WEGOVY (Page 5 of 11)

8.5 Geriatric Use

In the WEGOVY clinical trials, 233 (8.8%) WEGOVY-treated patients were between 65 and 75 years of age and 23 (0.9%) WEGOVY-treated patients were 75 years of age and over. 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.

8.6 Renal Impairment

No dose adjustment of WEGOVY is recommended for patients with renal impairment. In a study in subjects with renal impairment, including end-stage renal disease, no clinically relevant change in semaglutide pharmacokinetics was observed [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dose adjustment of WEGOVY 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 was observed [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Overdoses have been reported with other GLP-1 receptor agonists. Effects have included severe nausea, severe vomiting, and severe hypoglycemia. In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the long half-life of WEGOVY of approximately 1 week.

11 DESCRIPTION

WEGOVY (semaglutide) injection, for subcutaneous use, contains semaglutide, a human GLP-1 receptor agonist (or GLP-1 analog). The peptide backbone is produced by yeast fermentation. The main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid. Furthermore, semaglutide is modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4). A minor modification was made in position 34 to ensure the attachment of only one fatty di-acid. The molecular formula is C187 H291 N45 O59 and the molecular weight is 4113.58 g/mol.

Figure 1. Structural Formula of semaglutide
Structural formula
(click image for full-size original)

WEGOVY is a sterile, aqueous, clear, colorless solution. Each 0.5 mL single-dose pen contains a solution of WEGOVY containing 0.25 mg, 0.5 mg or 1 mg of semaglutide; and each 0.75 mL single-dose pen contains a solution of WEGOVY containing 1.7 or 2.4 mg of semaglutide. Each 1 mL of WEGOVY contains the following inactive ingredients: disodium phosphate dihydrate, 1.42 mg; sodium chloride, 8.25 mg; and water for injection. WEGOVY has a pH of approximately 7.4. Hydrochloric acid or sodium hydroxide may be added to adjust pH.

12 CLINICAL PHARMACOLOGY

12.1 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.

GLP-1 is a physiological regulator of appetite and caloric intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. Animal studies show that semaglutide distributed to and activated neurons in brain regions involved in regulation of food intake.

12.2 Pharmacodynamics

Semaglutide lowers body weight through decreased calorie intake. The effects are likely mediated by affecting appetite.

As with other GLP-1 receptor agonists, semaglutide stimulates insulin secretion and reduces glucagon secretion in a glucose-dependent manner. These effects can lead to a reduction of blood glucose.

Cardiac electrophysiology (QTc)

The effect of semaglutide on cardiac repolarization was tested in a thorough QTc trial. Semaglutide did not prolong QTc intervals at doses up to 1.5 mg at steady state.

12.3 Pharmacokinetics

Absorption

Absolute bioavailability of semaglutide is 89%. Maximum concentration of semaglutide is reached 1 to 3 days post dose.

Similar exposure was achieved with subcutaneous administration of semaglutide in the abdomen, thigh, or upper arm.

The average semaglutide steady state concentration following subcutaneous administration of WEGOVY was approximately 75 nmol/L in patients with either obesity (BMI greater than or equal to 30 kg/m2) or overweight (BMI greater than or equal to 27 kg/m2). The steady state exposure of WEGOVY increased proportionally with doses up to 2.4 mg once-weekly.

Distribution

The mean volume of distribution of semaglutide following subcutaneous administration in patients with obesity or overweight is approximately 12.5 L. Semaglutide is extensively bound to plasma albumin (greater than 99%) which results in decreased renal clearance and protection from degradation.

Elimination

The apparent clearance of semaglutide in patients with obesity or overweight is approximately 0.05 L/h.

With an elimination half-life of approximately 1 week, semaglutide will be present in the circulation

for about 5 to 7 weeks after the last dose of 2.4 mg.

Metabolism

The primary route of elimination for semaglutide is metabolism following proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain.

Excretion

The primary excretion routes of semaglutide-related material are via the urine and feces. Approximately 3% of the dose is excreted in the urine as intact semaglutide.

Special Populations

The effects of intrinsic factors on the pharmacokinetics of semaglutide are shown in Figure 2.

Figure 2. Impact of intrinsic factors on semaglutide exposure
fig 2
(click image for full-size original)

Data are steady-state dose-normalized average semaglutide exposures relative to a reference subject profile (non-Hispanic or Latino, white female aged 18 to less than 65 years, with a body weight of 110 kg and normal renal function, who injected in the abdomen). Body weight categories (74 and 143 kg) represent the 5% and 95% percentiles in the dataset.

Renal Impairment

Renal impairment did not impact the exposure of semaglutide in a clinically relevant manner. The pharmacokinetics of semaglutide were evaluated following a single dose of 0.5 mg semaglutide in a study of patients with different degrees of renal impairment (mild, moderate, severe, or ESRD) compared with subjects with normal renal function. The pharmacokinetics were also assessed in subjects with overweight (BMI 27-29.9 kg/m2) or obesity (BMI greater than or equal to 30 kg/m2) and mild to moderate renal impairment, based on data from clinical trials.

Hepatic Impairment

Hepatic impairment did not impact the exposure of semaglutide. The pharmacokinetics of semaglutide were evaluated following a single dose of 0.5 mg semaglutide in a study of patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function.

Drug Interactions

In vitro studies have shown very low potential for semaglutide to inhibit or induce CYP enzymes, or to inhibit drug transporters.

The delay of gastric emptying with semaglutide may influence the absorption of concomitantly administered oral medications [see Drug Interactions (7.2)]. The potential effect of semaglutide on the absorption of co-administered oral medications was studied in trials at semaglutide 1 mg steady-state exposure. No clinically relevant drug-drug interactions with semaglutide (Figure 3) were observed based on the evaluated medications. In a separate study, no apparent effect on the rate of gastric emptying was observed with semaglutide 2.4 mg.

Figure 3. Impact of semaglutide 1 mg on the pharmacokinetics of co-administered medications
fig 3
(click image for full-size original)

Relative exposure in terms of AUC and Cmax for each medication when given with semaglutide compared to without semaglutide. Metformin and oral contraceptive drug (ethinylestradiol/levonorgestrel) were assessed at steady state. Warfarin (S-warfarin/R-warfarin), digoxin and atorvastatin were assessed after a single dose.

Abbreviations: AUC: area under the curve, Cmax : maximum concentration, CI: confidence interval.

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