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Semaglutide

Class: Incretin Mimetics
Molecular Formula: C187H291N45O59
CAS Number: 910463-68-2
Brands: Ozempic

Medically reviewed on December 18, 2017

Warning

Warning: Risk of Thyroid C-cell Tumors1

See full prescribing information for complete boxed warning. 1

  • In rodents, semaglutide causes thyroid C-cell tumors. It is unknown whether semaglutide 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.1

  • Semaglutide is contraindicated in patients with a personal or family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors.1

Introduction

See also: Basaglar

Semaglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, is an incretin mimetic antidiabetic agent.1

Uses for Semaglutide

Semaglutide has the following uses:

Semaglutide 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

Semaglutide has the following limitations of use:

Not recommended as first-line therapy for patients inadequately controlled on diet and exercise.1

Has not been studied in patients with a history of pancreatitis. Consider another antidiabetic therapy.1

Not indicated for use in type 1 diabetes mellitus or treatment of diabetic ketoacidosis.1

Semaglutide Dosage and Administration

General

Semaglutide is available in the following dosage form(s) and strength(s):

  • Injection: 2 mg/1.5 mL (1.34 mg/mL) in prefilled pen that delivers 0.25 mg or 0.5 mg per injection.1

  • Injection: 2 mg/1.5 mL (1.34 mg/mL) in prefilled pen that delivers 1 mg per injection.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

  • Start at 0.25 mg once weekly. After 4 weeks, increase the dose to 0.5 mg once weekly. After at least 4 weeks, if additional glycemic control is needed, increase the dose to 1 mg once weekly.1

  • Administer once weekly at any time of day, with or without meals.1

  • If a dose is missed, administer within 5 days of missed dose.1

  • Inject subcutaneously in the abdomen, thigh, or upper arm.1

Cautions for Semaglutide

Contraindications

  • Personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).1

  • Known hypersensitivity to semaglutide or any of the product components.1

Warnings/Precautions

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. 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.1

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.1

Semaglutide is contraindicated in patients with a personal or family history of MTC and in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of semaglutide and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).1

Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with semaglutide. 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.1

Pancreatitis

In glycemic control trials, acute pancreatitis was confirmed by adjudication in 7 semaglutide-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 a semaglutide-treated patient. In a 2-year trial, acute pancreatitis was confirmed by adjudication in 8 semaglutide-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.1

After initiation of semaglutide, 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, semaglutide should be discontinued and appropriate management initiated; if confirmed, semaglutide should not be restarted.1

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 semaglutide (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 (semaglutide 8.2%, placebo 5.2%) than among patients without a known history of diabetic retinopathy (semaglutide 0.7%, placebo 0.4%).1

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.1

Never Share a Semaglutide Pen Between Patients

Semaglutide pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.1

Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

The risk of hypoglycemia is increased when semaglutide 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.1

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 semaglutide in patients reporting severe adverse gastrointestinal reactions.1

Hypersensitivity

Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported with GLP-1 receptor agonists. If hypersensitivity reactions occur, discontinue use of semaglutide; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previous hypersensitivity to semaglutide.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 semaglutide.1

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with semaglutide.1

Specific Populations

Pregnancy

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. Based on animal reproduction studies, there may be potential risks to the fetus from exposure to semaglutide during pregnancy. Semaglutide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.1

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.1

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 an 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.1

Clinical Considerations: 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.1

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.1

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.1

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).1

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).1

Lactation

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. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for semaglutide and any potential adverse effects on the breastfed infant from semaglutide or from the underlying maternal condition.1

In lactating rats, semaglutide was detected in milk at levels 3-12 fold lower than in maternal plasma.1

Females and Males of Reproductive Potential

Discontinue semaglutide in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide.1

Pediatric Use

Safety and efficacy of semaglutide have not been established in pediatric patients (younger than 18 years).1

Geriatric Use

In the pool of placebo- and active-controlled glycemic control trials, 744 (23.6%) semaglutide-treated patients were 65 years of age and over and 102 semaglutide-treated patients (3.2%) patients were 75 years of age and over. In SUSTAIN 6, the cardiovascular outcome trial, 788 (48.0%) semaglutide-treated patients were 65 years of age and over and 157 semaglutide-treated patients (9.6%) patients were 75 years of age and over.1

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.1

Renal Impairment

No dose adjustment of semaglutide 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.1

Hepatic Impairment

No dose adjustment of semaglutide 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.1

Common Adverse Effects

The most common adverse reactions, reported in ≥5% of patients treated with semaglutide are nausea, vomiting, diarrhea, abdominal pain, and constipation.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Semaglutide delays gastric emptying which may impact absorption of concomitantly administered oral medications.1

Actions

Mechanism of Action

Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1.1

GLP-1 is a physiological hormone that has multiple actions on glucose, mediated by the GLP-1 receptors.1

The principal mechanism of protraction resulting in the long half-life of semaglutide is albumin binding, which results in decreased renal clearance and protection from metabolic degradation. Furthermore, semaglutide is stabilized against degradation by the DPP-4 enzyme.1

Semaglutide reduces blood glucose through a mechanism where it stimulates insulin secretion and lowers glucagon secretion, both in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase.1

Advice to Patients

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).1

Inform patients that semaglutide causes thyroid C-cell tumors in rodents and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia, or dyspnea) to their physician.1

Inform patients of the potential risk for pancreatitis. Instruct patients to discontinue semaglutide promptly and contact their physician if pancreatitis is suspected (severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting).1

Inform patients to contact their physician if changes in vision are experienced during treatment with semaglutide.1

Advise patients that they must never share a semaglutide pen with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens.1

Advise patients treated with semaglutide of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs.1

Inform patients to stop taking semaglutide and seek medical advice promptly if symptoms of hypersensitivity reactions occur.1

Advise a pregnant woman of the potential risk to a fetus. Advise women to inform their healthcare provider if they are pregnant or intend to become pregnant.1

Inform patients of the potential risks and benefits of semaglutide and of alternative modes of therapy. Inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery as medication requirements may change.1

Advise patients that the most common side effects of semaglutide are nausea, vomiting, diarrhea, abdominal pain, and constipation. Inform patients that nausea, vomiting, and diarrhea are most common when first starting semaglutide, but decrease over time in the majority of patients.1

Instruct patients to reread the Medication Guide each time the prescription is renewed.1

Inform patients if a dose is missed, it should be administered as soon as possible within 5 days after the missed dose. If more than 5 days have passed, the missed dose should be skipped and the next dose should be administered on the regularly scheduled day. In each case, inform patients to resume their regular once-weekly dosing schedule.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Semaglutide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use only

1.34 mg/1 mL

Ozempic (available as prefilled injection pen that delivers 0.25 or 0.5 mg)

Novo Nordisk

1.34 mg/1 mL

Ozempic (available as prefilled injection pen that delivers 1 mg)

Novo Nordisk

AHFS Drug Information. © Copyright 2018, Selected Revisions December 18, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Novo Nordisk. Ozempic (semaglutide) SUBCUTANEOUS prescribing information. 2017 Dec. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79

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