Insulin Aspart/ Insulin Aspart Protamine

Registered South African indications:

• Diabetes mellitus

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypoglycaemia
• Intravenous administration

Cautions

• Pregnancy
• Severe renal impairment or ESRD
• Hepatic impairment
• Elderly
• Patients >75 years
• Intramuscular administration
• Risk factors for cardiac heart failure
• Hyperglycaemia
• Diabetic ketoacidosis
• Untreated hyperglycaemic events
• Conditions masking early warning symptoms of hypoglycaemia (e.g. intensified insulin therapy)
• Concomitant illness, especially infections and feverish conditions
• Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland
• Concomitant diseases or treatment where a delayed absorption of food is expected
• Presence of insulin antibodies
• Patients transferred between different types of insulin medicinal products
• Omission of a meal
• Unplanned, strenuous physical exercise
• Patient travelling between different time zones
• May impair ability to drive and operate machinery (as a result of hypoglycaemia)

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

Insulin-dependent diabetes mellitus 

• SC (inj): Initial: 0.4-0.5 units/kg/day; Maintenance range: 0.4-1.0 unit/kg/day in divided doses
• See link: General prescribing points on the principles of insulin dosing

For patients at higher risk of hypoglycaemia (on oral hypoglycaemic agents, malnutrition, elderly, and low cognitive status), conservative initial doses of 0.2 to 0.4 units/kg/day may be considered to avoid the potential for hypoglycaemia

Higher initial doses may be required in patients who are obese, sedentary, or presenting with ketoacidosis

The dosage should be determined according to the individual requirement of the patient

 Can be given as monotherapy or in combination with oral antidiabetic medicinal products and/or GLP-1 agonists

Insulin aspart/ Insulin aspart protamine should only be given by subcutaneous injection and never intravenously

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

Insulin-dependent diabetes mellitus 

• See link: General prescribing points on the principles of insulin dosing

Can be used in adolescents and children aged 10 years and above when premixed insulin is preferred

There is limited clinical experience with use in children aged 6–9 years and no data are available for use in children below 6 years

The dosage should be determined according to the individual requirement of the patient

Insulin aspart/ Insulin aspart protamine should only be given by subcutaneous injection and never intravenously

Pregnancy

• Caution
• There is limited clinical experience with insulin aspart/ Insulin aspart protamine in pregnancy
• Animal reproduction studies have not revealed any differences between insulin aspart and human insulin regarding embryotoxicity or teratogenicity
• Intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy
• Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimesters. After delivery, insulin requirements return rapidly to pre-pregnancy levels

Breastfeeding

• Compatible
• There are no restrictions on use during breastfeeding
• Insulin treatment of the breastfeeding mother presents no risk to the baby

Fertility

• Animal reproduction studies have not revealed any differences between insulin aspart and human insulin regarding fertility

Renal impairment

• eGFR ≥30-89 ml/min/1.73 m²: No dose adjustment recommended
• eGFR ≤29 ml/min/1.73 m² or ESRD: Caution; dose adjustment recommended
  Reduce recommended dose by up to 20%
  Monitor glucose target and renal function

Hepatic impairment

• Mild to moderate (Child-Pugh Classes A & B): Caution; no dose adjustment recommended
• Severe (Child-Pugh Class C): Caution; dose adjustment recommended
  Adjust insulin dose according to blood glucose target

Elderly

• Caution; dose adjustment recommended
  Conservative initial dose is required to avoid risk for hypoglycaemia
  Reduce the initial recommended dose by 10% to 20%
  Avoid intensive glucose control (risk for hypoglycaemia and CVS-related mortality)
  Control of geriatric patient's blood glucose needs to be individualised
  In cases of severe hypoglycaemia, dosage reductions of 20% to 40% have been recommended
• >75 years: Caution; no information available

Porphyria information

• Not porphyrinogenic (NP)

Drugs in sport

• Prohibited - At all times

Central Nervous System Disorders

• Peripheral neuropathy (painful neuropathy)

Cardiovascular Disorders

• Heart failure

Endocrine and Metabolic Disorders

• Hypoglycaemia
  - Cold sweats
  - Cool pale skin
  - Fatigue
  - Nervousness or tremor
  - Anxiousness
  - Unusual tiredness or weakness
  - Confusion
  - Difficulty in concentration
  - Drowsiness
  - Excessive hunger
  - Vision changes
  - Headache
  - Nausea
  - Palpitation
• Weight gain

Skin and Subcutaneous Tissue Disorders

• Urticaria
• Rash
• Eruptions
• Lipodystrophy
• Injection site reactions
  - Pain
  - Redness
  - Hives
  - Inflammation
  - Bruising
  - Swelling
  - Itching

Immune, Blood and Lymphatic System Disorders

• Anaphylactic reactions
  - Generalised skin rash
  - Itching
  - Sweating
  - Gastrointestinal upset
  - Angioneurotic oedema
  - Difficulties in breathing
  - Palpitation
  - Decreased blood pressure
• Oedema

Sensory Disorders

• Refraction disorders
• Diabetic retinopathy

• Agents known to increase and decrease insulin requirements
• Oral contraceptives
• Thiazides
• Glucocorticoids
• Thyroid hormones
• Sympathomimetics
• Growth hormone
• Danazol
• Oral antidiabetic agents
• GLP-1 receptor agonists
• Monoamine oxidase inhibitors (MAOI)
• Beta-blockers
• Angiotensin converting enzyme (ACE) inhibitors
• Angiotensin receptor blockers (ARBs)
• Salicylates
• Anabolic steroids
• Sulphonamides
• Pioglitazone
• Octreotide
• Lanreotide
• Alcohol

Diabetes mellitus 

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

Gestational diabetes mellitus 

• Blood glucose 4 times daily (1 fasting and 3 postprandial) until well-controlled

Dosing

• Insulin aspart/ Insulin aspart protamine is a biphasic suspension of 30% soluble insulin aspart (rapid-acting human insulin analogue) and 70% protamine-crystallised insulin aspart (intermediate-acting human insulin analogue)
• When injected subcutaneously, the onset of action will occur within 10 to 20 minutes of injection allowing it to be given immediately before a meal and, when necessary, soon after a meal
• Blood glucose monitoring and insulin dose adjustments are recommended to achieve optimal glycaemic control
• Adjustment of dose may be necessary if patients undertake increased physical activity, change their usual diet or during
  concomitant illness

Transfer from other insulin medicinal products

• Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type, origin (animal insulin, human insulin or insulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in the need for a change in dose
• Patients transferred to insulin aspart/ Insulin aspart protamine from another type of insulin may require an increased number of daily injections or a change in dose from that used with their usual insulin medicinal products
• If an adjustment is needed, it may occur with the first dose or during the first few weeks or months

Method of administration

• Insulin aspart/ Insulin aspart protamine is for subcutaneous administration only in the thigh or in the abdominal wall. If convenient, the gluteal or deltoid region may be used
• Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy  
• The influence of different injection sites on absorption has not been investigated. The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity
• Insulin suspensions are not to be used in insulin infusion pumps

Avoidance of medication errors

• Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between insulin aspart/ Insulin aspart protamine and other insulin products

Incompatibilities

• In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products

Special precautions for storage and handling

• Before opening, store in a refrigerator (2°C – 8°C). Do not freeze. Protect from light
• During use or when carried as a spare, store below 30°C for up to 4 weeks. 
• Avoid exposure to heat and sunlight
• Keep the cartridge in the outer carton and keep the cap on in order to protect it from light
• After removing products from the refrigerator, it is recommended to allow the product to reach room temperature before resuspending the insulin as instructed for first time use
• The necessity of resuspending the insulin aspart/ insulin aspart protamine suspension immediately before use is to be stressed to the patient
• Do not use this medicinal product if the resuspended liquid is not uniformly white, cloudy and aqueous
• Insulin aspart/ insulin aspart protamine which has been frozen must not be used
• The patient should be advised to discard the needle after each injection and needles, cartridges and pre-filled pens must not be shared

The blood glucose lowering effect of insulin aspart is due to the facilitated uptake of glucose following binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.

Insulin aspart/ Insulin aspart protamine is a biphasic insulin, which contains 30% soluble insulin aspart with a rapid onset of action. In insulin aspart, substitution of amino acid proline with aspartic acid at position B28 reduces the tendency to form hexamers as observed with soluble human insulin. The crystalline phase (70%) consists of protamine-crystallised insulin aspart, which has an activity profile similar to that of human NPH insulin.

COMBINATION PREPARATIONS

30% Insulin Aspart/ 70% Insulin Aspart Protamine

Injection (per ml) 100u

• NovoMix 30 (Novo Nordisk)