Insulin Aspart

Insulin aspart is a rapid-acting analogue of human insulin. Replacing the proline at position B28 with aspartic acid reduces the tendency of insulin molecules to form hexamers, so the injected insulin is absorbed faster and acts sooner and for a shorter time than soluble human insulin. Its blood glucose-lowering effect comes from facilitated glucose uptake after insulin binds to receptors on muscle and fat cells, together with inhibition of glucose output from the liver. Three EU formulations differ in their time-action profile: NovoRapid (the originator product), Fiasp and the premixed NovoMix 30.

Mechanism of Action

• Receptor binding: insulin aspart binds to the insulin receptor and activates its tyrosine kinase. The receptor phosphorylates intracellular substrates such as the insulin receptor substrate proteins, which switches on PI3 kinase and Akt and, through them, the glucose transporter GLUT4.
• Why it acts quickly: only insulin monomers can bind to the receptor. Human insulin is stored as hexamers, which must first dissociate; the B28 substitution weakens hexamer formation and so gives faster absorption and onset and a shorter duration.
• NovoRapid: a more rapid onset than soluble human insulin, with lower glucose concentrations in the first four hours after a meal. After subcutaneous injection the onset is within 10 to 20 minutes, the maximum effect between 1 and 3 hours, and the duration 3 to 5 hours. On a molar basis it is equipotent to soluble human insulin.
• Fiasp: a mealtime formulation of insulin aspart with added nicotinamide (vitamin B3), which makes the initial absorption faster than with NovoRapid. The onset of action was 5 minutes earlier, and the time to the maximum glucose infusion rate 11 minutes earlier, than with NovoRapid. The glucose-lowering effect in the first 30 minutes was greater, the total and maximum effects were comparable, the maximum effect occurred between 1 and 3 hours after injection, and the duration was shorter, lasting 3 to 5 hours.
• NovoMix 30: a biphasic suspension of 30% soluble insulin aspart, which acts rapidly and allows injection within 0 to 10 minutes of a meal, and 70% protamine-crystallised insulin aspart, whose activity profile resembles human NPH insulin. After subcutaneous injection the onset is within 10 to 20 minutes, the maximum effect between 1 and 4 hours, and the duration up to 24 hours.

Pharmacokinetics

• Absorption (NovoRapid): the time to maximum concentration is on average half that of soluble human insulin. In type 1 diabetes a subcutaneous dose of 0.15 unit/kg gave a mean maximum concentration of 492 ± 256 pmol/L after about 40 minutes (interquartile range 30–40), with concentrations back to baseline 4 to 6 hours after the dose. Absorption was somewhat slower in type 2 diabetes (maximum 352 ± 240 pmol/L after about 60 minutes). The variability between injections in time to maximum concentration is significantly lower than with soluble human insulin.
• Absorption (Fiasp): the added nicotinamide gives a faster initial absorption than NovoRapid, which explains the earlier onset of action.
• Distribution and elimination: binding to plasma proteins is low (under 10%), as with human insulin. The elimination half-life after subcutaneous injection in healthy subjects was about 81 minutes.
• Special populations: in elderly patients absorption is slower (time to maximum about 82 minutes, interquartile range 60–120) with a similar maximum concentration. In hepatic impairment absorption is slower and more variable, delaying the time to maximum from about 50 to about 85 minutes in moderate and severe impairment, while total exposure and maximum concentration are similar. Renal function had no apparent effect on exposure, maximum concentration or time to maximum.

• NovoRapid and Fiasp: treatment of diabetes mellitus in adults, adolescents and children aged 1 year and above.
• NovoMix 30 (premixed): treatment of diabetes mellitus in adults, adolescents and children aged 10 years and above.
• Biosimilars: Kirsty and Dazparda are authorised in the EU as biosimilar insulin aspart medicines. Their indications, doses and storage are given in their own SmPCs, which this page does not reproduce.
• Fixed-dose combination: insulin aspart is also a component of Ryzodeg (insulin degludec/insulin aspart), which has its own SmPC.

• Hypersensitivity to insulin aspart or to any of the excipients (NovoRapid, Fiasp and NovoMix 30).

Adverse reactions are mainly due to the pharmacological effect of insulin, and hypoglycaemia is the most frequently reported. The frequencies below follow the NovoRapid and NovoMix 30 SmPCs, which list the same reactions; reactions specific to Fiasp are marked.

Very common (≥1/10): hypoglycaemia (all three products).

Common (≥1/100 to <1/10): Fiasp only: allergic skin manifestations (eczema, rash, itchy rash, urticaria, dermatitis; 1.8% against 1.5% with the comparator) and injection or infusion site reactions (1.3% against 1.0%; in pump users 10.0% against 8.3%).

Uncommon (≥1/1,000 to <1/100): NovoRapid and NovoMix 30: urticaria, rash and eruptions; refraction disorders; diabetic retinopathy; lipodystrophy; injection site reactions; oedema. Fiasp: hypersensitivity (generalised rash and facial oedema, 0.2% against 0.3% with the comparator) and lipodystrophy (0.5% against 0.2%).

Rare (≥1/10,000 to <1/1,000): NovoRapid and NovoMix 30: peripheral neuropathy (painful neuropathy).

Very rare (<1/10,000): NovoRapid and NovoMix 30: anaphylactic reactions.

Not known: cutaneous amyloidosis (from postmarketing reports, all three products); Fiasp: anaphylactic reactions.

At the start of insulin treatment, refraction anomalies, oedema and injection site reactions (pain, redness, hives, inflammation, bruising, swelling, itching) may occur and are usually transitory. A rapid improvement in blood glucose control may be associated with acute painful neuropathy, which is usually reversible. Intensifying insulin therapy with an abrupt improvement in control may temporarily worsen diabetic retinopathy, while long-term improved control lowers the risk of progression.

Serious reactions: severe hypoglycaemia can lead to unconsciousness or convulsions, temporary or permanent impairment of brain function, and even death. Its symptoms usually start suddenly and include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiety, unusual tiredness or weakness, confusion, difficulty concentrating, drowsiness, excessive hunger, vision changes, headache, nausea and palpitations. Generalised hypersensitivity (rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulty breathing, palpitations, low blood pressure) is very rare but can be life-threatening. Lipodystrophy and cutaneous amyloidosis at the injection site can delay local insulin absorption.

A number of medicinal products affect glucose metabolism, so the insulin dose may need adjusting. The list below is from the NovoRapid SmPC; the Fiasp and NovoMix 30 SmPCs give their own.

• May reduce insulin requirement: oral antidiabetic medicines, monoamine oxidase inhibitors (MAOIs), beta-blockers, ACE inhibitors, salicylates, anabolic steroids and sulfonamides.
• May increase insulin requirement: oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.
• Beta-blockers may mask the symptoms of hypoglycaemia.
• Octreotide and lanreotide may either increase or decrease the insulin requirement.
• Alcohol may intensify or reduce the hypoglycaemic effect of insulin.
• Meals: changes in meal composition may alter the response to insulin aspart, and the dose may need adjusting.

Dosing is individual, set by the treating doctor according to the patient’s needs, with blood glucose monitoring and dose adjustment to reach good glycaemic control. The potency of insulin analogues is expressed in units, whereas that of human insulin is expressed in international units; for Fiasp, 1 unit corresponds to 1 international unit of human insulin or 1 unit of other fast-acting insulin analogues. The dose may need adjusting if the patient is more physically active, changes the usual diet or has another illness.

NovoRapid

• Regimen: normally used together with an intermediate-acting or long-acting insulin. The individual insulin requirement in adults and children is usually 0.5 to 1.0 unit/kg a day; in a basal-bolus regimen 50–70% of it may be provided by NovoRapid and the rest by the longer-acting insulin.
• Timing: given in immediate relation to a meal. After injection into the abdominal wall the onset is within 10–20 minutes, the maximum effect between 1 and 3 hours and the duration 3 to 5 hours.
• Pumps and intravenous use: the vial and the PumpCart cartridge can be used for continuous subcutaneous insulin infusion (CSII) in pump systems. The vial can also be used for intravenous administration by physicians or other healthcare staff.
• Transfer from other insulins: NovoRapid has a faster onset and shorter duration than soluble human insulin, and the dose of NovoRapid and of the basal insulin may need adjusting.

Fiasp

• Timing: injected subcutaneously up to 2 minutes before the start of a meal, with the option of giving it up to 20 minutes after starting the meal. The early onset of action must be considered when prescribing.
• Regimen: used with an intermediate- or long-acting insulin given at least once a day; in a basal-bolus regimen about 50% of the requirement may be provided by Fiasp. The total daily insulin requirement is usually 0.5 to 1 unit/kg.
• Starting dose, type 1 diabetes (insulin-naive patients): about 50% of the total daily insulin dose, divided between meals by their size and composition, with the rest as an intermediate- or long-acting insulin. As a general rule 0.2 to 0.4 units/kg is used to calculate the initial total daily dose.
• Starting dose, type 2 diabetes: 4 units at one or more meals is suggested.
• Missed mealtime dose (basal-bolus therapy): check blood glucose to decide whether a dose is needed, and resume the usual schedule at the next meal.
• Pumps: Fiasp is also supplied as a PumpCart cartridge and a vial that can be used in insulin infusion pumps. See the Fiasp SmPC for titration, special populations and instructions for pump and intravenous use.

NovoMix 30

• Type 2 diabetes: can be given alone or with oral antidiabetic medicines and/or GLP-1 receptor agonists. The recommended starting dose is 6 units at breakfast and 6 units at dinner (evening meal), or 12 units once daily at dinner. Once-daily dosing is generally moved to twice daily on reaching 30 units, by splitting the dose equally between breakfast and dinner. If twice-daily dosing causes recurrent daytime hypoglycaemia, the morning dose can be split into morning and lunchtime doses (three times daily).
• Weekly titration: use the lowest of the previous three days’ pre-meal glucose readings, and do not raise the dose if hypoglycaemia occurred in those days. Below 4.4 mmol/L (80 mg/dL), reduce by 2 units; 4.4–6.1 mmol/L (80–110 mg/dL), no change; 6.2–7.8 mmol/L (111–140 mg/dL), add 2 units; 7.9–10 mmol/L (141–180 mg/dL), add 4 units; above 10 mmol/L (180 mg/dL), add 6 units. Adjust once a week until the HbA1c target is reached.
• Adding a GLP-1 receptor agonist: reduce the NovoMix 30 dose by 20% if HbA1c is below 8%; if it is above 8%, a reduction should be considered. The dose is then adjusted individually.
• Type 1 diabetes: the insulin requirement is usually 0.5 to 1.0 unit/kg a day, which NovoMix 30 may meet fully or in part.
• Timing: the rapid-acting part allows injection closer to a meal than soluble human insulin, within 0 to 10 minutes of the meal. NovoMix 30 is for adults, adolescents and children aged 10 years and above.

Special Populations

• Elderly (65 years and over): NovoRapid can be used; intensify glucose monitoring and adjust the dose individually.
• Renal or hepatic impairment: insulin requirements may be reduced; intensify glucose monitoring and adjust the dose individually (NovoRapid).
• Children and adolescents: NovoRapid and Fiasp can be used from 1 year of age. NovoRapid is preferred over soluble human insulin when a rapid onset may help, for example in timing injections relative to meals. NovoMix 30 is for children from 10 years. The safety and efficacy of NovoRapid below 1 year of age have not been established (no data are available).
• Fiasp and NovoMix 30: their SmPCs give their own advice for special populations and for transfer from other insulins.

Hypoglycaemia

• Omitting a meal or unplanned strenuous exercise may lead to hypoglycaemia, as may an insulin dose that is too high for the requirement. If hypoglycaemia occurs or is suspected, NovoRapid must not be injected; once blood glucose has stabilised, the dose should be reconsidered.
• In children, doses (especially in basal-bolus regimens) should be matched to food intake, physical activity and the current blood glucose level.
• Warning symptoms may change or become less marked in patients whose control is greatly improved by intensified therapy, after a change between insulins, and may disappear in long-standing diabetes.
• With rapid-acting analogues hypoglycaemia may occur earlier after an injection than with soluble human insulin. Because NovoRapid is given in immediate relation to a meal, this matters in patients with other diseases or treatments that may delay the absorption of food. With Fiasp, hypoglycaemia may occur earlier than with other mealtime insulins because of its earlier onset.

Hyperglycaemia

Inadequate dosing or stopping treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis, which is potentially lethal. The first symptoms develop gradually over hours or days: thirst, frequent urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite and an acetone smell on the breath.

Illness, Travel and Transfer Between Insulins

• Illness, especially infection and fever, usually increases insulin requirements. Kidney or liver disease, and diseases of the adrenal, pituitary or thyroid gland, can also call for dose changes.
• Patients should seek the doctor’s advice before travelling between time zones, because insulin and meals may have to be taken at different times.
• Changing to another type or brand of insulin must be done under strict medical supervision. Changes in strength, brand, type, origin or method of manufacture may need a different dose; patients moved to NovoRapid may need more daily injections or a different dose, and early warning symptoms of hypoglycaemia may change.

Injection Site and Skin

Lipodystrophy (including lipohypertrophy and lipoatrophy) and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the injection area helps to reduce or prevent these reactions.

NovoRapid PumpCart

The PumpCart cartridge is only for use with an insulin infusion pump system designed for it, such as the Accu-Chek Insight and YpsoPump insulin pumps. Used with other devices it may cause incorrect dosing and hyper- or hypoglycaemia.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: NovoRapid can be used in pregnancy. Two randomised controlled trials (322 and 27 exposed pregnancies) did not indicate any adverse effect of insulin aspart on pregnancy or on the health of the foetus or newborn compared with human insulin. Intensified glucose control and monitoring are recommended throughout pregnancy, in type 1, type 2 and gestational diabetes, and when planning it. Insulin requirements usually fall in the first trimester, rise in the second and third, and return rapidly to pre-pregnancy values after delivery.
• Breastfeeding: there are no restrictions on NovoRapid during breastfeeding, and insulin treatment of a nursing mother presents no risk to the baby, although the dose may need adjusting.
• Fertility: animal studies showed no differences between insulin aspart and human insulin.
• Fiasp and NovoMix 30: see their SmPCs for their own statements.

Effect on Driving

The ability to concentrate and react may be impaired by hypoglycaemia, which is a risk when driving or operating machinery. Patients should be advised to take precautions to avoid hypoglycaemia while driving, particularly if they have reduced or absent awareness of the warning signs or frequent episodes.

Before first use, store in a refrigerator at 2–8 °C and do not freeze. Keep Fiasp away from the freezing element and NovoMix 30 away from the cooling element. Unopened vials, cartridges and pens must stay in the cold chain during transport and storage.

In use or when carried as a spare:

• NovoRapid vial and Penfill: below 30 °C; do not refrigerate or freeze; keep in the outer carton to protect from light.
• NovoRapid FlexPen and FlexTouch: below 30 °C; may be kept in a refrigerator (2–8 °C); do not freeze; keep the pen cap on to protect from light.
• NovoRapid InnoLet: below 30 °C; do not refrigerate or freeze; keep the pen cap on.
• NovoRapid PumpCart: as a spare, up to 2 weeks below 30 °C; after that, up to 7 days below 37 °C in a compatible insulin infusion pump system.
• Fiasp FlexTouch: not above 30 °C; may be kept in a refrigerator; do not freeze; keep the cap on to protect from light.
• Fiasp Penfill: not above 30 °C; do not refrigerate or freeze; an unused spare cartridge is kept in the outer carton to protect from light.
• Fiasp vial: not above 30 °C (time in a pump reservoir counts towards the limit); may be kept in a refrigerator; do not freeze; keep in the outer carton.
• Fiasp PumpCart: as a spare, up to 2 weeks below 30 °C; after that, up to 7 days below 37 °C in a compatible insulin infusion pump system; do not refrigerate or freeze.
• NovoMix 30 Penfill and FlexPen: below 30 °C; do not refrigerate or freeze; keep the cartridge in the outer carton, or the cap on the FlexPen, to protect from light.

The biosimilars (Kirsty, Dazparda) are stored as set out in their own SmPCs.

• NovoRapid: 30 months before opening. In use or carried as a spare, a maximum of 4 weeks (PumpCart as above).
• Fiasp: 30 months before opening. After first opening or when carried as a spare, a maximum of 4 weeks for the FlexTouch, Penfill and vial, and 2 weeks plus 7 days in a pump for the PumpCart.
• NovoMix 30: 2 years before opening. In use or carried as a spare, a maximum of 4 weeks.

Prescription only (Rx); NovoRapid is a medicinal product subject to medical prescription. Pens, cartridges and vials are used by the patient or a carer, or in a pump, so they are supplied to the patient or to the treating clinic on prescription, with cold-chain delivery at 2–8 °C. Where a vial is used intravenously by healthcare staff (NovoRapid), it is supplied to the hospital or clinic that administers it.