Semaglutide

Registered South African indications:

• Weight management, including weight loss and weight maintenance, as an adjunct to a reduced-calorie diet and increased physical activity in adults with an initial Body Mass Index (BMI) of
  - ≥30kg/m² (obesity), or
  - ≥27kg/m² to < 30kg/m² (overweight) in the presence of at least one weight-related comorbidity e.g., dysglycaemia (prediabetes or type 2 diabetes mellitus), hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease
• Weight management, as an adjunct to a reduced-calorie diet and increased physical activity in adolescents ages 12 years and above with
  - Obesity and
  - Body weight above 60kg

Risk of thyroid C-cell tumours

• In rodents, semaglutide triggers dose-dependent and treatment-duration-dependent thyroid C-cell tumours at clinically relevant exposures
• It is unknown whether semaglutide causes thyroid C-cell tumours, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumours 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)
• Patients should be counselled regarding the potential risk for MTC with the use of semaglutide and informed of symptoms of thyroid tumours (e.g., a mass in the neck, dysphagia, dyspnoea, 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

Registered South African contraindications

• Hypersensitivity to the active ingredient or to any of its excipients
• 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)

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Concomitant treatment with other products for weight management
• Type 1 diabetes
• Congestive heart failure New York Heart Association (NYHA) class IV
• Inflammatory bowel disease
• Diabetic gastroparesis

Gastrointestinal adverse reactions

• Use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions that can cause dehydration, which in rare cases can lead to a deterioration of renal function
• Patients should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion

Acute pancreatitis

• Acute pancreatitis has been observed with the use of GLP-1 receptor agonists
• Patients should be informed of the characteristic symptoms of acute pancreatitis
• If pancreatitis is suspected, semaglutide should be discontinued; if confirmed, semaglutide should not be restarted
• Caution should be exercised in patients with a history of pancreatitis
• In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis

Patients with type 2 diabetes

• Semaglutide must not be used as a substitute for insulin in patients with type 2 diabetes
• Semaglutide should not be used in combination with other GLP-1 receptor agonist products
• It has not been evaluated and an increased risk of adverse reactions related to overdose is considered likely
• When initiating semaglutide in patients with type 2 diabetes, consider reducing the dose of concomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycaemia

Hypoglycaemia in patients with type 2 diabetes

• Insulin and sulfonylurea are known to cause hypoglycaemia
• Patients treated with semaglutide in combination with a sulfonylurea or insulin may have an increased risk of hypoglycaemia
• The risk of hypoglycaemia can be lowered by reducing the dose of sulfonylurea or insulin when initiating treatment with a GLP-1 receptor agonists
• The addition of semaglutide in patients treated with insulin has not been evaluated

Diabetic retinopathy in patients with type 2 diabetes

• Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy
• Long-term glycaemic control decreases the risk of diabetic retinopathy
• Patients with a history of diabetic retinopathy should be monitored for worsening and treated according to local clinical guidelines

Warfarin considerations

• Semaglutide did not change overall exposure or Cmax of R- and S-warfarin following a single dose of warfarin, and the pharmacodynamic effects of warfarin as measured by the international normalised ratio were not affected in a clinically relevant manner. However, upon initiation of semaglutide treatment in patients on warfarin or other coumarin derivatives, frequent monitoring of international normalised ratio (INR) is recommended

Sodium content

• This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially ‘sodium- free’

Effects on ability to drive and use machines

• Semaglutide has no or negligible influence on the ability to drive or use machines. However, dizziness can be experienced mainly during the dose escalation period. Driving or use of machines should be done cautiously if dizziness occurs

Forms avail. In SA and covered in this monograph: ped

South African registered indications and dosages

Weight management, including weight loss and weight maintenance, as an adjunct to a reduced-calorie diet and increased physical activity in adults with an initial Body Mass Index (BMI) of
- ≥30kg/m² (obesity), or
- ≥27kg/m² to < 30kg/m² (overweight) in the presence of at least one weight-related comorbidity e.g., dysglycaemia (prediabetes or type 2 diabetes mellitus), hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease

• SC: Initial: 0.25mg, once-weekly; Escalate dose over a 16-week period to reduce likelihood of gastrointestinal symptoms; Maintenance: 2.4mg, once weekly (see table below); Max: 2.4mg/week

Table: Dose escalation schedule

Dose escalation	Weekly dose
Week 1 – 4	0.25mg
Week 5 – 8	0.5mg
Week 9 – 12	1mg
Week 13 – 16	1.7mg
Maintenance dose	2.4mg

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In case of significant gastrointestinal symptoms, consider delaying dose escalation or lowering to the previous dose until symptoms have improved. Weekly doses higher than 2.4mg are not recommended

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Method of administration
Subcutaneous use. Semaglutide is administered once weekly at any time of the day, with or without meals. May be injected subcutaneously in the abdomen, in the thigh or in the upper arm. The injection site can be changed. DO NOT administer intravenously or intramuscularly
The day of weekly administration can be changed if necessary as long as the time between two doses is at least 3 days (> 72 hours). After selecting a new dosing day, once-weekly dosing should be continued. Patients should be advised to read the instructions for use included in the patient information leaflet carefully before administration
For further information on administration see product specific information

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Missed dose
If a dose is missed, it should be administered as soon as possible and 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, patients can then resume their regular once weekly dosing schedule. If more doses are missed, reducing the starting dose for re-initiation should be considered

Forms avail. In SA and covered in this monograph: ped

South African registered indications and dosages

Weight management, as an adjunct to a reduced-calorie diet and increased physical activity in adolescents ages 12 years and above with
- Obesity* and
- Body weight above 60kg

Younger than 12 years

• Not established for use

Older than 12 years

• See adult dosage; Dose should be increased until 2.4mg (maintenance dose) or maximum tolerated dose has been reached; Consider table below with respect to BMI cut off points

*Obesity (BMI ≥ 95th percentile) as defined on sex- and age-specific BMI growth charts (CDC.gov) (see Table below)

Table: BMI cut-off points for obesity (≥ 95th percentile) by sex and age for paediatric patients aged 12 and older (CDC criteria)

Age (years)	BMI (kg/m2) at 95th Percentile
	Males	Females
12	24.2	25.2
12.5	24.7	25.7
13	25.1	26.3
13.5	25.6	26.8
14	26.0	27.2
14.5	26.4	27.7
15	26.8	28.1
15.5	27.2	28.5
16	27.5	28.9
16.5	27.9	29.3
17	28.2	29.6
17.5	28.6	30.0

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Treatment with semaglutide should be discontinued and re-evaluated if adolescent patients have not reduced their BMI by at least 5% after 12 weeks on the 2.4 mg or maximum tolerated dose

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No dose adjustment is required for adolescents ages 12 years and above. The safety and efficacy of semaglutide in children below 12 years of age have not been established

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Method of administration
Subcutaneous use. Semaglutide is administered once weekly at any time of the day, with or without meals. May be injected subcutaneously in the abdomen, in the thigh or in the upper arm. The injection site can be changed. DO NOT administer intravenously or intramuscularly
The day of weekly administration can be changed if necessary as long as the time between two doses is at least 3 days (> 72 hours). After selecting a new dosing day, once-weekly dosing should be continued. Patients should be advised to read the instructions for use included in the patient information leaflet carefully before administration
For further information on administration see product specific information

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Missed dose
If a dose is missed, it should be administered as soon as possible and 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, patients can then resume their regular once weekly dosing schedule. If more doses are missed, reducing the starting dose for re-initiation should be considered

Pregnancy

South African recommendations

• Caution; positive evidence of risk in animal studies
• Studies in animals have shown reproductive toxicity
• There are limited data from the use of semaglutide in pregnant women. Therefore, semaglutide should not be used during pregnancy
• Women of childbearing potential are recommended to use contraception when treated with semaglutide. If a patient wishes to become pregnant, or pregnancy occurs, semaglutide should be discontinued
• Semaglutide should be discontinued at least 2 months before a planned pregnancy due to the long half-life

Breastfeeding

South African recommendations

• Caution; not recommended
• In lactating rats, semaglutide was excreted in milk. A risk to a breast-fed child cannot be excluded
• Semaglutide should not be used during breast-feeding

Fertility

South African recommendations

• The effect of semaglutide on fertility in humans is unknown. Semaglutide did not affect male fertility in rats. In female rats, an increase in oestrous length and a small reduction in number of ovulations were observed at doses associated with maternal body weight loss

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
• Severe (eGFR < 30ml/min/1.73 m²) and in patients with end-stage renal disease: Caution; not recommended
  Experience with the use of semaglutide in patients with severe renal impairment is limited

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
  Semaglutide should be used cautiously in patients with mild or moderate hepatic impairment
• Severe: Caution; not recommended
  Experience with the use of semaglutide in patients with severe hepatic impairment is limited. Semaglutide is not recommended for use in patients with severe hepatic impairment

South African recommendations

• Caution; no dose adjustment recommended
  Therapeutic experience in patients ≥ 75 years of age is limited, and greater sensitivity of some older individuals cannot be excluded

Immune, Blood and Lymphatic System Disorders

Rare

• Anaphylactic reaction

Metabolism and Nutrition Disorders

Common

• Hypoglycaemia in patients with type 2 diabetes

Nervous System Disorders

Very common

• Headache

Common

• Dizziness

Eye Disorders

Common

• Diabetic retinopathy in patients with type 2 diabetes

Cardiac Disorders

Uncommon

• Hypotension
• Orthostatic hypotension
• Increased heart rate

Gastrointestinal Disorders

Very common

• Nausea and vomiting
• Diarrhoea
• Abdominal pain
• Constipation

Common

• Gastritis
• Gastro-oesophageal reflux disease
• Dyspepsia
• Eructation
• Flatulence
• Abdominal distension

Uncommon

• Acute pancreatitis

Hepatobiliary Disorders

Common

• Cholelithiasis

Skin and Subcutaneous Tissue Disorders

Common

• Hair loss

Rare

• Angioedema

General Disorders and Administration Site Conditions

Very common

• Fatigue

Common

• Injection site reactions

Investigations

Uncommon

• Increased amylase
• Increased lipase

 

• No significant interactions

• Body Mass Index (BMI)

Specific cases may require

• International normalised ratio (INR)

Additional observations

• Monitor for worsening diabetic retinopathy

Traceability

• In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded

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 calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. Clinical studies show that semaglutide reduces energy intake, increases feelings of satiety, fullness and control of eating, reduces feelings of hunger, and frequency and intensity of cravings.

GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. Clinical studies show that semaglutide reduces energy intake, increases feelings of satiety, fullness and control of eating, reduces feelings of hunger, and frequency and intensity of cravings. Animal studies show that semaglutide works in the brain through the GLP-1 receptor. Semaglutide has direct effects on areas in the brain involved in homeostatic regulation of food intake in the hypothalamus and the brainstem. Semaglutide affects the hedonic reward system through direct and indirect effects in brain areas including the septum, thalamus and amygdala. Semaglutide has shown an effect to change food intake away from more rewarding high fat and sweet items.

Semaglutide orchestrates the homeostatic and hedonic contributions with executive function to regulate caloric intake, appetite, reward and food choice. In addition, in clinical studies semaglutide was shown to reduce blood glucose in a glucose dependent manner by stimulating insulin secretion and lowering glucagon secretion when blood glucose is high. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. During hypoglycaemia, semaglutide diminishes insulin secretion and does not impair glucagon secretion.

GLP-1 receptors are also expressed in the heart, vasculature, immune system and kidneys. Semaglutide has a beneficial effect on plasma lipids, lowered systolic blood pressure and reduced inflammation in clinical studies. Furthermore, animal studies have shown that semaglutide attenuated the development of atherosclerosis and had an anti-inflammatory action in the cardiovascular system.