∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Injection: 2 mg/1.5 mL (1.34 mg/mL) available in:
`Single-patient-use pen that delivers 0.25 mg or 0.5 mg per injection (3).
`
`Single-patient-use pen that delivers 1 mg per injection (3).
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Personal or family history of medullary thyroid carcinoma or in patients
`
`with Multiple Endocrine Neoplasia syndrome type 2 (4).
`Known hypersensitivity to OZEMPIC or any of the product components
`(4).
`
`
`
`
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Pancreatitis: Has been reported in clinical trials. Discontinue promptly if
`
`pancreatitis is suspected. Do not restart if pancreatitis is confirmed (5.2).
`Diabetic Retinopathy Complications: Has been reported in a clinical trial.
`Patients with a history of diabetic retinopathy should be monitored (5.3).
`Never share an OZEMPIC pen between patients, even if the needle is
`changed (5.4).
`Hypoglycemia: When OZEMPIC is used with an insulin secretagogue or
`insulin, consider lowering the dose of the secretagogue or insulin to reduce
`the risk of hypoglycemia (5.5).
`Acute Kidney Injury: Monitor renal function in patients with renal
`impairment reporting severe adverse gastrointestinal reactions (5.6).
`Hypersensitivity Reactions: Discontinue OZEMPIC if suspected and
`promptly seek medical advice (5.7).
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`The most common adverse reactions, reported in ≥5% of patients treated with
`OZEMPIC are: nausea, vomiting, diarrhea, abdominal pain and constipation
`(6.1).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
`Inc., at 1-888-693-6742 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS-----------------------------------
`Oral Medications: OZEMPIC delays gastric emptying. May impact absorption of
`concomitantly administered oral medications (7.2).
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Females and Males of Reproductive Potential: Discontinue OZEMPIC in women
`at least 2 months before a planned pregnancy due to the long washout period for
`semaglutide (8.3).
`
`See 17 for PATIENT COUNSELING INFORMATION and
`Medication Guide.
` Revised: 01/2020
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`OZEMPIC® safely and effectively. See full prescribing information
`for OZEMPIC.
`
`OZEMPIC (semaglutide) injection, for subcutaneous use
`Initial U.S. Approval: 2017
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`In rodents, semaglutide causes thyroid C-cell tumors. It is
`unknown whether OZEMPIC causes thyroid C-cell tumors,
`including medullary thyroid carcinoma (MTC), in humans as
`the human relevance of semaglutide-induced rodent thyroid C-
`cell tumors has not been determined (5.1, 13.1).
`OZEMPIC is contraindicated in patients with a personal or
`family history of MTC or in patients with Multiple Endocrine
`Neoplasia syndrome type 2 (MEN 2). Counsel patients
`regarding the potential risk of MTC and symptoms of thyroid
`tumors (4, 5.1).
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Indications and Usage (1) 01/2020
`Warnings and Precautions, Macrovascular Outcomes (5.8)
` Removed 01/2020
`
` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`OZEMPIC is a glucagon-like peptide 1 (GLP-1) receptor agonist
`indicated as:
`an adjunct to diet and exercise to improve glycemic control in
`
`adults with type 2 diabetes mellitus (1).
`to reduce the risk of major adverse cardiovascular events in adults
`with type 2 diabetes mellitus and established cardiovascular
`disease (1).
`
`
`
`Limitations of Use:
`Has not been studied in patients with a history of pancreatitis.
`
`Consider another antidiabetic therapy (1, 5.2).
`Not indicated for use in type 1 diabetes mellitus or treatment of
`diabetic ketoacidosis (1).
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Start at 0.25 mg once weekly. After 4 weeks, increase the dose to
`
`0.5 mg once weekly. If after at least 4 weeks additional glycemic
`control is needed, increase to 1 mg once weekly (2.1).
`Administer once weekly at any time of day, with or without meals
`(2.1).
`If a dose is missed administer within 5 days of missed dose (2.1).
`Inject subcutaneously in the abdomen, thigh, or upper arm (2.2).
`
`
`
`
`
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`13
`
`8.6 Renal Impairment
` 8.7 Hepatic Impairment
`10
`OVERDOSAGE
`11
`DESCRIPTION
`12
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`14.1 Overview of Clinical Studies
`14.2 Monotherapy Use of OZEMPIC in Patients with Type 2
`Diabetes Mellitus
`14.3 Combination Therapy Use of OZEMPIC in Patients with Type 2
`Diabetes Mellitus
`14.4 Cardiovascular Outcomes Trials in Patients with Type 2
`Diabetes Mellitus and Cardiovascular Disease
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`17 PATIENT COUNSELING INFORMATION
`
`14
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: RISK OF THYROID C-CELL TUMORS
`
`1
`2
`
`3
`4
`5
`
`6
`
`7
`
`8
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Important Administration Instructions
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1 Risk of Thyroid C-Cell Tumors
`5.2 Pancreatitis
`5.3 Diabetic Retinopathy Complications
`5.4 Never Share an OZEMPIC Pen Between Patients
`5.5 Hypoglycemia with Concomitant Use of Insulin
`Secretagogues or Insulin
`5.6 Acute Kidney Injury
`5.7 Hypersensitivity
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Immunogenicity
`DRUG INTERACTIONS
`7.1 Concomitant Use with an Insulin Secretagogue (e.g.,
`Sulfonylurea) or with Insulin
`7.2 Oral Medications
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
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`FULL PRESCRIBING INFORMATION
`
`
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid
`C-cell tumors at clinically relevant exposures. It is unknown whether OZEMPIC causes
`thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human
`relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined [see
`Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)].
` OZEMPIC is contraindicated in patients with a personal or family history of MTC or in
`patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications
`(4)]. Counsel patients regarding the potential risk for MTC with the use of OZEMPIC and
`inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea,
`persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is
`of uncertain value for early detection of MTC in patients treated with OZEMPIC [see
`Contraindications (4) and Warnings and Precautions (5.1)].
`
`INDICATIONS AND USAGE
`1
`OZEMPIC is indicated:
`as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see
`
`Clinical Studies (14.1)].
`
`
`
`to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial
`infarction or non-fatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease
`[see Clinical Studies (14.4 )].
`
`Limitations of Use
` OZEMPIC has not been studied in patients with a history of pancreatitis. Consider other antidiabetic
`therapies in patients with a history of pancreatitis [see Warnings and Precautions (5.2)].
`
` OZEMPIC is not a substitute for insulin. OZEMPIC is not indicated for use in patients with type 1 diabetes
`mellitus or for the treatment of patients with diabetic ketoacidosis, as it would not be effective in these
`settings.
`
`DOSAGE AND ADMINISTRATION
`2
`Recommended Dosage
`2.1
` Start OZEMPIC with a 0.25 mg subcutaneous injection once weekly for 4 weeks. The 0.25 mg dose is
`intended for treatment initiation and is not effective for glycemic control.
`
` After 4 weeks on the 0.25 mg dose, increase the dosage to 0.5 mg once weekly.
`
`
`
`If additional glycemic control is needed after at least 4 weeks on the 0.5 mg dose, the dosage may be
`increased to 1 mg once weekly. The maximum recommended dosage is 1 mg once weekly.
`
` Administer OZEMPIC once weekly, on the same day each week, at any time of the day, with or without
`meals.
`
` The day of weekly administration can be changed if necessary as long as the time between two doses is at
`least 2 days (>48 hours).
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`If a dose is missed, administer OZEMPIC as soon as possible within 5 days after the missed dose. If more
`than 5 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day.
`In each case, patients can then resume their regular once weekly dosing schedule.
`
`Important Administration Instructions
`2.2
` Administer OZEMPIC subcutaneously to the abdomen, thigh, or upper arm. Instruct patients to use a
`different injection site each week when injecting in the same body region.
`
`
`
`Inspect OZEMPIC visually before use. It should appear clear and colorless. Do not use OZEMPIC if
`particulate matter and coloration is seen.
`
` When using OZEMPIC with insulin, instruct patients to administer as separate injections and to never mix
`the products. It is acceptable to inject OZEMPIC and insulin in the same body region but the injections
`should not be adjacent to each other.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Injection: 2 mg/1.5 mL (1.34 mg/mL) of semaglutide as a clear, colorless solution available in:
` Pre-filled, disposable, single-patient-use pen that delivers 0.25 mg (for treatment initiation) or 0.5 mg (for
`maintenance treatment) per injection.
`
` Pre-filled, disposable, single-patient-use pen that delivers 1 mg (for maintenance treatment) per injection.
`
`CONTRAINDICATIONS
`4
`OZEMPIC is contraindicated in patients with:
` A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine
`Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)].
`
` Known hypersensitivity to semaglutide or to any of the product components [see Warnings and Precautions
`(5.7)].
`
`WARNINGS AND PRECAUTIONS
`5
`Risk of Thyroid C-Cell Tumors
`5.1
`In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the
`incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant
`plasma exposures [see Nonclinical Toxicology (13.1)]. It is unknown whether OZEMPIC causes thyroid C-cell
`tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced
`rodent thyroid C-cell tumors has not been determined.
`
`Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the
`postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship
`between MTC and GLP-1 receptor agonist use in humans.
`
`OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2.
`Counsel patients regarding the potential risk for MTC with the use of OZEMPIC and inform them of symptoms
`of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
`
`Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of
`MTC in patients treated with OZEMPIC. Such monitoring may increase the risk of unnecessary procedures, due
`to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly
`elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50
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`ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients
`with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
`
`Pancreatitis
`5.2
`In glycemic control trials, acute pancreatitis was confirmed by adjudication in 7 OZEMPIC-treated patients (0.3
`cases per 100 patient years) versus 3 in comparator-treated patients (0.2 cases per 100 patient years). One case
`of chronic pancreatitis was confirmed in an OZEMPIC-treated patient. In a 2-year trial, acute pancreatitis was
`confirmed by adjudication in 8 OZEMPIC-treated patients (0.27 cases per 100 patient years) and 10 placebo-
`treated patients (0.33 cases per 100 patient years), both on a background of standard of care.
`
`After initiation of OZEMPIC, observe patients carefully for signs and symptoms of pancreatitis (including
`persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied
`by vomiting). If pancreatitis is suspected, OZEMPIC should be discontinued and appropriate management
`initiated; if confirmed, OZEMPIC should not be restarted.
`
`Diabetic Retinopathy Complications
`5.3
`In a 2-year trial involving patients with type 2 diabetes and high cardiovascular risk, more events of diabetic
`retinopathy complications occurred in patients treated with OZEMPIC (3.0%) compared to placebo (1.8%). The
`absolute risk increase for diabetic retinopathy complications was larger among patients with a history of
`diabetic retinopathy at baseline (OZEMPIC 8.2%, placebo 5.2%) than among patients without a known history
`of diabetic retinopathy (OZEMPIC 0.7%, placebo 0.4%).
`
`Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy.
`The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been
`studied. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic
`retinopathy.
`
`Never Share an OZEMPIC Pen Between Patients
`5.4
`OZEMPIC pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk
`for transmission of blood-borne pathogens.
`
`Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
`5.5
`The risk of hypoglycemia is increased when OZEMPIC is used in combination with insulin secretagogues (e.g.,
`sulfonylureas) or insulin. Patients may require a lower dose of the secretagogue or insulin to reduce the risk of
`hypoglycemia in this setting [see Adverse Reactions (6.1), Drug Interactions (7.1)].
`
`Acute Kidney Injury
`5.6
`There have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which
`may sometimes require hemodialysis, in patients treated with GLP-1 receptor agonists. Some of these events
`have been reported in patients without known underlying renal disease. A majority of the reported events
`occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function
`when initiating or escalating doses of OZEMPIC in patients reporting severe adverse gastrointestinal reactions.
`
`Hypersensitivity
`5.7
`Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported with GLP-1 receptor
`agonists. If hypersensitivity reactions occur, discontinue use of OZEMPIC; treat promptly per standard of care,
`and monitor until signs and symptoms resolve. Do not use in patients with a previous hypersensitivity to
`OZEMPIC [see Contraindications (4)].
`
`Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient
`with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown
`whether such patients will be predisposed to anaphylaxis with OZEMPIC.
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`ADVERSE REACTIONS
`6
`The following serious adverse reactions are described below or elsewhere in the prescribing information:
`
` Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
` Pancreatitis [see Warnings and Precautions (5.2)]
` Diabetic Retinopathy Complications [see Warnings and Precautions (5.3)]
` Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions
`(5.5)]
` Acute Kidney Injury [see Warnings and Precautions (5.6)]
` Hypersensitivity [see Warnings and Precautions (5.7)]
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
`reflect the rates observed in practice.
`
`Pool of Placebo-Controlled Trials
`The data in Table 1 are derived from 2 placebo-controlled trials (1 monotherapy trial and 1 trial in combination
`with basal insulin) in patients with type 2 diabetes [see Clinical Studies (14)]. These data reflect exposure of
`521 patients to OZEMPIC and a mean duration of exposure to OZEMPIC of 32.9 weeks. Across the treatment
`arms, the mean age of patients was 56 years, 3.4% were 75 years or older and 55% were male. In these trials
`71% were White, 7% were Black or African American, and 19% were Asian; 21% identified as Hispanic or
`Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.8 years and had a mean HbA1c of
`8.2%. At baseline, 8.9% of the population reported retinopathy. Baseline estimated renal function was normal
`(eGFR ≥90 mL/min/1.73m2) in 57.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m2) in 35.9% and
`moderately impaired (eGFR 30 to 60 mL/min/1.73m2) in 6.9% of patients.
`
`Pool of Placebo- and Active-Controlled Trials
`The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes
`participating in 7 placebo- and active-controlled glycemic control trials [see Clinical Studies (14)] including
`two trials in Japanese patients evaluating the use of OZEMPIC as monotherapy and add-on therapy to oral
`medications or insulin. In this pool, a total of 3150 patients with type 2 diabetes were treated with OZEMPIC
`for a mean duration of 44.9 weeks. Across the treatment arms, the mean age of patients was 57 years, 3.2%
`were 75 years or older and 57% were male. In these trials, 60% were White, 6% were Black or African
`American, and 31% were Asian; 16% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2
`diabetes for an average of 8.2 years and had a mean HbA1c of 8.2%. At baseline, 7.8% of the population
`reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m2) in 63.1%,
`mildly impaired (eGFR 60 to 90 mL/min/1.73m2) in 34.3%, and moderately impaired (eGFR 30 to 60
`mL/min/1.73m2) in 2.5% of the patients.
`
`Common Adverse Reactions
`Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of OZEMPIC in the
`pool of placebo-controlled trials. These adverse reactions occurred more commonly on OZEMPIC than on
`placebo, and occurred in at least 5% of patients treated with OZEMPIC.
`
`Table 1. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of OZEMPIC-Treated
`Patients with Type 2 Diabetes Mellitus
`Adverse Reaction
`Placebo
`(N=262)
`%
`6.1
`
`OZEMPIC 0.5 mg
`(N=260)
`%
`15.8
`
`OZEMPIC 1 mg
`(N=261)
`%
`20.3
`
`Nausea
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`Vomiting
`Diarrhea
`Abdominal pain
`Constipation
`
`2.3
`1.9
`4.6
`1.5
`
`5.0
`8.5
`7.3
`5.0
`
`9.2
`8.8
`5.7
`3.1
`
`In the pool of placebo- and active-controlled trials and in the 2-year cardiovascular outcomes trial, the types and
`frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1.
`
`Gastrointestinal Adverse Reactions
`In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among
`patients receiving OZEMPIC than placebo (placebo 15.3%, OZEMPIC 0.5 mg 32.7%, OZEMPIC 1 mg 36.4%).
`The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation. More patients
`receiving OZEMPIC 0.5 mg (3.1%) and OZEMPIC 1 mg (3.8%) discontinued treatment due to gastrointestinal
`adverse reactions than patients receiving placebo (0.4%).
`
`In addition to the reactions in Table 1, the following gastrointestinal adverse reactions with a frequency of <5%
`were associated with OZEMPIC (frequencies listed, respectively, as: placebo; 0.5 mg; 1 mg): dyspepsia (1.9%,
`3.5%, 2.7%), eructation (0%, 2.7%, 1.1%), flatulence (0.8%, 0.4%, 1.5%), gastroesophageal reflux disease (0%,
`1.9%, 1.5%), and gastritis (0.8%, 0.8%, 0.4%).
`
`Other Adverse Reactions
`Hypoglycemia
`
`Table 2 summarizes the incidence of events related to hypoglycemia by various definitions in the placebo-
`controlled trials.
`
`Table 2. Hypoglycemia Adverse Reactions in Placebo-Controlled Trials In Patients with Type 2 Diabetes
`Mellitus
`
`Placebo
`
`OZEMPIC 0.5 mg
`
`OZEMPIC 1 mg
`
`Monotherapy
` (30 weeks)
` Severe†
`Documented symptomatic
`(≤70 mg/dL glucose
`threshold)
` Severe† or Blood Glucose
`Confirmed Symptomatic
`(≤56 mg/dL glucose
`threshold)
`Add-on to Basal Insulin with or without Metformin
` (30 weeks)
`N=132
` Severe†
`0%
`Documented symptomatic
`15.2%
`(≤70 mg/dL glucose
`threshold)
` Severe† or Blood Glucose
`Confirmed Symptomatic
`(≤56 mg/dL glucose
`threshold)
`† “Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person.
`
`N=129
`0%
`0%
`
`1.6%
`
`5.3%
`
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`0%
`1.6%
`
`0%
`
`N=132
`0%
`16.7%
`
`8.3%
`
`N=130
`0%
`3.8%
`
`0%
`
`N=131
`1.5%
`29.8%
`
`10.7%
`
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`Hypoglycemia was more frequent when OZEMPIC was used in combination with a sulfonylurea [see Warnings
`and Precautions (5.5) and Clinical Studies (14)]. Severe hypoglycemia occurred in 0.8% and 1.2% of patients
`when OZEMPIC 0.5 mg and 1 mg, respectively, was co-administered with a sulfonylurea. Documented
`symptomatic hypoglycemia occurred in 17.3% and 24.4% of patients when OZEMPIC 0.5 mg and 1 mg,
`respectively, was co-administered with a sulfonylurea. Severe or blood glucose confirmed symptomatic
`hypoglycemia occurred in 6.5% and 10.4% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was co-
`administered with a sulfonylurea.
`
`Injection Site Reactions
`In placebo-controlled trials, injection site reactions (e.g., injection-site discomfort, erythema) were reported in
`0.2% of OZEMPIC-treated patients.
`
`Increases in Amylase and Lipase
`In placebo-controlled trials, patients exposed to OZEMPIC had a mean increase from baseline in amylase of
`13% and lipase of 22%. These changes were not observed in placebo-treated patients.
`
`Cholelithiasis
`In placebo-controlled trials, cholelithiasis was reported in 1.5% and 0.4% of patients-treated with OZEMPIC
`0.5 mg and 1 mg, respectively. Cholelithiasis was not reported in placebo-treated patients.
`
`Increases in Heart Rate
`In placebo-controlled trials, OZEMPIC 0.5 mg and 1 mg resulted in a mean increase in heart rate of 2 to 3 beats
`per minute. There was a mean decrease in heart rate of 0.3 beats per minute in placebo-treated patients.
`
`Fatigue, Dysgeusia and Dizziness
`Other adverse reactions with a frequency of >0.4% were associated with OZEMPIC include fatigue, dysgeusia
`and dizziness.
`
`Immunogenicity
`6.2
`Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated
`with OZEMPIC may develop anti-semaglutide antibodies. The detection of antibody formation is highly
`dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody
`(including neutralizing antibody) positivity in an assay may be influenced by several factors including assay
`methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
`For these reasons, the incidence of antibodies to semaglutide in the studies described below cannot be directly
`compared with the incidence of antibodies in other studies or to other products.
`
`Across the placebo- and active-controlled glycemic control trials, 32 (1.0%) OZEMPIC-treated patients
`developed anti-drug antibodies (ADAs) to the active ingredient in OZEMPIC (i.e., semaglutide). Of the 32
`semaglutide-treated patients that developed semaglutide ADAs, 19 patients (0.6% of the overall population)
`developed antibodies cross-reacting with native GLP-1. The in vitro neutralizing activity of the antibodies is
`uncertain at this time.
`
`DRUG INTERACTIONS
`7
`7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`The risk of hypoglycemia is increased when OZEMPIC is used in combination with insulin secretagogues (e.g.,
`sulfonylureas) or insulin. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea
`(or other concomitantly administered insulin secretagogues) or insulin [see Warnings and Precautions (5.5)].
`
`7.2 Oral Medications
`OZEMPIC causes a delay of gastric emptying, and thereby has the potential to impact the absorption of
`concomitantly administered oral medications. In clinical pharmacology trials, semaglutide did not affect the
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`absorption of orally administered medications to any clinically relevant degree [see Clinical Pharmacology
`(12.3)]. Nonetheless, caution should be exercised when oral medications are concomitantly administered with
`OZEMPIC.
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Risk Summary
`There are limited data with semaglutide use in pregnant women to inform a drug-associated risk for adverse
`developmental outcomes. There are clinical considerations regarding the risks of poorly controlled diabetes in
`pregnancy (see Clinical Considerations). Based on animal reproduction studies, there may be potential risks to
`the fetus from exposure to semaglutide during pregnancy. OZEMPIC 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 below the MRHD (rabbit) and ≥5-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 6–10% in women with pre-gestational diabetes with an
`HbA1c >7 and has been reported to be as high as 20–25% in women with a HbA1c >10. 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 fetal risk
`Poorly controlled diabetes during pregnancy increases the maternal risk for diabetic ketoacidosis, pre-
`eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled
`diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
`
`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 (0.1-, 0.4-, and 1.1-fold the MRHD) were administered to males for 4 weeks prior to and throughout
`mating and to females for 2 weeks prior to mating, and throughout organogenesis to Gestation Day 17. In
`parental animals, pharmacologically mediated reductions in body weight gain and food consumption were
`observed at all dose levels. In the offspring, reduced growth and fetuses with visceral (heart blood vessels) and
`skeletal (cranial bones, vertebra, ribs) abnormalities were observed at the human exposure.
`
`In an embryofetal development study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025 or 0.0075
`mg/kg/day (0.03-, 0.3-, and 2.3-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 ≥0.0025 mg/kg/day, at clinically relevant
`exposures.
`
`In an embryofetal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075,
`and 0.15 mg/kg twice weekly (1.0-, 5.2-, and 14.9-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 ≥0.075 mg/kg twice weekly (>5X human exposure).
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`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 (0.7-, 3.3-, and 7.2-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 ≥0.075 mg/kg twice weekly (>3X human exposure).
`
`Lactation
`8.2
`Risk Summary
`There are no data on the presence of semaglutide in human milk, the effects on the breastfed infant, or the
`effects on milk production. Semaglutide was present in the milk of lactating rats, however, due to species-
`specific differences in lactation physiology, the clinical relevance of these data are not clear (see Data). The
`developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need
`for OZEMPIC and any potential adverse effects on the breastfed infant from OZEMPIC 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.
`
`Females and Males of Reproductive Potential
`8.3
`Discontinue OZEMPIC in women at least 2 months before a planned pregnancy due to the long washout period
`for semaglutide [see Use in Specific Populations (8.1)].
`
`Pediatric Use
`8.4
`Safety and efficacy of OZEMPIC have not been established in pediatric patients (younger than 18 years).
`
`Geriatric Use
`8.5
`In the pool of placebo- and active-controlled glycemic control trials, 744 (23.6%) OZEMPIC-treated patients
`were 65 years of age and over and 102 OZEMPIC-treated patients (3.2%) patients were 75 years of age and
`over. In SUSTAIN 6, the cardiovascular outcome trial, 788 (48.0%) OZEMPIC-treated patients were 65 years
`of age and over and 157 OZEMPIC-treated patients (9.6%) patients were 75 years of age and over.
`
`No overall differences in safety or efficacy were detected between these patients and younger patients, but
`greater sensitivity of some older individuals cannot be ruled out.
`
`Renal Impairment
`8.6
`No dose adjustment of OZEMPIC is recommended for patients with renal impairment. In subjects with renal
`impairment including end-stage renal disease (ESRD), no clinically relevant change in semaglutide
`pharmacokinetics (PK) was observed [see Clinical Pharmacology (12.3)].
`
`8.7 Hepatic Impairment
`No dose adjustment of OZEMPIC is recommended for patients with hepatic impairment. In a study in subjects
`with different degrees of hepatic impairment, no clinically relevant change in semaglutide pharmacokinetics
`(PK) was observed [see Clinical Pharmacology (12.3)].
`
`OVERDOSAGE
`10
`In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical
`signs and symptoms. A prolonged period of observation and treatment fo