Ozempic: Package Insert and Label Information

OZEMPIC- semaglutide injection, solution
A-S Medication Solutions

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)].

1 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)].
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 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.

3 DOSAGE FORMS AND STRENGTHS

Injection: clear, colorless solution available in 3 pre-filled, disposable, single-patient-use pens:

Dose per Injection

Total Strength per Total Volume

Strength per mL

0.25 mg

0.5 mg

2 mg / 1.5 mL

1.34 mg/mL

1 mg

4 mg / 3 mL

1.34 mg/mL

2 mg

8 mg / 3 mL

2.68 mg/mL

4 CONTRAINDICATIONS

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)].
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)].

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 (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 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 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.

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 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.

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 Adverse Reactions (6.1) and Drug Interactions (7)].

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 Reactions (6.3)].

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.

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, respectively. Cholelithiasis was not reported in placebo-treated patients. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

6 ADVERSE REACTIONS

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)]

• Acute Gallbladder Disease [see Warnings and Precautions (5.8)]

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)

%

OZEMPIC 0.5 mg

(N=260)

%

OZEMPIC 1 mg

(N=261)

%

Nausea

6.1

15.8

20.3

Vomiting

2.3

5.0

9.2

Diarrhea

1.9

8.5

8.8

Abdominal pain

4.6

7.3

5.7

Constipation

1.5

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 (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)

N=129

N=127

N=130

Severe

0%

0%

0%

Documented symptomatic (≤70 mg/dL glucose threshold)

0%

1.6%

3.8%

Severe or Blood Glucose Confirmed Symptomatic (≤56 mg/dL glucose threshold)

1.6%

0%

0%

Add-on to Basal Insulin with or without Metformin

(30 weeks)

N=132

N=132

N=131

Severe

0%

0%

1.5%

Documented symptomatic (≤70 mg/dL glucose threshold)

15.2%

16.7%

29.8%

Severe or Blood Glucose Confirmed Symptomatic (≤56 mg/dL glucose threshold)

5.3%

8.3%

10.7%

“Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person.

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.

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