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Semaglutide

Pronunciation

(sem a GLOO tide)

Dosage Forms

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

Solution Pen-injector, Subcutaneous:

Ozempic: 1 mg per dose [2 mg/1.5 mL] (1.5 mL); 0.25 mg or 0.5 mg per dose [2 mg/1.5 mL] (1.5 mL) [contains phenol, propylene glycol]

Brand Names: U.S.

  • Ozempic

Pharmacologic Category

  • Antidiabetic Agent, Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist

Pharmacology

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.

Distribution

Vd: ~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: 1 to 3 days after a single dose; steady state achieved after 4 to 5 weeks

Half-Life Elimination

~1 week

Protein Binding

>99% to albumin

Use: Labeled Indications

Diabetes mellitus, type 2: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

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

Dosing: Adult

Diabetes mellitus, type 2: 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: 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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

No dosage adjustment necessary.

Administration

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 at least 48 hours between two 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.

Storage

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.

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

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. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Consider therapy modification

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

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. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. 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 (13%)

Gastrointestinal: Increased serum lipase (22%), nausea (16% to 20%)

1% to 10%:

Endocrine & metabolic: Hypoglycemia (2% to 4%)

Gastrointestinal: Diarrhea (9%), vomiting (5% to 9%), abdominal pain (6% to 7%), constipation (3% to 5%), dyspepsia (3% to 4%), eructation (1% to 3%), flatulence (2%), gastroesophageal reflux disease (2%), cholelithiasis (≤2%)

Immunologic: Antibody development (1%)

Frequency not defined: Cardiovascular: Increased heart rate

<1%, postmarketing, and/or case reports: Acute pancreatitis, discomfort at injection site, dizziness, dysgeusia, erythema at injection site, fatigue

ALERT: U.S. 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.

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 GLP-1. In clinical trials, the percentage of patients developing antibodies to semaglutide and native GLP-1 were 1% and 0.6% respectively.

• 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 with the majority of patients requiring hospitalization or cholecystectomy; gallbladder studies and further clinical assessment are indicated if cholelithiasis is suspected.

• 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:

• Diabetic retinopathy: Increased complications associated with diabetic retinopathy have been observed with semaglutide (3%) compared to placebo (1.8%) over a 2-year trial; 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.

• Gastroparesis: Slows gastric emptying; potentially may impact absorption of concomitantly administered oral medication; use caution.

Concurrent drug therapy issues:

• 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: 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 2018a]); renal function; signs/symptoms of pancreatitis; triglycerides; signs/symptoms of gallbladder disease

Pregnancy Considerations

Adverse events were observed in animal reproduction studies.

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother. 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. Agents other than semaglutide are currently recommended to treat diabetes in pregnant women (ADA 2018c).

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

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, constipation, nausea, vomiting, or abdominal pain. Have patient report immediately to prescriber signs of thyroid cancer (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), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating), or vision changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

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