semaglutide (Rx)

>10% (SC)

Nausea (15.8-20.3%)

Documented symptomatic hypoglycemia, adjunctive therapy [≤70 mg/dL glucose threshold] (16.7-29.8%)

Severe or symptomatic hypoglycemia, adjunctive therapy [≤56 mg/dL glucose threshold] (8.3-10.7%)

>10% (PO)

Nausea (11-20%)

Abdominal pain (10-11%)

1-10% (SC)

Vomiting (5-9.2%)

Diarrhea (8.5-8.8%)

Abdominal pain (5.7-7.3%)

Constipation (3.1-5%)

Dyspepsia (2.7-3.5%)

Eructation (1.1-2.7%)

Documented symptomatic hypoglycemia, monotherapy [≤70 mg/dL glucose threshold] (1.6-3.8%)

Flatulence (0.4-1.5%)

GERD(1.5-1.9%)

1-10% (PO)

Diarrhea (9-10%)

Decreased appetite (6-9%)

Vomiting (6-8%)

Constipation (5-6%)

Abdominal distension (2-3%)

Dyspepsia (0.6-3%)

GERD (2%)

Gastritis (2%)

Eructation (0.6-2%)

Flatulence (1-2%)

Cholelithiasis (1%)

<1% (SC)

Gastritis (0.4-0.8%)

Cholelithiasis (0.4%)

Fatigue (>0.4%)

Dysgeusia (>0.4%)

Dizziness (>0.4%)

Injection site reaction (0.2%)

Frequency Not Defined (PO)

Increased amylase and lipase

Increased HR

Hypersensitivity: Anaphylaxis, angioedema, rash, urticaria

Contraindications

Personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2

Known hypersensitivity to semaglutide or to any of the product components

Cautions

Based on findings in rats and mice, semaglutide may cause thyroid C-cell tumors, including MTC, in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined

In control trials, acute pancreatitis was reported (0.3 events [SC] and 0.1 events [PO] per 100 patient years); after initiating treatment, monitor for signs and symptoms of pancreatitis (eg, persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting); if pancreatitis suspected, discontinue semaglutide and do not restart if confirmed

Patients treated with semaglutide showed an increased risk of diabetic retinopathy complications compared with placebo/comparator; rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy

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

Postmarketing reports describe acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis in patients treated with GLP-1 receptor agonists; a majority of 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 GI reactions

Serious hypersensitivity reactions (eg, anaphylaxis, angioedema) have been reported with GLP-1 receptor agonists; if hypersensitivity reactions occur, discontinue treatment, treat promptly, and monitor until signs and symptoms resolve (see Contraindications)

Drug interactions overview

• Coadministration with insulin secretagogues (eg, sulfonylureas) or insulin may increase the risk of hypoglycemia; consider a lower dose of the secretagogue or insulin to reduce risk of hypoglycemia in this setting; inform patients using concomitant medications of risk of hypoglycemia and educate them on signs and symptoms of hypoglycemia
• Exercise caution when semaglutide is concomitantly administered with oral medications; semaglutide causes a delay of gastric emptying, thereby potentially impacting oral absorption of such medications

Pregnancy

Data are insufficient regarding use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes

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

Discontinue treatment in women at least 2 months before a planned pregnancy, owing to the long washout period for semaglutide

Clinical Considerations

• Poorly controlled diabetes during pregnancy increases maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications
• Poorly controlled diabetes increases fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity

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

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

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Glucagon-like peptide-1 (GLP-1) agonist

Incretins, such as GLP-1, enhance glucose-dependent insulin secretion by pancreatic beta-cells, suppress inappropriately elevated glucagon secretion, and slow gastric emptying

Absorption

SC

• Bioavailability: 89%
• Peak plasma time: 1-3 days
• Plasma concentration, steady-state: 65 ng/mL (0.5 mg/week); 123 ng/mL (1 mg/week)
• Similar exposure is achieved with SC administration of semaglutide in the abdomen, thigh, or upper arm

PO

• Absolute bioavailability: 0.4-1%
• Peak plasma time: 1 hr
• Plasma concentration, steady-state: 6.7 nmol/L (7 mg/day); 14.6 nmol/L (14 mg/day)
• Steady-state: 4-5 weeks

Distribution

Vd: 12.5 L (SC); 8 L (PO)

Protein binding: >99% (bound to plasma albumin)

Metabolism

Primary route: Proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain

Excretion

Half-life: ~1 week

Clearance: 0.05 L/hr (SC); 0.04 L/hr (PO)

Excretion: Primary excretion routes are urine and feces; ~3% of absorbed dose is excreted in urine unchanged

SC Administration

Administer SC to abdomen, thigh, or upper arm

Administer once weekly, on the same day each week, at any time of the day, with or without meals

Day of weekly administration can be changed if necessary as long as the time between 2 doses is at least 2 days (>48 hours)

Use a different injection site each week when injecting in the same body region

Visually inspect before use; drug should appear clear and colorless

Do not use semaglutide if particulate matter and coloration is seen

When used with insulin, administer as separate injections and never mix the products; it is acceptable to inject semaglutide and insulin in the same body region but injections should not be adjacent to each other

Missed SC dose

• If missed dose is ≤5 days: Administer dose as soon as possible
• If missed dose >5 days: Skip missed dose and administer next dose on the regularly scheduled day; patients can then resume their regular once weekly dosing schedule

Oral Administration

Take at least 30 minutes before first food, beverage, or other oral medication of the day with no more than 4 oz of plain water only

Waiting <30 minutes, or taking with food, beverages (other than plain water), or other oral medications decrease efficacy by decreasing semaglutide absorption

Waiting to take after 30 minutes to eat may increase semaglutide absorption

Swallow tablets whole; do not split, crush, or chew

Missed oral dose

• If a dose is missed, the missed dose should be skipped, and the next dose should be taken the following day

Storage

SC

• Unused SC pens

  • Refrigerate at 36-46ºF (2-8ºC)
  • Do not store in freezer or directly adjacent to the refrigerator cooling element
  • Do not freeze and do not use if frozen

• After first SC use

  • Store at room temperature, 59-86°F (15-30°C) or refrigerate at 36-46ºF (2-8ºC) for up to 56 days
  • Do not freeze
  • Keep pen cap on when not in use
  • Protect from excessive heat and sunlight

Oral tablets

• Store at 68-77ºF (20-25ºC); excursions permitted to 59-86ºF (15-30ºC)
• Store and dispense in the original carton
• Store tablet in the original blister card until use to protect tablets from moisture
• Store product in a dry place away from moisture