Liraglutide

Registered South African indications:

• Glycaemic control in type 2 diabetes mellitus
• Management of weight

Contraindications

South African recommendations

For the indication of glycaemic control in type 2 diabetes mellitus

• Hypersensitivity to liraglutide or any of its excipients
• A history of previous pancreatitis
• Type 1 diabetes mellitus
• Pregnancy
• Lactation

For the indication of management of weight

• Hypersensitivity to liraglutide or to any of the excipients
• Pregnancy
• Lactation

Recommendations in other jurisdictions

• Hypersensitivity to the active substance or to any of the excipients

Cautions

• Pregnancy (Recommendations in other jurisdictions) 
• Breastfeeding (Recommendations in other jurisdictions) 
• Renal impairment (Severe and end-stage renal disease (CrCl <30ml/min) in weight management therapy)
• Hepatic impairment (weight management therapy)
• Severe hepatic impairment (type 2 diabetes mellitus therapy)
• Elderly (≥75 years) (weight management therapy)
• Type 1 diabetes mellitus
• Treatment of diabetic ketoacidosis
• Rapid discontinuation or dose reduction of insulin
• Use as insulin substitute
• Congestive heart failure New York Heart Association (NYHA) class IV
• Inflammatory bowel disease
• Diabetic gastroparesis
• History of pancreatitis
• Thyroid disease
• Dehydrated patients
• Patients treated with other products for weight management
• Obesity secondary to endocrinological or eating disorders
• Obesity secondary to products that may cause weight gain
• May impair ability to drive and operate machinery

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

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Glycaemic control in type 2 diabetes mellitus (Additional agent(s) may be required)
- Adjunct to diet and exercise to achieve glycaemic control in patients with type 2 diabetes mellitus as monotherapy or in combination with one or more oral antidiabetic medicines (metformin, sulphonylureas or a thiazolidinedione) when previous therapy does not achieve adequate glycaemic control

• SC: Initial: 0.6mg, dly; Titrate by 0.6mg at intervals of 1 week to reduce gastrointestinal adverse effects; Maintenance: 1.8mg, dly based on clinical response

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Daily doses higher than 1.8mg are not recommended

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Can be injected in the abdomen, thigh, or upper arm at any time, independent of meals. The injection site and timing can be changed without dose adjustment

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Liraglutide can be added to existing metformin or combined metformin and thiazolidinedione therapy. The current dose of metformin and thiazolidinedione can be continued unchanged

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Liraglutide can be added to existing sulphonylurea or combined metformin and sulfonylurea therapy. The dose of the sulphonylurea may need to be reduced by approximately half to minimize the risk of hypoglycaemia

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Self-monitoring of blood glucose is not needed to adjust the dose of liraglutide, however, it may become necessary when initiating treatment with liraglutide in combination with a sulphonylurea

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Medically supervised chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity in adult patients with an initial body mass index (BMI) of
- ≥30kg/m² (obese), or
- ≥27kg/m² to <30kg/m² (overweight) in the presence of at least one weight-related comorbidity such as dysglycaemia (pre-diabetes or type 2 diabetes mellitus), hypertension, dyslipidaemia or obstructive sleep apnoea

• SC: Initial: 0.6mg, dly; Titrate by 0.6mg at intervals of 1 week to improve gastrointestinal tolerability; Maintenance: 3.0mg, dly

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If escalation to the next dose step is not tolerated for 2 consecutive weeks, consider discontinuing treatment

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Daily doses higher than 3.0mg are not recommended

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If a patient has not lost at least 5% of the initial body weight after 12 weeks on the 3.0mg/day dose, treatment with liraglutide should be discontinued

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Liraglutide (for weight loss) should not be used in combination with another GLP-1 receptor agonist in patients with type 2 diabetes mellitus

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When initiating liraglutide (for weight loss) in patients with type 2 diabetes mellitus, it should be considered to reduce the dose of coadministered insulin or insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycaemia. Blood glucose self-monitoring is necessary to adjust the dose of insulin or insulin-secretagogues

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Liraglutide is for subcutaneous use only. It must not be administered intravenously or intramuscularly

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Liraglutide is administered once daily at any time, independent of meals. It should be injected in the abdomen, thigh or upper arm

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The injection site and timing can be changed without dose adjustment. However, it is preferable that liraglutide is injected around the same time of the day, when the most convenient time of the day has been chosen

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If a dose is missed within 12 hours from when it is usually taken, the patient should take the dose as soon as possible. If there is less than 12 hours to the next dose, the patient should not take the missed dose and resume the once-daily regimen with the next scheduled dose. An extra dose or increase in dose should not be taken to make up for the missed dose

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

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Management of weight as an adjunct to healthy nutrition and physical activity counselling for weight management
- Body weight >60kg and
- Obesity (BMI corresponding to ≥30kg/m² for adults by international cut-off points)
Note: IOTF BMI cut-off points for obesity by sex between 12–18 years* (See additional prescribing points)

Younger than 12 years, and/or ≤60kg

• Not recommended use

12 years and older and >60kg

• See adult dosage

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The dose should be increased until 3.0mg (maintenance dose) or maximum tolerated dose has been reached. Daily doses higher than 3.0mg are not recommended

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Liraglutide is for subcutaneous use only. It must not be administered intravenously or intramuscularly

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Liraglutide is administered once daily at any time, independent of meals. It should be injected in the abdomen, thigh or upper arm

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The injection site and timing can be changed without dose adjustment. However, it is preferable that liraglutide is injected around the same time of the day, when the most convenient time of the day has been chosen

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If a dose is missed within 12 hours from when it is usually taken, the patient should take the dose as soon as possible. If there is less than 12 hours to the next dose, the patient should not take the missed dose and resume the once-daily regimen with the next scheduled dose. An extra dose or increase in dose should not be taken to make up for the missed dose

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For the indication of glycaemic control in type 2 diabetes mellitus liraglutide has not been studied in paediatric patients below 18 years of age

Pregnancy

South African recommendations

For the indication of glycaemic control in type 2 diabetes mellitus

• Contraindicated
• There are no adequate data for use of liraglutide in pregnant women
• Liraglutide crossed the placental barrier in rabbits. Studies in animals have shown reproductive toxicity and liraglutide should therefore not be used during pregnancy
• The use of insulin is recommended. If a patient wishes to become pregnant, or pregnancy occurs, treatment with liraglutide should be discontinued

For the indication of management of weight

• Contraindicated
• The safety of liraglutide in pregnancy has not been established
• Liraglutide should not be used during pregnancy
• If a patient wishes to become pregnant, or pregnancy occurs, treatment with liraglutide should be discontinued

Recommendations in other jurisdictions

• Caution; not recommended
• There are no adequate data from the use of liraglutide in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown
• Liraglutide should not be used during pregnancy, and the use of insulin is recommended instead (for the treatment of insufficiently controlled type 2 diabetes mellitus). If a patient wishes to become pregnant, or pregnancy occurs, treatment with liraglutide should be discontinued

Breastfeeding

South African recommendations

For the indication of glycaemic control in type 2 diabetes mellitus

• Contraindicated
• It is not known whether liraglutide is excreted in human milk
• In lactating rats, up to 3% of the maternal dose was present in breast milk. Women on treatment with liraglutide should not breastfeed

For the indication of management of weight

• Contraindicated
• The safety of liraglutide in lactation has not been established
• Liraglutide should not be used during lactation

Recommendations in other jurisdictions

• Caution; not recommended
• It is not known whether liraglutide is excreted in human milk. Animal studies have shown that the transfer of liraglutide and metabolites of close structural relationship into milk is low. Non-clinical studies have shown a treatment-related reduction of neonatal growth in suckling rat pups. Because of lack of experience, liraglutide should not be used during breastfeeding

Fertility

• Apart from a slight decrease in the number of live implants, animal studies did not indicate harmful effects with respect to fertility

Renal Impairment

Type 2 diabetes mellitus therapy

• No dose adjustment recommended
  There is no therapeutic experience in patients with end-stage renal disease, and liraglutide is therefore not recommended for use in these patients 

Weight management therapy

• Mild to moderate (CrCl ≥30ml/min): No dose adjustment recommended
• Severe and end-stage renal disease (CrCl <30ml/min): Caution; no dose adjustment recommended
  Liraglutide is not recommended for use in patients with severe renal impairment including patients with end-stage renal disease

Hepatic Impairment

Type 2 diabetes mellitus therapy

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  Liraglutide is not recommended for use in patients with severe hepatic impairment

Weight management therapy

• Caution; no dose adjustment recommended
  Liraglutide is not recommended for use in patients with severe hepatic impairment and should be used cautiously in patients with mild or moderate hepatic impairment

Elderly

Type 2 diabetes mellitus therapy

• No dose adjustment recommended

Weight management therapy

• Caution; no dose adjustment recommended
  Therapeutic experience in patients ≥75 years of age is limited and use in these patients is not recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache 
• Dizziness
• Insomnia
• Dysgeusia 
• Fatigue 

Cardiovascular Disorders

• Increased heart rate/ tachycardia 

Respiratory Disorders

• Nasopharyngitis 
• Bronchitis 

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea 
• Constipation 
• Dry mouth 
• Dyspepsia 
• Gastritis 
• Gastro-oesophageal reflux disease 
• Upper abdominal pain 
• Flatulence 
• Eructation 
• Abdominal distension 
• Pancreatitis (including necrotising pancreatitis) 
• Increased lipase 
• Increased amylase 
• Toothache 
• Delayed gastric emptying 
• Intestinal obstruction 

Hepatobiliary Disorders

• Cholelithiasis 
• Cholecystitis 

Genitourinary Disorders

• Acute renal failure 
• Renal impairment 

Endocrine and Metabolic Disorders

• Hypoglycaemia
• Dehydration
• Anorexia 
• Decreased appetite 

Skin and Subcutaneous Tissue Disorders

• Rash 
• Urticaria 
• Pruritus 
• Injection site reactions 

Immune System Disorders

• Anaphylactic reactions

• Warfarin
• Coumarin derivatives
• Paracetamol
• Atorvastatin
• Griseofulvin
• Digoxin
• Lisinopril

• Blood glucose
• Hb1Ac
• Renal function
• Triglycerides
• Heart rate

Specific cases may require

• International Normalised Ratio  (when coadministered with warfarin)
• Body weight (at week 16 when used for chronic weight management)

Additional observations

• Signs and symptoms of
  - Pancreatitis
  - Gallbladder disease
• Emergence of worsening depression
• Suicidal thoughts/behaviour
• Changes in behaviour

IOTF BMI cut-off points for obesity by sex between 12–18 years

Age (years)	Body mass index 30kg/m2
	Males	Females
12	26.02	26.67
12.5	26.43	27.24
13	26.84	27.76
13.5	27.25	28.20
14	27.63	28.57
14.5	27.98	28.87
15	28.30	29.11
15.5	28.60	29.29
16	28.88	29.43
16.5	29.14	29.56
17	29.41	29.69
17.5	29.70	29.84
18	30.00	30.00

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 

Incompatibilities

• Substances added to liraglutide may cause degradation of liraglutide
• Liraglutide must not be mixed with other medicinal products, e.g. infusion fluids

Hypoglycaemia

• Patients receiving liraglutide in combination with a sulfonylurea or insulin may have an increased risk of hypoglycaemia 
• The risk of hypoglycaemia can be lowered by a reduction in the dose of sulfonylurea or insulin 

Liraglutide is a GLP-1 analogue with 97% sequence homology to human GLP-1 that binds to and activates the GLP-1 receptor. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells. Unlike native GLP-1, liraglutide has a pharmacokinetic and pharmacodynamic profile in humans suitable for once daily administration. Following subcutaneous administration, the protracted action profile is based on three mechanisms: self-association, which results in slow absorption; binding to albumin; and higher enzymatic stability towards the dipeptidyl peptidase -4 (DPP-4) and neutral endopeptidase (NEP) enzymes, resulting in a long plasma half-life.

Liraglutide action is mediated via a specific interaction with GLP-1 receptors, leading to an increase in cyclic adenosine monophosphate (cAMP). Liraglutide stimulates insulin secretion in a glucose-dependent manner. Simultaneously, liraglutide lowers inappropriately high glucagon secretion, also in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. Conversely, during hypoglycaemia liraglutide diminishes insulin secretion and does not impair glucagon secretion. The mechanism of blood glucose-lowering also involves a minor delay in gastric emptying. Liraglutide reduces body weight and body fat mass through mechanisms involving reduced hunger and lowered energy intake, GLP-1 is a physiological regulator of appetite and food intake, but the exact mechanism of action is not entirely clear.

In animal studies, peripheral administration of liraglutide led to uptake in specific brain regions involved in regulation of appetite, where liraglutide via specific activation of the GLP-1 receptor (GLP-1R) increased key satiety and decreased key hunger signals, thereby leading to lower body weight. GLP-1 receptors are also expressed in specific locations in the heart, vasculature, immune system, and kidneys. In mouse models of atherosclerosis, liraglutide prevented aortic plaque progression and reduced inflammation in the plaque. In addition, liraglutide had a beneficial effect on plasma lipids. Liraglutide did not reduce the plaque size of already established plaques.

Disposable pen (per ml) 6mg

• Victoza (Novo Nordisk) originator
• Saxenda (Novo Nordisk) originator