Insulin Degludec/ Liraglutide

Registered South African indications:

• Diabetes mellitus

Contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment (mild to moderate)
• Porphyria
• Type 1 diabetes mellitus
• Treatment of diabetic ketoacidosis
• Omission of a meal
• Unplanned strenuous physical exercise
• Adrenal, pituitary or thyroid gland disease
• Blood glucose control is greatly improved (e.g. by intensified therapy)
• Long-standing diabetes mellitus
• Inadequate dosing
• Discontinuation of antidiabetic therapy
• Concomitant illness, especially infections
• Untreated hyperglycaemic events
• Change in the injection site
• Diabetic retinopathy
• Pre-existing thyroid disease
• Inflammatory bowel disease
• Diabetic gastroparesis
• Patients with poor vision
• Transfer from doses of basal insulin <20 and >50 units
• Congestive heart failure New York Heart Association (NYHA) class IV 
• Coadministration with piogliatazone, especially in patients with risk factors for development of cardiac failure 
• May impair ability to drive and operate machinery

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

Insufficiently controlled type 2 diabetes mellitus
- To improve glycaemic control as an adjunct to diet and exercise in addition to other oral medicinal products for the treatment of diabetes

One dose step = 1 unit insulin degludec/ 0.036mg liraglutide

Add-on to oral glucose lowering medicines

• SC (inj): Initial: 10 dose steps (10 units insulin degludec and 0.36mg liraglutide); Max: 50 dose steps (50 units insulin degludec and 1.8mg liraglutide)/24hrs
• See link: General prescribing points on the principles of insulin dosing

Insulin degludec/ liraglutide is to be dosed in accordance with the individual patient's needs. It is recommended to optimise glycaemic control via dose adjustment based on fasting plasma glucose

Insulin degludec/ liraglutide can be administered at any time of the day, preferably at the same time of the day

When Insulin degludec/ liraglutide is added to sulfonylurea therapy, a reduction in the dose of sulfonylurea should be considered

See additional prescribing points for transfer from other therapies

Adjustment of dose may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness

Patients who forget a dose are advised to take it upon discovery and then resume their usual once-daily dosing schedule. A minimum of 8hrs between injections should always be ensured. This also applies when administration at the same time of the day is not possible

Not established for use in children 

Pregnancy

• Caution; not recommended
• There is no clinical experience with the use of insulin degludec/ liraglutide, insulin degludec or liraglutide in pregnant women. If a patient wishes to become pregnant, or pregnancy occurs, treatment with insulin degludec/ liraglutide should be discontinued
• Animal reproduction studies with insulin degludec have not revealed any differences between insulin degludec and human insulin regarding embryotoxicity and teratogenicity. Animal studies with liraglutide have shown reproductive toxicity. The potential risk for humans is unknown

Breastfeeding

• Caution; not recommended
• There is no clinical experience with the use of insulin degludec/ liraglutide during breastfeeding. It is not known whether insulin degludec or liraglutide is excreted in human milk. Because of lack of experience, insulin degludec/ liraglutide should not be used during breastfeeding
• In rats, insulin degludec was secreted in milk; the concentration in milk was lower than in plasma. Animal studies have shown that the transfer of liraglutide and metabolites of close structural relationship into milk was low. Non-clinical studies with liraglutide have shown a treatment-related reduction of neonatal growth in suckling rat pups

Fertility

• There is no clinical experience with insulin degludec/ liraglutide in relation to fertility
• Animal reproduction studies with insulin degludec have not revealed any adverse effects on fertility. Apart from a slight decrease in the number of live implants, animal studies with liraglutide did not indicate harmful effects with respect to fertility

Renal Impairment

• Mild, moderate and severe: Caution; dose adjustment recommended
  When insulin degludec/ liraglutide is used in patients with mild, moderate or severe renal impairment, glucose monitoring is to be intensified and the dose adjusted on an individual basis
• End-stage renal disease: Not recommended for use

Hepatic Impairment

• Mild to moderate: Caution; dose adjustment recommended
  Insulin degludec/ liraglutide can be used in patients with mild or moderate hepatic impairment. Glucose monitoring is to be intensified and the dose adjusted on an individual basis
• Severe: Not recommended for use
  Due to the liraglutide component, Insulin degludec/ liraglutide is not recommended for use in patients with severe hepatic impairment 

Elderly

• Caution; dose adjustment recommended
  Glucose monitoring should be intensified and the dose adjusted on an individual basis 

Porphyria Information

• Probably not porphyrinogenic (PNP) 

Drugs in Sport

• Prohibited - At all times 

Central Nervous System Disorders

• Unconsciousness
• Seizures
• Temporary or permanent impairment of brain function (or even death) 
• Fatigue
• Nervousness
• Tremor
• Anxiousness
• Unusual tiredness/ weakness
• Confusion
• Difficulty in concentration
• Drowsiness
• Headache

Cardiovascular Disorders

• Increased heart rate
• Hypotension 
• Heart failure (when coadministered with pioglitazone)

Respiratory Disorders

• Dyspnoea

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Constipation
• Dyspepsia
• Gastritis
• Abdominal pain
• Gastroesophageal reflux disease
• Abdominal distension
• Eructation
• Flatulence
• Pancreatitis (including necrotising pancreatitis)

Hepatobiliary Disorders

• Cholelithiasis
• Cholecystitis

Endocrine and Metabolic Disorders

• Hypoglycaemia
• Decreased appetite
• Dehydration
• Increased lipase
• Increased amylase
• Excessive hunger
• Hyperglycaemia (inadequate dosing) 
  - Thirst
  - Increased frequency of urination
  - Nausea and vomiting
  - Drowsiness
  - Flushed dry skin
  - Dry mouth
  - Loss of appetite
  - Acetone odour of breath
• Hyperosmolar coma
• Weight gain (when coadministered with pioglitazone)

Skin and Subcutaneous Tissue Disorders

• Urticaria
• Rash
• Pruritus
• Acquired lipodystrophy
• Cutaneous amyloidosis
• Injection site reactions
  - Haematoma
  - Pain
  - Haemmorrhage
  - Erythema
  - Nodules
  - Swelling
  - Discolouration
  - Pruritus
  - Warmth
  - Injection site mass
  - Cutaneous amyloidosis
• Cold sweats
• Cool pale skin
• Swelling of face
• Lipodystrophy 
  - Lipohypertrophy 
  - Lipoatrophy 

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Anaphylactic reactions
• Oedema
  - Peripheral oedema

Sensory Disorders

• Vision changes
• Temporary worsening of diabetic retinopathy 

• Antidiabetic medicinal products
• Monoamine oxidase inhibitors (MAOI)
• Beta-blockers
• Angiotensin converting enzyme (ACE) inhibitors
• Salicylates
• Anabolic steroids
• Sulfonamides
• Oral contraceptives
• Thiazides
• Glucocorticoids
• Thyroid hormones
• Sympathomimetics
• Growth hormones
• Danazol
• Octreotide/ lanreotide
• Warfarin
• Coumarin derivatives
• Paracetamol 
• Atorvastatin 
• Griseofulvin 
• Digoxin 
• Lisinopril 
• Oral contraceptives 

Other interactions

• Alcohol

• Blood glucose
• Electrolytes
• HbA1c
• Renal function
• Hepatic function
• Weight
• Triglycerides

Specific cases may require

• International Normalised Ratio (INR) (when coadministered with coumarin derivatives)

Additional observations

• Signs and symptoms of
  - Pancreatitis
  - Gallbladder disease
  - Heart failure
  - Weight gain
  - Oedema

Administration directions

• DO NOT administer IV or IM
• Insulin degludec/ liraglutide is administered SC by injection in the thigh, the upper arm or the abdomen
• Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis
• Insulin degludec/ liraglutide must not be drawn from the cartridge of the pre-filled pen into a syringe
• Patients should be instructed to always use a new needle. The re-use of insulin pen needles increases the risk of blocked needles, which may cause under- or overdosing

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

Transfer from GLP-1 receptor agonist

• Therapy with GLP-1 receptor agonists should be discontinued prior to initiation of insulin degludec/ liraglutide
• When transferring from a GLP-1 receptor agonist, the recommended starting dose of insulin degludec/ liraglutide is 16 dose steps (16 units insulin degludec and 0.6 mg liraglutide)
• The recommended starting dose should not be exceeded. If transferring from a long-acting GLP-1 receptor agonist (e.g. once-weekly dosing), the prolonged action should be considered
• Treatment with insulin degludec/ liraglutide should be initiated at the moment the next dose of the long-acting GLP-1 receptor agonist would have been taken
• Close glucose monitoring is recommended during the transfer and in the following weeks

Transfer from any insulin regimen that includes a basal insulin component

• Therapy with other insulin regimens should be discontinued prior to initiation of insulin degludec/ liraglutide
• When transferring from any other insulin therapy that includes a basal insulin component, the recommended starting dose of insulin degludec/ liraglutide is 16 dose steps (16 units insulin degludec and 0.6 mg liraglutide)
• The recommended starting dose should not be exceeded, but may be reduced to avoid hypoglycaemia in selected cases
• Close glucose monitoring is recommended during the transfer and in the following weeks

Avoidance of medication errors

• Patients must be instructed to always check the pen label before each injection to avoid accidental mix-ups between insulin degludec/ liraglutide and other injectable diabetes medicinal products
• Patients must visually verify the dialed units on the dose counter of the pen. Therefore, the requirement for patients to self-inject is that they can read the dose counter on the pen
• Patients who are blind or have poor vision must be instructed to always get help/assistance from another person who has good vision and is trained in using the insulin device
• To avoid dosing errors and potential overdose, patients and healthcare professionals should never use a syringe to draw the medicinal product from the cartridge in the pre-filled pen
• In the event of blocked needles, patients must follow the instructions described in the instructions for use accompanying the package leaflet

Insulin degludec/ liraglutide is a combination product consisting of insulin degludec and liraglutide having complementary mechanisms of action to improve glycaemic control. Insulin degludec is a basal insulin that forms soluble multi-hexamers upon subcutaneous injection, resulting in a depot from which insulin degludec is continuously and slowly absorbed into the circulation leading to a flat and stable glucose-lowering effect of insulin degludec with a low day-to-day variability in insulin action. Insulin degludec binds specifically to the human insulin receptor and results in the same pharmacological effects as human insulin. The blood glucose-lowering effect of insulin degludec is due to the facilitated uptake of glucose following the binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.

Liraglutide is a Glucagon-Like Peptide-1 (GLP-1) analogue with 97% sequence homology to human GLP-1 that binds to and activates the GLP-1 receptor (GLP-1R). 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 IV (DPP-IV) and neutral endopeptidase (NEP) enzymes, resulting in a long plasma half-life. Liraglutide action is mediated via a specific interaction with GLP-1 receptors and improves glycaemic control by lowering fasting and postprandial blood glucose. Liraglutide stimulates insulin secretion and lowers inappropriately high glucagon secretion 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-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.

COMBINATION PREPARATIONS

Insulin Degludec / Liraglutide

Injection (per ml) 100u/3.6mg

• Xultophy (Novo Nordisk) originator