0ZEMPiC®
`semaglutide injection o.smg, 1mg,2mg
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use OZEMPIC® safely
`and effectively. See lull 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).
`
`. 03/2022
`. 03/2022
`..... 03/2022
`
`--- RECENT MAJOR CHANGES ---
`Dosage and Administration, Recommended Dosage (2.1)
`Contraindications (4)
`Warning and Precautions, Acute Gallbladder Disease (5 8)
`--- 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
`mellilus (1).
`• to reduce lhe 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 for treatment of type 1 diabetes mellitus (1 ).
`--- DOSAGE AND ADMINISTRATION ---
`• Start at 0.25 mg once weekly. After 4 weeks, increase the dose to 0.5 mg once weekly.
`• If additional glycemic control is needed, increase the dose to 1 mg once weekly after at least 4
`weeks on the 0.5 mg dose (2.1).
`• If additional glycemic control is needed, increase the dose to 2 mg once weekly after at least 4
`weeks on the 1 mg dose (21)
`• 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)
`
`--- DOSAGE FORMS AND STRENGTHS --(cid:173)
`Injection 2 mg/3 ml (0 68 mg/ml) available in
`• Single-patient-use pen that delivers 0.25 mg or 0.5 mg per injection (3)
`Injection 2 mg/1.5 ml (134 mg/ml) available in
`• Single-patient-use pen that delivers 0.25 mg or 0.5 mg per injection (3)
`Injection 4 mg/3 ml (1.34 mg/ml) available in
`• Single-patient-use pen that delivers 1 mg per injection (3).
`Injection: 8 mg/3 ml (2.68 mg/ml) available in
`• Single-patient-use pen that delivers 2 mg per injection (3)
`--- CONTRAINDICATIONS ---
`• Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine
`Neoplasia syndrome type 2 (4)
`• Serious hypersensitivity reaction to semaglutide or any of the excipients in OZEMPIC® (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: Concomitant use with an insulin secretagogue or insulin may increase the risk of
`hypoglycemia, including severe hypoglycemia. Reducing dose of insulin secretagogue or insulin
`may be necessary (5 5).
`• Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe
`adverse gastrointestinal reactions (5.6)
`• Hypersensitivity Reactions: Serious hypersensitivity reactions (e.q., anaphylaxis and
`angioedema) have been reported. Discontinue OZEMPIC® if suspected and promptly seek
`medical advice (5.7)
`• Acute Gallbladder Disease: If cholelithiasis or cholecyslitis are suspected, gallbladder studies
`are indicated (5 8).
`
`--- 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.lda.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 al least
`2 months before a planned pregnancy due lo the long washout period for semaglulide (8.3).
`See 17 lor PATIENT COUNSELING INFORMATION and Medication Guide.
`Revised: 10/2022
`
`2
`
`3
`4
`5
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: RISK OF THYROID C-CELL TUMORS
`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 Pancreatilis
`5.3 Diabetic Retinopathy Complications
`5.4 Never Share an OZEMPIC® Pen Between Patients
`5.5 Hypoglycemia wilh Concomilanl Use of Insulin
`Secretagogues or Insulin
`5.6 Acute Kidney Injury
`5.7 Hypersensitivity
`5.8 Acute Gallbladder Disease
`
`6
`
`7
`
`8
`
`10
`11
`
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2 lmmunogenicity
`6.3
`Postmarketing Experience
`DRUG INTERACTIONS
`7.1
`Concomitant Use wilh an Insulin Secrelagogue
`(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 Polenlial
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6
`Renal Impairment
`8.7 Hepatic Impairment
`OVERDOSAGE
`DESCRIPTION
`
`13
`
`14
`
`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 wilh
`Type 2 Diabetes Mellitus
`14.3 Combination Therapy Use of OZEMPIC® in
`Patients wilh Type 2 Diabetes Mellitus
`14.4 Cardiovascular Outcomes Trial of OZEMPIC®
`in Patients with Type 2 Diabetes Mellitus and
`Cardiovascular Disease
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`PATIENT COUNSELING INFORMATION
`17
`*Sections or subseclioris omitted from the full prescribing
`information are not listed.
`
`Novo Nordisk Exhibit 2008
`Mylan Pharms. Inc.v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`FULL PRESCRIBING INFORMATION
`WARNING: RISK OF THYROID C-CELL TUMORS
`• In rodents, semaglutide causes dose-dependent and treatment-duration(cid:173)
`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)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)1. 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)].
`
`OZEMPIC® (semaglutide) injection, for subcutaneous use
`5 WARNINGS AND PRECAUTIONS
`5.1 Risk of Thyroid C-Cell Tumors
`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 (MTG),
`in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been
`determined.
`Cases of MTG 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 MTG and GlP-1 receptor agonist use in humans.
`OZEMPIC® is contraindicated in patients with a personal or family history of MTG or in patients
`with MEN 2. Counsel patients regarding the potential risk for MTG with the use of OZEMPIC(E
`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 MTG in patients treated with OZEMPIC®. Such monitoring may increase the risk al
`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 MTG and
`patients with MTG usually have calcitonin values >50 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.
`5.2 Pancreatitis
`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 conlirmed in an OZEMPIC®-treated
`patient. In a 2-year trial, acute pancreatitis was confirmed by adjudication in 8 OZEMPIC®-lreated
`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.
`·
`5.3 Diabetic Retinopathy Complications
`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 retinopalhy 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 relinopathy should be
`monitored for progression of diabetic retinopathy.
`5.4 Never Share an OZEMPIC® Pen Between Patients
`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.
`5.5 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
`Patients receiving OZEMPIC® in combination with an insulin secretagogue (e.g., sulfonylurea) or
`insulin may have an increased risk of hypoglycemia, including severe hypoglycemia [see Adverst
`Reactions (61) and Drug Interactions (7)1.
`The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other
`concomitantly administered insulin secretagogue) or insulin. Inform patients using these
`concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms
`of hypoglycemia.
`5.6 Acute Kidney Injury
`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.
`5. 7 Hypersensitivity
`Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients
`treated with OZEMPIC®. 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) and Adverse Reaction5
`(63)1
`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 DZEMPIC®.
`5.8 Acute Gallbladder Disease
`Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported
`in GlP-1 receptor agonist trials and postmarketing. In placebo-controlled trials, cholelithiasis
`was reported in 1.5% and 0.4% of patients-treated with OZEMPIC® 0.5 mg and 1 mg, respec(cid:173)
`tively. Cholelithiasis was not reported in placebo-treated patients If cholelithiasis is suspected,
`gallbladder studies and appropriate clinical follow-up are indicated.
`
`INDICATIONS AND USAGE
`OZEMPIC® is indicated
`• as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus.
`• 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.
`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)I
`• OZEMPIC® is not indicated for use in patients with type 1 diabetes mellitus.
`2
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`• Start OZEMPIC® with a 0.25 mg subcutaneous injection once weekly for 4 weeks. The 0.25 mg
`dosage is intended for treatment initiation and is not effective for glycemic control.
`• After 4 weeks on the 0.25 mg dosage, 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 dosage, the dosage
`may be increased to 1 mg once weekly.
`• If additional glycemic control is needed after at least 4 weeks on the 1 mg dosage, the dosage
`may be increased to 2 mg once weekly. The maximum recommended dosage is 2 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).
`• 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.
`2.2 Important Administration Instructions
`• 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
`DZEMPIC® 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 iniections should not be adjacent to each other.
`3
`DOSAGE FORMS AND STRENGTHS
`Injection: clear, colorless solution available in 3 pre-filled, disposable, single(cid:173)
`patient-use pens:
`Dose per
`Total Strength
`Injection
`per Total Volume
`0.25 mg
`2 mg/ 3 ml
`0.5 mg
`0.25 mg
`2 mg /15 ml
`0.5 mg
`1 mg
`4 mg /3 ml
`2 mg
`8 mg /3 ml
`4
`CONTRAINDICATIONS
`OZEMPIC® is contraindicated in patients with:
`• A personal or family history of medullary thyroid carcinoma (MTG) or in patients with Multiple
`Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (51)].
`• A serious hypersensitivity reaction to semaglutide or to any of the excipients in OZEMPIC®.
`Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported
`with OZEMPIC® [see Warnings and Precautions (5.7)).
`
`I
`
`I
`
`Strength
`per ml
`0.68 mg/ml
`
`1.34 mg/ml
`1.34 mg/ml
`2.68 mg/ml
`
`Novo Nordisk Exhibit 2008
`Mylan Pharms. Inc.v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`OZEMPIC® (semaglutide) injection, for subcutaneous use
`Other Adverse Reactions
`Hypoglycemia
`Table 2 summarizes the incidence of events related to hypoglycemia by various delinitions in the
`placebo-controlled trials.
`Table 2. Hypoglycemia Adverse Reactions in Placebo-Controlled Trials in Patients
`with Type 2 Diabetes Mellitus
`
`3
`
`Placebo
`
`OZEMPIC® 0.5 mg OZEMPIC® 1 mg
`
`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 (51))
`• 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))
`• Acute Gallbladder Disease {see Warnings and Precautions (5.8}}
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying condilions, 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 2c90 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)1 including two trials in Japanese patients evaluating the use al 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% al 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 :i:5% of
`OZEMPIC®-Treated Patients with Type 2 Diabetes Mellitus
`OZEMPIC® 1 mg
`Placebo
`DZEMPIC® 0.5 mg
`(N=262)
`(N=261)
`(N=260)
`Adverse Reaction
`%
`%
`%
`Nausea
`6.1
`15.8
`20.3
`Vomiting
`2.3
`9.2
`5.0
`Diarrhea
`1.9
`8.5
`8.8
`Abdominal pain
`4.6
`7.3
`5.7
`1.5
`Constipation
`5.0
`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.
`In a clinical trial with 959 patients treated with OZEMPIC® 1 mg or OZEMPIC® 2 mg once weekly
`as add-on to metformin with or without sulfonylurea treatment for 40 weeks, no new safety signals
`were identified.
`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 the trial with OZEMPIC® 1 mg and 2 mg, gastrointestinal adverse reactions occurred more
`frequently among patients receiving OZEMPIC® 2 mg (34 0%) vs OZEMPIC® 1 mg (30.8%).
`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 (O 8%, 0.8%,
`0.4%)
`
`N=129
`0%
`0%
`
`1.6%
`
`N=132
`0%
`15.2%
`
`5.3%
`
`0%
`
`N=132
`0%
`16.7%
`
`8.3%
`
`N=130
`0%
`3.8%
`
`0%
`
`N=131
`1.5%
`29.8%
`
`10.7%
`
`N=127
`0%
`1.6%
`
`Monotherapy
`(30 weeks)
`Sever et
`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 Mellormin
`(30 weeks)
`Severe'
`Documented symptomatic
`(<70 mg/dL glucose threshold)
`Severe! or Blood Glucose
`Confirmed Symptomatic
`(<56 mg/dL glucose threshold)
`"Severe" hypoglycemia adverse reaclions are episodes requiring lhe assistance of another person.
`Hypoglycemia was more frequent when OZEMPIC® was used in combination with a sulfonylurea
`{see Warnings and Precautions (55) 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% al
`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% al
`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.q., 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 al 2 to 3 beats per minute. There was a mean decrease in heart rate al 0.3 beats per minute in
`placebo-treated patients.
`Fatigue Dysqeusia and Dizziness
`Other adverse reactions with a frequency of >0.4% were associated with OZEMPIC® include
`fatigue, dysgeusia and dizziness.
`6.2 lmmunogenicity
`Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals,
`patients treated with OZEMPIC® may develop anti-semaglutide antibodies. The detection al
`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 vi/re
`neutralizing activity of the antibodies is uncertain at this time.
`6.3 Postmarketing Experience
`The following adverse reactions have been reported during post-approval use of semaglutide, the
`active ingredient of OZEMPIC®. 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.
`Hypersensitivity: anaphylaxis, angioedema, rash, urticaria.
`Hepatobiliary cholecystitis, cholecystectomy
`DRUG INTERACTIONS
`7
`7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sutfonylurea) or with
`Insulin
`When initiating OZEMPIC®, consider reducing the dose of concomitantly administered insulin
`secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia {see Warning5
`and Precautions (5.5) and Adverse Reactions (6)).
`
`Novo Nordisk Exhibit 2008
`Mylan Pharms. Inc.v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`OZEMPIC® (semaglutide) injection, for subcutaneous use
`7.2 Oral Medications
`8.5 Geriatric Use
`In the pool of placebo- and active-controlled glycemic control trials, 744 (23.6%) OZEMPIC®(cid:173)
`OZEMPIC®causes a delay of gastric emptying, and thereby has the potential to impact the absorption
`treated patients were 65 years of age and over and 102 OZEMPIC®-treated patients (3.2%) patients
`of concomilantly administered oral medications. In clinical pharmacology trials, semaglutide did
`were 75 years of age and over. In SUSTAIN 6, the cardiovascular outcome trial, 788 (48.0%)
`not affecl the absorption of orally administered medications to any clinically relevant degree [see
`OZEMPIC®-treated patients were 65 years of age and over and 157 OZEMPIC®-treated patients
`Clinical Pharmacology (12.3)}. Nonetheless, caution should be exercised when oral medications
`are concomitantly administered with OZEMPIC®.
`(9.6%) patients were 75 years of age and over.
`No overall differences in safety or efficacy were detected between these patients and younger
`8
`USE IN SPECIFIC POPULATIONS
`patients, but greater sensitivity of some older individuals cannot be ruled out.
`8.1 Pregnancy
`8.6 Renal Impairment
`Risk Summary
`No dose adjustment of OZEMPIC® is recommended for patients with renal impairment. In subjects
`There are limited data with semaglutide use in pregnant women to inform a drug-associated risk for
`with renal impairment including end-stage renal disease (ESRD), no clinically relevant change in
`adverse developmental outcomes. There are clinical considerations regarding the risks of poorly
`semaglutide pharmacokinetics (PK) was observed [see Clinical Pharmacology (12.3)/.
`controlled diabetes in pregnancy (see Clinical Considerations) Based on animal reproduction
`8.7 Hepatic Impairment
`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 lhe potential risk
`No dose adjustment of OZEMPIC® is recommended for patients with hepatic impairment. In a
`to the fetus.
`study in subjects with different degrees of hepatic impairment, no clinically relevant change in
`semaglutide pharmacokinetics (PK) was observed [see Clinical Pharmacology (123)/.
`In pregnant rats administered semaglutide during organogenesis, embryofetal mortality, structural
`abnormalities and alterations to growth occurred at maternal clinical exposure based on AUG.
`OVER DOSAGE
`10
`In rabbits and cynomolgus monkeys administered semaglutide during organogenesis, early
`In the event of overdose, appropriale supportive treatment should be initiated according to the
`pregnancy losses or structural abnormalities were observed at clinical exposure (rabbit) and
`patient's clinical signs and symptoms. A prolonged period of observation and treatment for these
`~2-fold the MRHD (monkey). These findings coincided with a marked maternal body weight loss in
`symptoms may be necessary, taking into account the long half-life of OZEMPIC® of approximately
`both animal species (see Data).
`1 week.
`In the U.S general population, the estimated background risk of major birth defects and miscarriage
`11
`DESCRIPTION
`in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated
`background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with OZEMPIC® (semaglutide) injection, for subcutaneous use, contains semaglutide, a human GLP-1
`a peri-conceptional HbA1, >7 and has been reported to be as high as 20 to 25% in women with
`receptor agonist (or GLP-1 analog). The peptide backbone is produced by yeast fermentation.
`a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated
`The main protraction mechanism of semaglutide is albumin binding, facilitated by modification of
`population is unknown.
`position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid. Furthermore, semaglutide is
`modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-pepti(cid:173)
`Clinical Considerations
`dase 4 (DPP-4) A minor modification was made in position 34 to ensure the attachment of only one
`Disease-Associated Maternal and/or Embryo/fetal Risk
`fatty di-acid. The molecular formula is C1a1H291N4sOs9 and the molecular weight is 4113.58 g/mol
`Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre(cid:173)
`Structural formula:
`gestational diabetes. Poorly controlled diabetes during pregnancy increases the maternal risk
`for diabetic ketoacidosis, pre- eclampsia, spontaneous abortions, preterm delivery, 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 embryoletal development study in rats, subcutaneous doses of 0.01,
`0.03 and 0.09 mg/kg/day (0 06-, 0.2-, and 0.6-fold lhe MRHD) were administered to males for 4
`weeks