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Semaglutide

Generic name: semaglutide systemic

Brand names: Ozempic, Rybelsus

Boxed 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 semaglutide 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.

Semaglutide 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 for MTC with the use of semaglutide and inform them of symptoms of thyroid tumors (eg, 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 semaglutide.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Pen-injector, Subcutaneous:

Ozempic (0.25 or 0.5 MG/DOSE): 0.25 mg or 0.5 mg per dose [2 mg/1.5 mL] (1.5 mL) [contains phenol, propylene glycol]

Ozempic (1 MG/DOSE): 1 mg per dose [2 mg/1.5 mL] (1.5 mL) [contains phenol, propylene glycol]

Tablet, Oral:

Rybelsus: 3 mg, 7 mg, 14 mg

Pharmacology

Mechanism of Action

Semaglutide is selective glucagon-like peptide-1 (GLP-1) receptor agonist. Acting on the same receptor as the endogenous hormone incretin, semaglutide increases glucose-dependent insulin secretion, decreases inappropriate glucagon secretion, and slows gastric emptying. Increases first- and second-phase insulin secretion.

Pharmacokinetics/Pharmacodynamics

Distribution

Vd: Oral: ~8 L; SubQ: ~12.5 L

Metabolism

Proteolytic cleavage of the peptide backbone with sequential beta-oxidation of the fatty acid sidechain

Excretion

Urine (~3% as unchanged drug), feces

Time to Peak

Plasma: Oral: 1 hour; SubQ: 1 to 3 days

Half-Life Elimination

~1 week

Protein Binding

>99% to albumin

Use: Labeled Indications

Diabetes mellitus, type 2: Glycemic control: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; risk reduction of major cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (Ozempic only).

Contraindications

Hypersensitivity to semaglutide or any component of the formulation; personal or family history of medullary thyroid carcinoma (MTC); patients with multiple endocrine neoplasia syndrome type 2 (MEN2)

Canadian labeling: Additional contraindications (not in US labeling): Pregnancy; breastfeeding

Dosage and Administration

Dosing: Adult

Diabetes mellitus, type 2:

Oral: Initial: 3 mg once daily for 30 days, then increase to 7 mg once daily for at least 30 days; if further glycemic control is necessary, increase to 14 mg once daily. Note: The 3 mg dose is not effective for glycemic control and is intended only for therapy initiation.

SubQ: Initial: 0.25 mg once weekly for 4 weeks then increase to 0.5 mg once weekly for at least 4 weeks; if further glycemic control is necessary, increase to a maximum of 1 mg once weekly. Note: The 0.25 mg dose is not effective for glycemic control and is intended only for therapy initiation. If changing the day of administration is necessary, allow at least 48 hours between 2 doses.

Missed doses: Missed dose should be administered as soon as possible within 5 days; if greater than 5 days has elapsed, skip the missed dose and resume on the next regularly scheduled day.

Conversion from oral to SubQ semaglutide:

If current oral dose is 7 mg once daily: There are no recommendations provided in the manufacturer's labeling.

If current oral dose is 14 mg once daily: Convert to 0.5 mg SubQ once weekly, beginning the day after the last oral dose.

Conversion from SubQ to oral semaglutide:

If current SubQ dose is 0.5 mg once weekly: Convert to 7 or 14 mg orally once daily, beginning within 7 days of the last injection.

If current SubQ dose is 1 mg once weekly: There are no recommendations provided in the manufacturer's labeling.

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer on an empty stomach, ≥30 minutes before the first food, beverage, or other oral medications of the day with ≤4 oz of plain water only. The manufacturer recommends eating 30 to 60 minutes after the dose. Swallow tablets whole; do not split, crush, or chew.

SubQ: Administer by SubQ injection into the abdomen, thigh, or upper arm at any time of day on the same day each week, with or without food. If changing the day of administration is necessary, allow ≥48 hours between 2 doses. Rotate injection sites weekly if injecting in the same area of the body. Do not mix with other products (administer as separate injections). Avoid adjacent injections if administering other agents in the same area of the body. Solution should be clear; do not use if particulate matter and coloration are seen.

Dietary Considerations

Oral: Administer on an empty stomach, ≥30 minutes before the first food, beverage, or other oral medications of the day with ≤4 oz of plain water only. The manufacturer recommends eating 30 to 60 minutes after the dose.

Storage

Injection: Prior to initial use, store at 2°C to 8°C (36°F to 46°F). After initial use, store at 2°C to 8°C (36°F to 46°F) or 15°C to 30°C (59°F to 86°F) for up to 56 days; discard after 56 days. Do not freeze (discard if freezing occurs) or store directly adjacent to the refrigerator cooling element. Protect from excessive heat and sunlight. Keep pen capped when not in use.

Oral: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store in original blister card; protect from moisture.

Drug Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulins: Glucagon-Like Peptide-1 Agonists may enhance the hypoglycemic effect of Insulins. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Consider therapy modification

Levothyroxine: Semaglutide may increase the serum concentration of Levothyroxine. Monitor therapy

Maitake: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Consider therapy modification

Sulfonylureas: Glucagon-Like Peptide-1 Agonists may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Adverse Reactions

>10%:

Endocrine & metabolic: Increased amylase (10% to 13%)

Gastrointestinal: GI adverse effects (32% to 41%), increased serum lipase (oral: 30% to 34%; SubQ: 22%), nausea (11% to 20%), abdominal pain (6% to 11%)

1% to 10%:

Endocrine & metabolic: Hypoglycemia (2% to 4%), severe hypoglycemia (oral: 1%)

Gastrointestinal: Diarrhea (9% to 10%), decreased appetite (oral: 6% to 9%), vomiting (5% to 9%), constipation (3% to 6%), dyspepsia (3% to 4%), eructation (≤3%), abdominal distension (oral: 2% to 3%), flatulence (1% to 2%), gastritis (oral: 2%), gastroesophageal reflux disease (2%), cholelithiasis (≤2%)

Immunologic: Antibody development (≤1%)

<1%: Acute pancreatitis, discomfort at injection site, dizziness, dysgeusia, erythema at injection site, fatigue

Frequency not defined:

Cardiovascular: Increased heart rate

Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction

Postmarketing: Acute renal failure, chronic renal failure

Warnings/Precautions

Concerns related to adverse effects:

  • Antibody formation: Use may be associated with the development of anti-semaglutide antibodies as well as antibodies cross-reacting with native glucagon-like peptide-1 (GLP-1). In clinical trials, the percentage of patients developing antibodies to semaglutide and native GLP-1 were 1% and 0.6%, respectively, for injection, and 0.5% and 0.2%, respectively, for oral. The development of antibodies does not appear to affect the overall semaglutide exposure (Carlsson Petri 2018).
  • Gallbladder disease: Use of GLP-1 agonists may increase risk of gallbladder and bile duct disease (Faillie 2016). Cholelithiasis has been reported in patients treated with semaglutide.
  • Hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported with GLP-1 agonists; permanently discontinue therapy in the event of a hypersensitivity reaction. Use with caution in patients with a history of anaphylaxis or angioedema to other GLP-1 receptor agonists; potential for cross-sensitivity is unknown.
  • Pancreatitis: Cases of acute and chronic pancreatitis have been reported; monitor for signs and symptoms of pancreatitis (eg, persistent severe abdominal pain which may radiate to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue use. Do not resume unless an alternative etiology of pancreatitis is confirmed. It is not known if semaglutide increases risk for development of pancreatitis in patients with a history of pancreatitis; consider alternative antidiabetic therapy in these patients.
  • Renal effects: Acute renal failure and chronic renal failure exacerbation (including severe cases requiring hemodialysis) have been reported; some cases have been reported in patients with no known preexisting renal disease. Reports primarily occurred in patients with nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating therapy or increasing doses in patients reporting severe adverse GI reactions.
  • Thyroid tumors: [US Boxed Warning]: Dose-dependent and treatment duration-dependent thyroid C-cell tumors have developed in animal studies with semaglutide therapy; it is unknown whether semaglutide will cause 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. Patients should be counseled on the potential risk of MTC with the use of semaglutide and informed of symptoms of thyroid tumors (eg, neck mass, dysphagia, dyspnea, persistent hoarseness). Use is contraindicated in patients with a personal or a family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2). Cases of MTC in humans have been reported in patients treated with the GLP-1 receptor agonist liraglutide. Consultation with an endocrinologist is recommended in patients who develop elevated calcitonin concentrations or have thyroid nodules detected during imaging studies or physical exam. Routine monitoring of serum calcitonin or using thyroid ultrasound monitoring is of uncertain value for early detection of MTC in patients treated with semaglutide.

Disease-related concerns:

  • Bariatric surgery:

- Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy, and closely monitor the patient for the duration of therapy; acute and chronic kidney failure exacerbation may occur. A majority of cases occurred in patients with nausea, vomiting, diarrhea, and/or dehydration. Nausea is common and fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2013).

- Excessive glucagon-like peptide-1 exposure: Closely monitor for efficacy and assess for signs and symptoms of pancreatitis if therapy is initiated after surgery; gastric bypass and sleeve gastrectomy (but not gastric band) significantly increase endogenous postprandial GLP-1 concentrations (Korner 2009; Peterli 2012). Administration of exogenous GLP-1 agonists may be redundant to surgery effects.

  • Diabetic retinopathy: Increased complications associated with diabetic retinopathy have been observed with semaglutide compared to placebo; risk may be increased in patients with a history of diabetic retinopathy at baseline. Monitor for worsening of diabetic retinopathy, particularly in those with a prior history of the disease. Long-term effects of semaglutide on diabetic retinopathy complications are unknown.

Concurrent drug therapy issues:

  • Delayed gastric emptying: Semaglutide slows gastric emptying, which may alter the absorption of other medications. Monitor narrow therapeutic index medications for increased or decreased response.
  • Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

  • Multiple dose injection pens (Ozempic): According to the Centers for Disease Control and Prevention (CDC), pen-shaped injection devices should never be used for more than one person (even when the needle is changed) because of the risk of infection. The injection device should be clearly labeled with individual patient information to ensure that the correct pen is used (CDC 2012).

Other warnings/precautions:

  • Appropriate use: Diabetes mellitus: Do not use in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis; not a substitute for insulin.
  • Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Monitoring Parameters

Plasma glucose, HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2019]); renal function; signs/symptoms of pancreatitis; triglycerides; signs/symptoms of gallbladder disease

Pregnancy

Pregnancy Considerations

Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia (ACOG 201 2018). To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2020; Blumer 2013).

Agents other than semaglutide are currently recommended to treat diabetes mellitus in pregnancy (ADA 2020).

In females of reproductive potential, semaglutide should be discontinued for ≥2 months prior to a planned pregnancy.

Patient Education

What is this drug used for?

  • It is used to lower blood sugar in patients with high blood sugar (diabetes).

Frequently reported side effects of this drug

  • Diarrhea
  • Constipation
  • Lack of appetite
  • Nausea
  • Vomiting
  • Abdominal pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

  • Thyroid cancer like new lump or swelling in the neck, pain in the front of the neck, persistent cough, persistent change in voice like hoarseness, or difficulty swallowing or breathing
  • Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
  • Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting
  • Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating
  • Vision changes
  • Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Source: Wolters Kluwer Health. Last updated January 30, 2020.