-treated group was 3.2 episodes per 100 patient years of exposure. In addition, one episode of severe hypoglycemia requiring intravenous glucose was reported in a WEGOVY-treated patient versus none in placebo-treated patients. The risk of hypoglycemia was increased when WEGOVY was used with a sulfonylurea. Patients without Type 2 Diabetes Episodes of hypoglycemia have been reported with GLP-1 receptor agonists in adult patients without type 2 diabetes mellitus. In WEGOVY clinical trials in adult patients without type 2 diabetes mellitus, there was no systematic capturing or reporting of hypoglycemia. In a cardiovascular outcomes trial in adult patients without type 2 diabetes, 3 episodes of serious hypoglycemia were reported in WEGOVY-treated patients versus 1 episode in placebo. Patients with a history of bariatric surgery (a risk factor for hypoglycemia) had more events of serious hypoglycemia while taking WEGOVY (2.3%, 2/87) than placebo (0%, 0/97). Acute Kidney Injury Acute kidney injury occurred in clinical trials in 7 adult patients (0.4 cases per 100 patient years) receiving WEGOVY versus 4 patients (0.2 cases per 100 patient years of exposure) receiving placebo. Some of these adverse reactions occurred in association with gastrointestinal adverse reactions or dehydration. In addition, 2 patients treated with WEGOVY had acute kidney injury with dehydration in other clinical trials. The risk of renal adverse reactions with WEGOVY was increased in adult patients with a history of renal impairment (trials included 65 patients with a history of moderate or severe renal impairment at baseline), and occurred more frequently during dose titration. Retinal Disorders in Patients with Type 2 Diabetes In a trial of adult patients with type 2 diabetes and BMI greater than or equal to 27 kg/m 2 , retinal disorders were reported by 6.9% of patients treated with WEGOVY (semaglutide 2.4 mg), 6.2% of patients treated with semaglutide 1 mg, and 4.2% of patients treated with placebo. The majority of events were reported as diabetic retinopathy (4.0%, 2.7%, and 2.7%, respectively) and non-proliferative retinopathy (0.7%, 0%, and 0%, respectively). Increase in Heart Rate Mean increases in resting heart rate of 1 to 4 beats per minute (bpm) were observed with routine clinical monitoring in WEGOVY-treated adult patients compared to placebo in clinical trials. In trials in which adult patients were randomized prior to dose-escalation, more patients treated with WEGOVY, compared with placebo, had maximum changes from baseline at any visit of 10 to 19 bpm (41% versus 34%, respectively) and 20 bpm or more (26% versus 16%, respectively). In a clinical trial in pediatric patients aged 12 years and older with normal baseline heart rate, more patients treated with WEGOVY compared to placebo had maximum changes in heart rate of 20 bpm or more (54% versus 39%). Hypotension and Syncope Adverse reactions related to hypotension (hypotension, orthostatic hypotension, and decreased blood pressure) were reported in 1.3% of WEGOVY-treated adult patients versus 0.4% of placebo-treated patients and syncope was reported in 0.8% of WEGOVY-treated patients versus 0.2% of placebo-treated patients. Some reactions were related to gastrointestinal adverse reactions and volume loss associated with WEGOVY. Hypotension and orthostatic hypotension were more frequently seen in patients on concomitant antihypertensive therapy. In a clinical trial in pediatric patients aged 12 years and older, hypotension was reported in 2.3% of WEGOVY-treated patients versus 0% in placebo-treated patients. Appendicitis Appendicitis (including perforated appendicitis) occurred in 10 (0.5%) WEGOVY-treated adult patients and 2 (0.2%) patients receiving placebo. Gastrointestinal Adverse Reactions In clinical trials in adults, 73% of WEGOVY-treated patients and 47% of patients receiving placebo reported gastrointestinal adverse reactions, including severe reactions that were reported more frequently among patients receiving WEGOVY (4.1%) than placebo (0.9%). The most frequently reported reactions were nausea (44% vs. 16%), vomiting (25% vs. 6%), and diarrhea (30% vs. 16%). Other reactions that occurred at a higher incidence among WEGOVY-treated adult patients included dyspepsia, abdominal pain, abdominal distension, eructation, flatulence, gastroesophageal reflux disease, gastritis, hemorrhoids, and hiccups. These reactions increased during dose escalation. In the pediatric clinical trial, 62% of WEGOVY-treated patients and 42% of placebo-treated patients reported gastrointestinal disorders. The most frequently reported reactions were nausea (42% vs. 18%), vomiting (36% vs. 10%), and diarrhea (22% vs. 19%). Other gastrointestinal-related reactions that occurred at a higher incidence than placebo among WEGOVY-treated pediatric patients included abdominal pain, constipation, eructation, gastroesophageal reflux disease, dyspepsia, and flatulence. Permanent discontinuation of treatment as a result of a gastrointestinal adverse reaction occurred in 4.3% of WEGOVY-treated adult patients versus 0.7% of placebo-treated patients. In a pediatric clinical trial, 2.3% of patients treated with WEGOVY versus 1.5% of patients who received placebo discontinued treatment as a result of gastrointestinal adverse reactions. Injection Site Reactions In clinical trials in adults, 1.4% of WEGOVY-treated patients and 1.0% of patients receiving placebo experienced injection site reactions (including injection site pruritus, erythema, inflammation, induration, and irritation). Hypersensitivity Reactions Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported with WEGOVY. In a pediatric clinical trial, rash was reported in 3% of WEGOVY-treated patients and 0% of placebo-treated patients, and urticaria was reported in 3% of WEGOVY-treated patients and 0% of placebo-treated patients . In adult clinical trials, allergic reactions occurred in 16% (8/50) of WEGOVY-treated patients with anti-semaglutide antibodies and in 7% (114/1659) of WEGOVY-treated patients who did not develop anti-semaglutide antibodies [see Clinical Pharmacology ]. Fractures In the cardiovascular outcomes trial in adults, more fractures of the hip and pelvis were reported on WEGOVY than on placebo in female patients: 1.0% (24/2448) vs. 0.2% (5/2424), and in patients ages 75 years and older: 2.4% (17/703) vs. 0.6% (4/663), respectively. Urolithiasis In a cardiovascular outcomes trial, 1.2% of WEGOVY-treated patients and 0.8% of patients receiving placebo reported urolithiasis, including serious reactions that were reported more frequently among patients receiving WEGOVY (0.6%) than placebo (0.4%). Dysgeusia In clinical trials in adults, 1.7% of WEGOVY-treated patients and 0.5% of placebo-treated patients reported dysgeusia. Laboratory Abnormalities Amylase and Lipase Adult and pediatric patients treated with WEGOVY had a mean increase from baseline in amylase of 15-16% and lipase of 39%. These changes were not observed in the placebo group. The clinical significance of elevations in lipase or amylase with WEGOVY is unknown in the absence of other signs and symptoms of pancreatitis. Liver Enzymes In a pediatric clinical trial, increases in alanine aminotransferase (ALT) greater than or equal to 5 times the upper limit of normal were observed in 4 (3%) WEGOVY-treated patients compared with 0% of placebo-treated patients. In some patients, increases in ALT and AST were associated with other confounding factors (such as gallstones). In the cardiovascular outcomes trial in adults, increases in total bilirubin greater than or equal to 3 times the upper limit of normal were observed in 0.3% (30/8585) of WEGOVY-treated patients versus 0.2% (14/8579) of placebo-treated patients. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of WEGOVY. 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 Disorders: acute pancreatitis and necrotizing pancreatitis, sometimes resulting in death; ileus Hypersensitivity: anaphylaxis, angioedema, rash, urticaria Renal and Urinary Disorders: acute kidney injury

7 DRUG INTERACTIONS WEGOVY delays gastric emptying. May impact absorption of concomitantly administered oral medications. Use with caution . 7.1 Concomitant Use with Insulin or an Insulin Secretagogue (e.g., Sulfonylurea) WEGOVY lowers blood glucose and can cause hypoglycemia. The risk of hypoglycemia is increased when WEGOVY is used in combination with insulin or insulin secretagogues (e.g., sulfonylureas). The addition of WEGOVY in patients treated with insulin has not been evaluated. When initiating WEGOVY, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions and Adverse Reactions ] . 7.2 Oral Medications WEGOVY causes a delay of gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials with semaglutide 1 mg, semaglutide did not affect the absorption of orally administered medications [see Clinical Pharmacology ] . Nonetheless, monitor the effects of oral medications concomitantly administered with WEGOVY.

• Pregnancy: May cause fetal harm. When pregnancy is recognized, discontinue WEGOVY .
• Females and Males of Reproductive Potential: Discontinue WEGOVY at least 2 months before a planned pregnancy because of the long half-life of semaglutide . 8.1 Pregnancy Pregnancy Exposure Registry There will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to semaglutide during pregnancy. Pregnant women exposed to WEGOVY and healthcare providers are encouraged to contact Novo Nordisk at 1-877-390-2760 or www.wegovypregnancyregistry.com. Risk Summary Based on animal reproduction studies, there may be potential risks to the fetus from exposure to semaglutide during pregnancy. Additionally, weight loss offers no benefit to a pregnant patient and may cause fetal harm. When a pregnancy is recognized, advise the pregnant patient of the risk to a fetus, and discontinue WEGOVY (see Clinical Considerations) . Available pharmacovigilance data and data from clinical trials with WEGOVY use in pregnant patients are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. 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 below the MRHD (rabbit) and greater than or equal to 2-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 and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those who already have overweight or obesity, because of the obligatory weight gain that occurs in maternal tissues during pregnancy. Data Animal Data In a combined fertility and embryofetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.04-, 0.1-, and 0.4-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 (0.01-, 0.1-, and 0.9-fold the MRHD) were administered throughout organogenesis from Gestation Day 6 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 greater than or equal to 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 (0.4-, 2-, and 6-fold the MRHD) were administered throughout organogenesis, from Gestation Day 16 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 greater than or equal to 0.075 mg/kg twice weekly (greater than or equal to 2 times 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 (0.2-, 1-, and 3-fold the MRHD) were administered from Gestation Day 16 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 greater than or equal to 0.075 mg/kg twice weekly (greater than or equal to 1-time human exposure). 8.2 Lactation Risk Summary There are no data on the presence of semaglutide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Semaglutide was present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk ( see Data ) . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for WEGOVY and any potential adverse effects on the breastfed infant from WEGOVY or from the underlying maternal condition. Data In lactating rats, semaglutide was detected in milk at levels 3-12-fold lower than in maternal plasma. 8.3 Females and Males of Reproductive Potential Because of the potential for fetal harm, discontinue WEGOVY in patients at least 2 months before they plan to become pregnant to account for the long half-life of semaglutide [see Use in Specific Populations ] . 8.4 Pediatric Use The safety and effectiveness of WEGOVY as an adjunct to a reduced calorie diet and increased physical activity for weight reduction and long-term maintenance have been established in pediatric patients aged 12 years and older with obesity. Use of WEGOVY for this indication is supported by a 68-week, double-blind, placebo-controlled clinical trial in 201 pediatric patients aged 12 years and older with a BMI corresponding to ≥95th percentile for age and sex and from studies in adult patients with obesity [see Clinical Studies ] . Adverse reactions with WEGOVY treatment in pediatric patients aged 12 years and older were generally similar to those reported in adults. Pediatric patients aged 12 years and older treated with WEGOVY had greater incidences of cholelithiasis, cholecystitis, hypotension, rash, and urticaria compared to adults treated with WEGOVY [see Adverse Reactions ] . There are insufficient data in pediatric patients with type 2 diabetes treated with WEGOVY for obesity to determine if there is an increased risk of hypoglycemia with WEGOVY treatment similar to that reported in adults. Inform patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. In pediatric patients aged 12 years and older with type 2 diabetes, monitor blood glucose prior to starting WEGOVY and during WEGOVY treatment. When initiating WEGOVY in pediatric patients aged 12 years and older with type 2 diabetes, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ] . The safety and effectiveness of WEGOVY have not been established in pediatric patients less than 12 years of age. 8.5 Geriatric Use In the WEGOVY clinical trials for weight reduction and long-term maintenance, 233 (9%) WEGOVY-treated patients were aged 65 to 75 years and 23 (1%) WEGOVY-treated patients were aged 75 years and older [see Clinical Studies ] . In a cardiovascular outcomes trial, 2656 (30%) WEGOVY-treated patients were aged 65 to 75 years and 703 (8%) WEGOVY-treated patients were aged 75 years and older [see Clinical Studies ] . No overall difference in effectiveness was observed between patients aged 65 years and older and younger adult patients. In the cardiovascular outcomes trial, patients aged 75 years and older reported more fractures of the hip and pelvis on WEGOVY than on placebo. Patients aged 75 years and older (WEGOVY-treated and placebo-treated) reported more serious adverse reactions overall compared to younger adult patients [see Adverse Reactions ]. 8.6 Renal Impairment No dose adjustment of WEGOVY is recommended for patients with renal impairment. In a study in patients with renal impairment, including end-stage renal disease, no clinically relevant change in semaglutide pharmacokinetics was observed [see Clinical Pharmacology ] . 8.7 Hepatic Impairment No dose adjustment of WEGOVY is recommended for patients with hepatic impairment. In a study in patients with different degrees of hepatic impairment, no clinically relevant change in semaglutide pharmacokinetics was observed [see Clinical Pharmacology ] .