insulin aspart: prescribing information – dosing, contraindications, interactions, side effects

Treatment of diabetes mellitus in adults, adolescents and children aged 1 year and above.

Posology

Fiasp is a mealtime insulin for subcutaneous administration up to 2 minutes before the start of the meal, with the option to administer up to 20 minutes after starting the meal (see section 5.1).

Dosing with Fiasp is individual and determined in accordance with the needs of the patient. Fiasp given by subcutaneous injection should be used in combination with intermediate-acting or long- acting insulin given at least once a day. In a basal-bolus treatment regimen approximately 50% of this requirement may be provided by Fiasp and the remaining by intermediate-acting or long-acting insulin.

The individual total daily insulin requirement in adults, adolescents and children may vary and is usually between 0.5 and 1 unit/kg/day.
Blood glucose monitoring and insulin dose adjustment 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. Blood glucose levels should be monitored adequately under these conditions.

The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

Patients on basal-bolus treatment who forget a mealtime dose are advised to monitor their blood glucose level to decide if an insulin dose is needed. Patients should resume their usual dosing schedule at the next meal.

The potency of insulin analogues, including Fiasp, is expressed in units. One (1) unit of Fiasp corresponds to 1 international unit of human insulin or 1 unit of other fast-acting insulin analogues.

The early onset of action must be considered when prescribing Fiasp (see section 5.1).

Initiation
Patients with type 1 diabetes mellitus
The recommended starting dose in insulin naïve patients with type 1 diabetes is approximately 50% of the total daily insulin dose and should be divided between the meals based on the size and composition of the meals. The remainder of the total daily insulin dose should be administered as intermediate- acting or long-acting insulin. As a general rule, 0.2 to 0.4 units of insulin per kilogram of body weight can be used to calculate the initial total daily insulin dose in insulin naïve patients with type 1 diabetes.

Patients with type 2 diabetes mellitus
Suggested initial dose is 4 units at one or more meals. Number of injections and subsequent titration will depend on the individual glycaemic target and the size and composition of the meals.

Dose adjustment may be considered daily based on self-measured plasma glucose (SMPG) on the previous day(s) according to Table 1.
- Pre-breakfast dose should be adjusted according to the pre-lunch SMPG the previous day
- Pre-lunch dose should be adjusted according to the pre-dinner SMPG the previous day
- Pre-dinner dose should be adjusted according to the bedtime SMPG the previous day

Table 1 Dose adjustment
SMPG (see above)
Dose adjustment mmol/L mg/dL
Unit
<4
<71
-1
4–6
71–108
No adjustment
>6
>108
+1

Special populations
Elderly patients (≥ 65 years old)
The safety and efficacy of Fiasp have been established in elderly patients aged 65 to 75 years. Close glucose monitoring is recommended and the insulin dose should be adjusted on an individual basis (see section 5.1 and 5.2). The therapeutic experience in patients ≥ 75 years of age is limited.

Renal impairment
Renal impairment may reduce the patient’s insulin requirements. In patients with renal impairment, glucose monitoring should be intensified and the dose adjusted on an individual basis (see section 5.2).

Hepatic impairment
Hepatic impairment may reduce the patient’s insulin requirements. In patients with hepatic impairment, glucose monitoring should be intensified and the dose adjusted on an individual basis (see section 5.2).

Paediatric population
Fiasp can be used in adolescents and children from the age of 1 year (see section 5.1). There is no clinical experience with the use of Fiasp in children below the age of 2 years.
Fiasp is recommended to be administered prior to the meal (0-2 minutes), with the flexibility to administer up to 20 minutes after starting the meal in situations, when there is uncertainty about the meal intake.

Transfer from other insulin medicinal products
Close glucose monitoring is recommended during the transfer from other mealtime insulins and in the initial weeks thereafter. Converting from another mealtime insulin can be done on a unit-to-unit basis.
Transferring a patient from another type, brand or manufacturer of insulin to Fiasp must be done under strict medical supervision and may result in the need for a change in dose.

Doses and timing of concurrent intermediate-acting or long-acting insulin medicinal products or other concomitant antidiabetic treatment may need to be adjusted.

Method of administration

Subcutaneous injection
Fiasp is recommended to be administered subcutaneously by injection in the abdominal wall or the upper arm (see section 5.2). Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see sections 4.4 and 4.8).

Fiasp 100 units/mL FlexTouch solution for injection in pre-filled pen
The pre-filled pen (FlexTouch) delivers 1–80 units in steps of 1 unit.
FlexTouch is accompanied by a package leaflet with detailed instructions for use to be followed. For instructions on administration, see “Instructions for Use” at the end of the package leaflet.

The pre-filled pen is only suitable for subcutaneous injections. If administration by syringe or intravenous injection is necessary, a vial should be used. If administration by infusion pump is necessary, a vial or a PumpCart cartridge should be used.

Fiasp 100 units/mL Penfill solution for injection in cartridge
Administration with a reusable insulin pen

If administration by syringe or intravenous injection is necessary, a vial should be used. If administration by infusion pump is necessary, a vial or a PumpCart cartridge should be used (see section 6.6).

Fiasp 100 units/mL solution for injection in vial
Administration with a syringe
The vial is to be used with insulin syringes with the corresponding unit scale (units-100 or 100 units/mL).

Continuous subcutaneous insulin infusion (CSII)
Fiasp solution for injection in vial can be used for CSII in pumps suitable for insulin infusion and will cover both the bolus insulin requirement (approximately 50%) and basal insulin. It can be administered in accordance with the instructions provided by the pump manufacturer, preferably in the abdomen. When used with an insulin infusion pump, it should not be diluted or mixed with any other insulin medicinal products.

Patients using CSII should be instructed in the use of the pump and use the correct reservoir and tubing for pump (see section 6.6). The infusion set (tubing and cannula) should be changed in accordance with the instructions in the product information supplied with the infusion set.

Patients administering Fiasp by CSII must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure.

Fiasp 100 units/mL PumpCart solution for injection in cartridge
Administration via CSII
The cartridge (PumpCart) is only for use with an insulin infusion pump system designed to be used with this cartridge (see section 6.6).

Fiasp will cover both the bolus insulin requirement (approximately 50%) and basal insulin. It can be administered in accordance with the instructions provided by the pump manufacturer, preferably in the abdomen. Infusion site should be rotated within the same region to reduce the risk of lipodystrophy.
Patients using CSII should be instructed in the use of the pump and use the correct tubing for pump (see section 6.6). The infusion set (tubing and cannula) should be changed in accordance with the instructions in the product information supplied with the infusion set.

Patients administering Fiasp by CSII must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure.

The cartridge (PumpCart) is only suitable for CSII in pump systems suitable for insulin infusion. If administration by syringe or intravenous injection is necessary, a vial should be used.

Intravenous use
Fiasp 100 units/mL solution for injection in vial
If necessary, Fiasp can be administered intravenously by health care professionals.
For intravenous use, it should be used at concentrations from 0.5 unit/mL to 1 unit/mL insulin aspart in infusion systems – using polypropylene infusion bags.
Fiasp must not be mixed with any other insulin or any other medicinal product except those mentioned in section 6.6. For instructions on dilution of the medicinal product before administration, see section 6.6 Monitoring of blood glucose is necessary during insulin infusion. Care should be taken to ensure that the insulin is injected into the infusion bag and not simply the entry port.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of safety profile

The most frequently reported adverse reaction during treatment is hypoglycaemia (see section ‘Description of selected adverse reactions’ below).

Tabulated list of adverse reactions

Adverse reactions listed below (Table 2) are based on data from 6 completed therapeutic confirmatory trials in adults. Frequency categories are defined according to the following convention: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Table 2 Adverse reactions from clinical trials
MedDRA system organ class
Very common
Common
Uncommon
Not known
Immune system disorders

Hypersensitivity
Anaphylactic reactions
Metabolism and nutrition disorders
Hypoglycaemia

Skin and subcutaneous tissue disorders

Allergic skin manifestations
Lipodystrophy
Cutaneous amyloidosis†
General disorders and administration site conditions
Injection/infus ion site reactions

† ADR from postmarketing sources.

Description of selected adverse reactions

Allergic reactions
Allergic skin manifestations reported with Fiasp (1.8% vs. 1.5% for comparator) include eczema, rash, rash pruritic, urticaria and dermatitis.

With Fiasp generalised hypersensitivity reactions (manifested by generalised skin rash and facial oedema) was reported uncommonly (0.2% vs. 0.3% for comparator).

Hypoglycaemia
Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. The symptoms of hypoglycaemia usually occur suddenly. They may include 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 and palpitation (see sections 4.4 and 5.1). Hypoglycaemia may occur earlier after an injection/infusion of Fiasp compared to other mealtime insulins due to the earlier onset of action.

Skin and subcutaneous tissue disorders
Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Lipodystrophy was reported at the injection/infusion site in patients treated with Fiasp (0.5% vs. 0.2% in comparator). Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (see section 4.4).

Injection/infusion site reactions
Injection site reactions (including rash, redness, inflammation, pain and bruising) were reported in patients treated with Fiasp (1.3% vs. 1.0% in comparator). In patients using CSII (N=261): Infusion site reactions (including redness, inflammation, irritation, pain, bruising and itching) were reported in patients treated with Fiasp (10.0% vs. 8.3% in comparator). These reactions are usually mild and transitory and they normally disappear during continued treatment.

Paediatric population

Safety and efficacy have been investigated in a therapeutic confirmatory trial in children with type 1 diabetes aged 2 to less than 18 years. In the trial, 519 patients were treated with Fiasp. Overall the frequency, type and severity of adverse reactions in the paediatric population do not indicate differences to the experience in the adult population. Lipodystrophy (including lipohypertrophy, lipoatrophy) at the injection site was reported more often in this trial with paediatric patients compared to trials in adults (see above). In the paediatric population lipodystrophy was reported with a frequency of 2.1% for Fiasp vs. 1.6% for NovoRapid.

Other special populations

Based on results from clinical trials with insulin aspart in general, the frequency, type and severity of adverse reactions observed in elderly patients and in patients with renal or hepatic impairment do not indicate any differences to the broader experience in the general population. The safety profile in very elderly patients (≥ 75 years) or patients with moderate to severe renal impairment or hepatic impairment is limited. Fiasp has been administered to elderly patients for the investigation of pharmacokinetic properties (see section 5.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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.

Hypoglycaemia

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement (see sections 4.8 and 4.9).

Patients, whose blood glucose control is greatly improved, e.g. by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia and should be advised accordingly. Usual warning symptoms may disappear in patients with long-standing diabetes.

The timing of hypoglycaemia usually reflects the time-action profile of the administered insulin formulation. Hypoglycaemia may occur earlier after an injection/infusion when compared to other mealtime insulins due to the earlier onset of action of Fiasp (see section 5.1).

Since Fiasp should be administered up to 2 minutes before the start of the meal with the option to administer up to 20 minutes after starting the meal, the time to onset of action must be taken into account when prescribing to patients with concomitant diseases or treatment where a delayed absorption of food might be expected.

Paediatric population
Close monitoring of blood glucose levels is recommended if administering this medicinal product after the start of the last meal of the day, in order to avoid nocturnal hypoglycaemia.

Hyperglycaemia and diabetic ketoacidosis

The use of inadequate doses or discontinuation of treatment, especially in patients requiring insulin, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.

Continuous subcutaneous insulin infusion (CSII)
Pump or infusion set malfunctions can lead to a fast onset of hyperglycaemia and ketosis. Prompt identification and correction of the cause of hyperglycaemia or ketosis is necessary. Interim therapy with subcutaneous injection may be required.

Misuse of PumpCart

The cartridge (PumpCart) is only for use with an insulin infusion pump system designed to be used with this cartridge. It must not be used with other devices not designed for the cartridge, as this may result in incorrect insulin dosing and subsequent hyper- or hypoglycaemia (see section 6.6).

Skin and subcutaneous tissue disorders

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia.
Blood glucose monitoring is recommended after the change in the injection site from an affected to an unaffected area, and dose adjustment of antidiabetic medicinal products may be considered.

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, human insulin or human 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 Fiasp from another type of insulin may require a change in dose from that used with their usual insulin medicinal products.

Concomitant illness

Concomitant illness, especially infections and feverish conditions, usually increases the patient’s insulin requirements. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland may require changes in the insulin dose.

Combination of pioglitazone and insulin medicinal products

Cases of congestive heart failure have been reported when pioglitazone were used in combination with insulin, especially in patients with risk factors for development of congestive heart failure. This should be kept in mind if treatment with the combination of Pioglitazone and insulin medicinal products is considered. If the combination is used, patients should be observed for signs and symptoms of congestive heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.

Insulin initiation and glucose control intensification

Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, acute painful peripheral neuropathy and peripheral oedema. However, long-term glycaemic control decreases the risk of diabetic retinopathy and neuropathy.

Insulin antibodies

Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- or hypoglycaemia.

Avoidance of accidental mix-ups/medication errors

Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between this medicinal product and other insulin medicinal products.

Patients must visually verify the units of the dose prior to administering. Therefore, the requirement for patients to self-administer is that they can read the dose scale. Patients, who are blind or have poor vision, must be instructed to always get assistance from another person who has good vision and is trained in administration of insulins.

Travelling between time zones

Before travelling between different time zones, the patient should seek the doctor’s advice.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

A number of medicinal products are known to interact with the glucose metabolism.

The following substances may reduce insulin requirement:
Oral antidiabetics, monoamine oxidase inhibitors (MAOIs), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids, sulphonamides and GLP-1 receptor agonist.

The following substances may increase insulin requirement:
Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.

Beta-blocking agents may mask the symptoms of hypoglycaemia.

Octreotide/lanreotide may either increase or decrease the insulin requirement.

Alcohol may intensify or reduce the hypoglycaemic effect of insulin.

Pregnancy

Fiasp can be used in pregnancy.

Data from two randomised controlled clinical trials conducted with insulin aspart (322 + 27 exposed pregnancies) do not indicate any adverse effect of insulin aspart on pregnancy or on the health of the foetus/new born when compared to soluble human insulin.

Intensified blood glucose control and monitoring of pregnant women with diabetes (type 1 diabetes, type 2 diabetes or gestational 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 normally return rapidly to pre-pregnancy values.

Breast-feeding

There are no restrictions on treatment with Fiasp during breast-feeding. Insulin treatment of the breast-feeding mother presents no risk to the baby. However, the dose may need to be adjusted.

Fertility

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

The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g., driving a car or using machines).

Patients should be advised to take precautions to avoid hypoglycaemia while driving. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.

A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop over sequential stages if a patient is dosed with more insulin than required:

• Mild hypoglycaemic episodes can be treated by oral administration of glucose or other products containing sugar. It is therefore recommended that the diabetic patient always carries glucose- containing products.

• Severe hypoglycaemic episodes, where the patient is not able to treat him/herself, can be treated with glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or with glucose given intravenously by a healthcare professional. Glucose must be given intravenously if the patient does not respond to glucagon within 10 to 15 minutes. Upon regaining consciousness, administration of oral carbohydrate is recommended for the patient in order to prevent a relapse.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs used in diabetes, insulins and analogues for injection, fast-acting ATC code: A10AB05.

Mechanism of action

Fiasp is a fast-acting insulin aspart formulation.
The primary activity of Fiasp is the regulation of glucose metabolism. Insulins, including insulin aspart, the active substance in Fiasp, exert their specific action through binding to insulin receptors.
Receptor-bound insulin lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and adipose tissue and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis and enhances protein synthesis.

Pharmacodynamic effects

Fiasp is a mealtime insulin aspart formulation in which the addition of nicotinamide (vitamin B3) results in a faster initial absorption of insulin compared to NovoRapid.

The onset of action was 5 minutes earlier and time to maximum glucose infusion rate was 11 minutes earlier with Fiasp than with NovoRapid. The maximum glucose-lowering effect of Fiasp occurred between 1 and 3 hours after injection. The glucose-lowering effect during the first 30 minutes (AUCGIR, 0–30 min ) was 51 mg/kg with Fiasp and 29 mg/kg with NovoRapid (Fiasp/NovoRapid ratio:
1.74 [1.47;2.10]95% CI). The total glucose-lowering effect and maximum (GIRmax) glucose-lowering effect were comparable between Fiasp and NovoRapid. Total and maximum glucose-lowering effect of Fiasp increase linearly with increasing dose within the therapeutic dose range.

Fiasp has an earlier onset of action compared to NovoRapid (see section 5.2), leading to a subsequent increased early glucose-lowering effect. This must be considered when prescribing Fiasp.

The duration of action was shorter for Fiasp compared to that of NovoRapid and lasted for 3–5 hours.

The day-to-day variability within-patients in glucose-lowering effect was low for Fiasp both for early (AUCGIR, 0-1h, CV~26%), total (AUCGIR, 0-12h, CV~18%) and maximum glucose-lowering effect (GIRmax, CV~19%).

Clinical efficacy and safety

Fiasp has been studied in 2 068 adult patients with type 1 diabetes (1 143 patients) and type 2 diabetes (925 patients) in 3 randomised efficacy and safety trials (18–26 weeks of treatment). Furthermore, Fiasp has been studied in 777 paediatric subjects with type 1 diabetes in a randomised efficacy and safety trial (26 weeks of treatment). No children below the age of 2 years were randomised in the trial.

Patients with type 1 diabetes mellitus
The treatment effect of Fiasp in achieving glycaemic control was assessed when administered at mealtime or postmeal. Fiasp administered at mealtime was non-inferior to NovoRapid in reducing HbA1c, and the improvement in HbA1c was statistically significant in favour of Fiasp. Fiasp administered postmeal achieved similar HbA1c reduction as NovoRapid dosed at mealtime (Table 3).

Table 3 Results from 26 week basal-bolus clinical trial in patients with type 1 diabetes

Absorption

Fiasp is a mealtime insulin aspart formulation in which the addition of nicotinamide (vitamin B3) results in a faster initial absorption of insulin. Insulin appeared in the circulation approximately 4 minutes after administration (Figure 1). The onset of appearance was twice as fast (corresponding to 5 minutes earlier), time to 50% maximum concentration was 9 minutes shorter with Fiasp compared to NovoRapid with four times as much insulin available during first 15 minutes and with twice as much insulin available during the first 30 minutes.

Fiasp
NovoRapid
Insulin aspart concentration (pmol/L)
Time (min)

Figure 1 Mean insulin profile in patients with type 1 diabetes after subcutaneous injection.

The total insulin exposure was comparable between Fiasp and NovoRapid. The mean Cmax for a dose of 0.2 units/kg body weight is 298 pmol/L and comparable to NovoRapid.

Total exposure and maximum insulin concentration increases proportionally with increasing subcutaneous dose of Fiasp within the therapeutic dose range.

The absolute bioavailability of insulin aspart after subcutaneous administration of Fiasp in the abdomen, deltoid and thigh was approximately 80%.

After administration of Fiasp, the fast onset of appearance is maintained regardless of injection site.
Time to maximum concentration and total insulin aspart exposure were all comparable between the abdomen, upper arm and the thigh. Early insulin exposure and maximum concentration were comparable for the abdomen and upper arm regions, but lower for the thigh.

Continuous subcutaneous insulin infusion (CSII)

The onset of exposure in a CSII setting (time to reach maximum concentration) was 26 minutes shorter with Fiasp compared to NovoRapid resulting in approximately three times as much insulin available during the first 30 minutes (Figure 2).

Insulin aspart concentration baseline-adjusted (pmol/L)
Fiasp
NovoRapid
Time since bolus injection (min)

NovoMix 30 is indicated for treatment of diabetes mellitus in adults, adolescents and children aged 10 years and above.

NovoMix 50 is indicated for treatment of diabetes mellitus in adults.

Posology

The potency of insulin analogues, including insulin aspart, is expressed in units, whereas the potency of human insulin is expressed in international units.

NovoMix 30 dosing is individual and determined in accordance with the needs of the patient. Blood glucose monitoring and insulin dose adjustments are recommended to achieve optimal glycaemic control.

In patients with type 2 diabetes, NovoMix 30 can be given as monotherapy. NovoMix 30 can also be given in combination with oral antidiabetic medicinal products and/or GLP-1 receptor agonists. For patients with type 2 diabetes, the recommended starting dose of NovoMix 30 is 6 units at breakfast and 6 units at dinner (evening meal). NovoMix 30 can also be initiated once daily with 12 units at dinner (evening meal). When using NovoMix 30 once daily, it is generally recommended to move to twice daily when reaching 30 units by splitting the dose into equal breakfast and dinner doses. If twice daily dosing with NovoMix 30 results in recurrent daytime hypoglycaemic episodes, the morning dose can be split into morning and lunchtime doses (thrice daily dosing).

VV-LAB-103275

Posology

The potency of insulin analogues, including insulin aspart, is expressed in units, whereas the potency of human insulin is expressed in international units.

NovoMix 50 dosing is individual and determined in accordance with the needs of the patient. Blood glucose monitoring and insulin dose adjustments are recommended to achieve optimal glycaemic control.

The individual insulin requirement is usually between 0.5 and 1.0 unit/kg/day. NovoMix 50 may fully or partially meet this requirement.

In patients with type 2 diabetes, NovoMix 50 can be given as monotherapy or in combination with metformin when the blood glucose is inadequately controlled with metformin alone.

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

VV-LAB-103275

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile

Adverse reactions observed in patients using NovoMix are mainly due to the pharmacological effect of insulin aspart.

The most frequently reported adverse reaction during treatment is hypoglycaemia. The frequencies of hypoglycaemia vary with patient population, dose regimens and level of glycaemic control, please see Description of selected adverse reactions below.

At the beginning of the insulin treatment, refraction anomalies, oedema and injection site reactions (pain, redness, hives, inflammation, bruising, swelling and itching at the injection site) may occur.
These reactions are usually of a transitory nature. Fast improvement in blood glucose control may be associated with acute painful neuropathy, which is usually reversible. Intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.

Tabulated list of adverse reactions

The adverse reactions listed below are based on clinical trial data and classified according to MedDRA frequency and System Organ Class. Frequency categories are defined according to the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Immune system disorders
Uncommon – Urticaria, rash, eruptions

Very rare – Anaphylactic reactions*

Metabolism and nutrition disorders

Very common – Hypoglycaemia*

Nervous system disorders
Rare – Peripheral neuropathy (painful neuropathy)

Eye disorders

Uncommon – Refraction disorders

Uncommon – Diabetic retinopathy

VV-LAB-103275

Summary of the safety profile

Adverse reactions observed in patients using NovoMix are mainly due to the pharmacological effect of insulin aspart.

The most frequently reported adverse reaction during treatment is hypoglycaemia. The frequencies of hypoglycaemia vary with patient population, dose regimens and level of glycaemic control, please see Description of selected adverse reactions below.

At the beginning of the insulin treatment, refraction anomalies, oedema and injection site reactions (pain, redness, hives, inflammation, bruising, swelling and itching at the injection site) may occur.
These reactions are usually of a transitory nature. Fast improvement in blood glucose control may be associated with acute painful neuropathy, which is usually reversible. Intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.

Tabulated list of adverse reactions

The adverse reactions listed below are based on clinical trial data and classified according to MedDRA frequency and System Organ Class. Frequency categories are defined according to the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

VV-LAB-103275

NovoMix 30 must not be administered intravenously, as it may result in severe hypoglycaemia.
Intramuscular administration should be avoided. NovoMix 30 is not to be used in insulin infusion pumps.

Before travelling between different time zones, the patient should seek the doctor’s advice since this may mean that the patient has to take the insulin and meals at different times.

Hyperglycaemia

Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis. Usually, the first symptoms of hyperglycaemia develop gradually over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath.
In type 1 diabetes, untreated hyperglycaemic events eventually lead to diabetic ketoacidosis, which is potentially lethal.

Hypoglycaemia

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. In case of hypoglycaemia or if hypoglycaemia is suspected, NovoMix must not be injected. After stabilisation of the patient’s blood glucose, adjustment of the dose should be considered (see sections 4.2, 4.8 and 4.9).

VV-LAB-103275

NovoMix 50 must not be administered intravenously, as it may result in severe hypoglycaemia.
Intramuscular administration should be avoided. NovoMix 50 is not to be used in insulin infusion pumps.
VV-LAB-103275

A number of medicinal products are known to interact with the glucose metabolism.

The following substances may reduce the patient’s insulin requirements:
Oral antidiabetic medicinal products, GLP-1 receptor agonists, monoamine oxidase inhibitors (MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulfonamides.

The following substances may increase the patient’s insulin requirements:
Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.

Beta-blockers may mask the symptoms of hypoglycaemia.

Octreotide/lanreotide may either increase or decrease the insulin requirement.

Alcohol may intensify or reduce the hypoglycaemic effect of insulin.

A number of medicinal products are known to interact with the glucose metabolism.

The following substances may reduce the patient’s insulin requirements:
Oral antidiabetic medicinal products, monoamine oxidase inhibitors (MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulfonamides.

The following substances may increase the patient’s insulin requirements:
Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.

Beta-blockers may mask the symptoms of hypoglycaemia.

Octreotide/lanreotide may either increase or decrease the insulin requirement.

Alcohol may intensify or reduce the hypoglycaemic effect of insulin.

Pregnancy

There is limited clinical experience with NovoMix 30 in pregnancy.

Animal reproduction studies have not revealed any differences between insulin aspart and human insulin regarding embryotoxicity or teratogenicity.

In general, 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.

Breast-feeding

There are no restrictions on treatment with NovoMix 30 during breast-feeding. Insulin treatment of the nursing mother presents no risk to the baby. However, the NovoMix 30 dose may need to be adjusted.

VV-LAB-103275

Pregnancy

There is limited clinical experience with NovoMix 50 in pregnancy.

VV-LAB-103275

The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).

Patients should be advised to take precautions to avoid hypoglycaemia while driving or operating a machine. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving or operating a machine should be considered in these circumstances.

A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop over sequential stages if too high doses relative to the patient’s requirement are administered:

• Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient always carries sugar-containing products.
• Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated with glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or with glucose given intravenously by a healthcare professional. Glucose must be given intravenously, if the patient does not respond to glucagon within 10 to 15 minutes. Upon regaining consciousness, administration of oral carbohydrates is recommended for the patient in order to prevent a relapse.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, intermediate- or long-acting combined with fast-acting. ATC code: A10AD05.

NovoMix 30 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).

Mechanism of action and pharmacodynamic effects

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.

NovoMix 30 is a biphasic insulin, which contains 30% soluble insulin aspart. This has a rapid onset of action, thus allowing it to be given closer to a meal (within zero to 10 minutes of the meal) when compared to 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.

When NovoMix 30 is injected subcutaneously, the onset of action will occur within 10 to 20 minutes of injection. The maximum effect is exerted between 1 and 4 hours after injection. The duration of action is up to 24 hours (Figure 1).

VV-LAB-103275

Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, intermediate- or long-acting combined with fast-acting. ATC code: A10AD05.

NovoMix 50 is a biphasic suspension of 50% soluble insulin aspart (rapid-acting human insulin analogue) and 50% protamine-crystallised insulin aspart (intermediate-acting human insulin analogue).

Mechanism of action and pharmacodynamic effects

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.

NovoMix 50 is a biphasic insulin, which contains 50% soluble insulin aspart. This has a rapid onset of action, thus allowing it to be given closer to a meal (within zero to 10 minutes of the meal) when compared to soluble human insulin. The crystalline phase (50%) consists of protamine-crystallised insulin aspart, which has an activity profile similar to that of human NPH insulin.

When NovoMix 50 is injected subcutaneously, the onset of action will occur within 10 to 20 minutes of injection. The maximum effect is exerted between 1 and 4 hours after injection. The duration of action is 14 to 24 hours (Figure 1).

VV-LAB-103275

Absorption, distribution and elimination

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 insulin aspart in the soluble phase of NovoMix 30 comprises 30% of the total insulin; this is absorbed more rapidly from the subcutaneous layer than the soluble insulin component of biphasic human insulin. The remaining 70% is in crystalline form as protamine-crystallised insulin aspart; this has a prolonged absorption profile similar to human NPH insulin.

The maximum serum insulin concentration is, on average, 50% higher with NovoMix 30 than with biphasic human insulin 30. The time to maximum concentration is, on average, half of that for biphasic human insulin 30. In healthy volunteers, a mean maximum serum concentration of 140 ± 32 pmol/l was reached about 60 minutes after a subcutaneous dose of 0.20 unit/kg body weight. The mean half life (t½) of NovoMix 30, reflecting the absorption rate of the protamine bound fraction, was about 8– 9 hours. Serum insulin levels returned to baseline 15–18 hours after a subcutaneous dose. In type 2 diabetic patients, the maximum concentration was reached about 95 minutes after dosing, and concentrations well above zero for not less than 14 hours post-dosing were measured.

Special populations

The pharmacokinetics of NovoMix 30 have not been investigated in elderly patients or in patients with renal or hepatic impairment.

Paediatric population
The pharmacokinetics of NovoMix 30 have not been investigated in children or adolescents. However, the pharmacokinetic and pharmacodynamic properties of soluble insulin aspart have been investigated in children (6–12 years) and adolescents (13–17 years) with type 1 diabetes. Insulin aspart was rapidly absorbed in both age groups, with similar tmax as in adults. However, Cmax differed between the age groups, stressing the importance of the individual titration of insulin aspart.

Absorption, distribution and elimination

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 insulin aspart in the soluble phase of NovoMix 50 comprises 50% of the total insulin; this is absorbed more rapidly from the subcutaneous layer than the soluble insulin component of biphasic human insulin. The remaining 50% is in crystalline form as protamine-crystallised insulin aspart; this has a prolonged absorption profile similar to human NPH insulin.

In healthy volunteers, a mean maximum serum concentration of 445 ± 135 pmol/l was reached about 60 minutes after a subcutaneous dose of 0.30 unit/kg body weight. In type 2 patients with diabetes, the maximum concentration was reached about 95 minutes after dosing.

Special populations

The pharmacokinetics of NovoMix 50 have not been investigated in paediatrics, elderly patients or in patients with renal or hepatic impairment.

NovoRapid is indicated for treatment of diabetes mellitus in adults, adolescents and children aged 1 year and above.

Posology

The potency of insulin analogues, including insulin aspart, is expressed in units, whereas the potency of human insulin is expressed in international units.

NovoRapid dosing is individual and determined in accordance with the needs of the patient. It should normally be used in combination with intermediate-acting or long-acting insulin.

Moreover NovoRapid vial and NovoRapid PumpCart can be used for continuous subcutaneous insulin infusion (CSII) in pump systems.

NovoRapid vial can also be used if intravenous administration of insulin aspart, by physicians or other healthcare staff, is applicable.

Blood glucose monitoring and insulin dose adjustments are recommended to achieve optimal glycaemic control.

The individual insulin requirement in adults and children is usually between 0.5 and 1.0 unit/kg/day.
In a basal-bolus treatment regimen 50–70% of this requirement may be provided by NovoRapid and the remainder by intermediate-acting or long-acting insulin.

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

Special populations

Elderly (≥ 65 years old)
NovoRapid can be used in elderly patients.
In elderly patients, glucose monitoring should be intensified and the insulin aspart dose adjusted on an individual basis.

Renal and hepatic impairment
Renal or hepatic impairment may reduce the patient’s insulin requirements.
In patients with renal or hepatic impairment, glucose monitoring should be intensified and the insulin aspart dose adjusted on an individual basis.

Paediatric population
NovoRapid can be used in children and adolescents aged 1 year and above in preference to soluble human insulin when a rapid onset of action might be beneficial, for example, in the timing of the injections in relation to meals (see sections 5.1 and 5.2).

The safety and efficacy of NovoRapid in children below 1 year of age have not been established.
No data are available.

Transfer from other insulin medicinal products

When transferring from other insulin medicinal products, adjustment of the NovoRapid dose and the dose of the basal insulin may be necessary. NovoRapid has a faster onset and a shorter duration of action than soluble human insulin. When injected subcutaneously into the abdominal wall, the onset of action will occur within 10–20 minutes of injection. The maximum effect is exerted between 1 and 3 hours after the injection. The duration of action is 3 to 5 hours.

Close glucose monitoring is recommended during the transfer and in the initial weeks thereafter (see section 4.4).

Method of administration

NovoRapid is a rapid-acting insulin analogue.
NovoRapid is administered subcutaneously by injection in the abdominal wall, the thigh, the upper arm, the deltoid region or the gluteal region. Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see sections 4.4 and 4.8). Subcutaneous injection in the abdominal wall ensures a faster absorption than other injection sites. Compared to soluble human insulin the faster onset of action of NovoRapid is maintained regardless of the injection site. The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

Due to the faster onset of action, NovoRapid should generally be given immediately before a meal.
When necessary NovoRapid can be given soon after a meal.

NovoRapid vial/NovoRapid PumpCart
Continuous Subcutaneous Insulin Infusion (CSII)
NovoRapid may be used for CSII in pump systems suitable for insulin infusion. CSII should be administered in the abdominal wall. Infusion sites should be rotated.

When used with an insulin infusion pump, NovoRapid should not be mixed with any other insulin medicinal products.

Patients using CSII should be comprehensively instructed in the use of the pump system and use the correct reservoir and tubing for the pump (see section 6.6). The infusion set (tubing and cannula) should be changed in accordance with the instructions in the product information supplied with the infusion set.

Patients administering NovoRapid by CSII must have an alternative insulin delivery method available in case of pump system failure.

NovoRapid vial
Intravenous use
If necessary, NovoRapid can be administered intravenously which should be carried out by physicians or other healthcare staff.

For intravenous use, infusion systems with NovoRapid 100 units/ml at concentrations from 0.05 unit/ml to 1.0 unit/ml insulin aspart in the infusion fluids 0.9% sodium chloride, 5% dextrose or 10% dextrose including 40 mmol/l potassium chloride using polypropylene infusion bags, are stable at room temperature for 24 hours.

Although stable over time, a certain amount of insulin will be initially adsorbed to the material of the infusion bag. Monitoring of blood glucose is necessary during insulin infusion.

Mixing two types of insulins
NovoRapid can only be mixed with NPH (Neutral Protamine Hagedorn) insulin in a syringe for subcutaneous use. When NovoRapid is mixed with NPH insulin, NovoRapid should be drawn into the syringe first, and the mixture should be injected immediately after mixing. Insulin mixtures should not be administered intravenously or used with a subcutaneous insulin infusion pump.

Administration with a syringe
NovoRapid vials are for use with insulin syringes with the corresponding unit scale. See also section

Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

Summary of the safety profile

Adverse reactions observed in patients using NovoRapid are mainly due to the pharmacologic effect of insulin.

The most frequently reported adverse reaction during treatment is hypoglycaemia. The frequencies of hypoglycaemia vary with patient population, dose regimens and level of glycaemic control (see section 4.8, Description of selected adverse reactions).

At the beginning of the insulin treatment, refraction anomalies, oedema and injection site reactions (pain, redness, hives, inflammation, bruising, swelling and itching at the injection site) may occur.
These reactions are usually of transitory nature. Fast improvement in blood glucose control may be associated with acute painful neuropathy, which is usually reversible. Intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.

Tabulated list of adverse reactions

Adverse reactions listed below are based on clinical trial data and classified according to MedDRA frequency and System Organ Class. Frequency categories are defined according to the following convention: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100);
rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Immune system disorders
Uncommon – Urticaria, rash, eruptions

Very rare – Anaphylactic reactions*

Metabolism and nutrition disorders

Very common – Hypoglycaemia*

Nervous system disorders
Rare – Peripheral neuropathy (painful neuropathy)

Eye disorders

Uncommon – Refraction disorders

Uncommon – Diabetic retinopathy

Skin and subcutaneous tissue disorders
Uncommon – Lipodystrophy*

Not known – Cutaneous amyloidosis*†

General disorders and administration site conditions
Uncommon – Injection site reactions
Uncommon – Oedema

* see section 4.8, Description of selected adverse reactions.
† ADR from postmarketing sources.

Description of selected adverse reactions

Anaphylactic reactions:
The occurrence of generalised hypersensitivity reactions (including generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulties in breathing, palpitation and reduction in blood pressure) is very rare but can potentially be life threatening.

Hypoglycaemia:
The most frequently reported adverse reaction is hypoglycaemia. It may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.
The symptoms of hypoglycaemia usually occur suddenly. They may include 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 and palpitation.

In clinical trials, the frequency of hypoglycaemia varied with patient population, dose regimens and level of glycaemic control. During clinical trials the overall rates of hypoglycaemia did not differ between patients treated with insulin aspart compared to human insulin.

Skin and subcutaneous tissue disorders:
Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (see section 4.4).

Paediatric population

Based on post-marketing sources and clinical trials, the frequency, type and severity of adverse reactions observed in the paediatric population do not indicate any differences to the broader experience in the general population.

Other special populations

Based on post-marketing sources and clinical trials, the frequency, type and severity of adverse reactions observed in the elderly patients and in patients with renal or hepatic impairment do not indicate any differences to the broader experience in the general population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Before travelling between different time zones, the patient should seek the doctor’s advice since this may mean that the patient has to take the insulin and meals at different times.

NovoRapid PumpCart
Misuse of NovoRapid PumpCart
NovoRapid PumpCart is only for use with an insulin infusion pump system designed to be used with this cartridge, such as the Accu-Chek Insight and YpsoPump insulin pumps. It must not be used with other devices not designed for NovoRapid PumpCart, as this may result in incorrect insulin dosing and subsequent hyper- or hypoglycaemia.

Hyperglycaemia

Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis. Usually the first symptoms of hyperglycaemia develop gradually over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath.
In type 1 diabetes, untreated hyperglycaemic events eventually lead to diabetic ketoacidosis, which is potentially lethal.

Hypoglycaemia

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.
Especially in children, care should be taken to match insulin doses (especially in basal-bolus regimens) with food intake, physical activities and current blood glucose level in order to minimise the risk of hypoglycaemia.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. In case of hypoglycaemia or if hypoglycaemia is suspected NovoRapid must not be injected. After stabilisation of patient’s blood glucose adjustment of the dose should be considered (see sections 4.8 and 4.9).

Patients whose blood glucose control is greatly improved, e.g. by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia, and should be advised accordingly. Usual warning symptoms may disappear in patients with longstanding diabetes.

A consequence of the pharmacodynamics of rapid-acting insulin analogues is that if hypoglycaemia occurs, it may occur earlier after an injection when compared with soluble human insulin.

Since NovoRapid should be administered in immediate relation to a meal, the rapid onset of action should be considered in patients with concomitant diseases or treatment where a delayed absorption of food might be expected.

Concomitant illness, especially infections and feverish conditions, usually increases the patient’s insulin requirements. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland can require changes in the insulin dose.

When patients are transferred between different types of insulin medicinal products, the early warning symptoms of hypoglycaemia may change or become less pronounced than those experienced with their previous insulin.

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, human insulin or human 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 NovoRapid 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.

Injection site reactions

As with any insulin therapy, injection site reactions may occur and include pain, redness, hives, inflammation, bruising, swelling and itching. Continuous rotation of the injection site within a given area reduces the risk of developing these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of NovoRapid.

Skin and subcutaneous tissue disorders

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia.
Blood glucose monitoring is recommended after the change in the injection site from an affected to an unaffected area, and dose adjustment of antidiabetic medications may be considered.

Combination of NovoRapid with pioglitazone

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. This should be kept in mind if treatment with the combination of pioglitazone and NovoRapid is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.

Avoidance of accidental mix-ups/medication errors

Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between NovoRapid and other insulin products.

Insulin antibodies

Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- or hypoglycaemia.

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.

A number of medicinal products are known to interact with the glucose metabolism.

The following substances may reduce the patient's insulin requirements:
Oral antidiabetic medicinal products, monoamine oxidase inhibitors (MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulphonamides.

The following substances may increase the patient’s insulin requirements:
Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.

Beta-blockers may mask the symptoms of hypoglycaemia.

Octreotide/lanreotide may either increase or decrease the insulin requirement.

Alcohol may intensify or reduce the hypoglycaemic effect of insulin.

Pregnancy

NovoRapid (insulin aspart) can be used in pregnancy. Data from two randomised controlled clinical trials (322 and 27 exposed pregnancies) do not indicate any adverse effect of insulin aspart on pregnancy or on the health of the foetus/newborn when compared to human insulin (see section 5.1).

Intensified blood glucose control and monitoring of pregnant women with diabetes (type 1 diabetes, type 2 diabetes or gestational 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 trimester. After delivery, insulin requirements normally return rapidly to pre-pregnancy values.

Breast-feeding

There are no restrictions on treatment with NovoRapid during breast-feeding. Insulin treatment of the nursing mother presents no risk to the baby. However, the NovoRapid dose may need to be adjusted.

Fertility

Animal reproduction studies have not revealed any differences between insulin aspart and human insu- lin regarding fertility.

The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).

Patients should be advised to take precautions to avoid hypoglycaemia while driving. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.

A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop over sequential stages if too high doses relative to the patient’s requirement are administered:

• Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient always carries sugar-containing products.
• Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated with glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or with glucose given intravenously by physicians or other healthcare staff. Glucose must be given intravenously, if the patient does not respond to glucagon within 10 to 15 minutes. Upon regaining consciousness, administration of oral carbohydrates is recommended for the patient in order to prevent a relapse.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, fast-acting.
ATC code: A10AB05.

Mechanism of action and pharmacodynamic effects

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.

NovoRapid produces a more rapid onset of action compared to soluble human insulin, together with a lower glucose concentration, as assessed within the first four hours after a meal. NovoRapid has a shorter duration of action compared to soluble human insulin after subcutaneous injection.

Fig. I. Blood glucose concentrations following a single pre-meal dose of NovoRapid injected immediately before a meal (solid curve) or soluble human insulin administered 30 minutes before a meal (hatched curve) in patients with type 1 diabetes mellitus.

When NovoRapid is injected subcutaneously, the onset of action will occur within 10 to 20 minutes of injection. The maximum effect is exerted between 1 and 3 hours after injection. The duration of action is 3 to 5 hours.

Clinical efficacy

Clinical trials in patients with type 1 diabetes have demonstrated a lower postprandial blood glucose with NovoRapid compared to soluble human insulin (Fig. I). In two long-term open label trials in patients with type 1 diabetes comprising 1070 and 884 patients, respectively, NovoRapid reduced glycated haemoglobin by 0.12 [95% C.I. 0.03; 0.22] percentage points and by 0.15 [95% C.I. 0.05;
0.26] percentage points compared to human insulin; a difference of limited clinical significance.

Clinical trials in patients with type 1 diabetes have demonstrated a reduced risk of nocturnal hypoglycaemia with insulin aspart compared with soluble human insulin. The risk of daytime hypoglycaemia was not significantly increased.

Insulin aspart is equipotent to soluble human insulin on a molar basis.

Special populations

Elderly (≥ 65 years old)
A randomised, double-blind cross-over PK/PD trial comparing insulin aspart with soluble human insulin was performed in elderly patients with type 2 diabetes (19 patients aged 65–83 years, mean age 70 years). The relative differences in the pharmacodynamic properties (GIRmax,AUCGIR, 0–120 min) between insulin aspart and soluble human insulin in the elderly were similar to those seen in healthy subjects and in younger patients with diabetes.

Paediatric population
A clinical trial comparing preprandial soluble human insulin with postprandial insulin aspart was performed in small children (20 patients aged 2 to less than 6 years, studied for 12 weeks, among those four were younger than 4 years old) and a single dose PK/PD trial was performed in children (6– 12 years) and adolescents (13–17 years). The pharmacodynamic profile of insulin aspart in children was similar to that seen in adults.

Absorption, distribution and elimination

In NovoRapid substitution of amino acid proline with aspartic acid at position B28 reduces the tendency to form hexamers as observed with soluble human insulin. NovoRapid is therefore more rapidly absorbed from the subcutaneous layer compared to soluble human insulin.

The time to maximum concentration is, on average, half of that for soluble human insulin. A mean maximum plasma concentration of 492±256 pmol/l was reached 40 (interquartile range: 30–40) minutes after a subcutaneous dose of 0.15 unit/kg bodyweight in type 1 diabetic patients. The insulin concentrations returned to baseline about 4 to 6 hours after dose. The absorption rate was somewhat slower in type 2 diabetic patients, resulting in a lower Cmax (352±240 pmol/l) and later tmax (60 (interquartile range: 50–90) minutes). The intra-individual variability in time to maximum concentration is significantly less for NovoRapid than for soluble human insulin, whereas the intra- individual variability in Cmax for NovoRapid is larger.

Special populations

Elderly (≥ 65 years old)
The relative differences in pharmacokinetic properties between insulin aspart and soluble human insulin in elderly patients (65–83 years, mean age 70 years) with type 2 diabetes were similar to those observed in healthy subjects and in younger patients with diabetes. A decreased absorption rate was observed in elderly patients, resulting in a later tmax (82 (interquartile range: 60–120) minutes), whereas Cmax was similar to that observed in younger patients with type 2 diabetes and slightly lower than in patients with type 1 diabetes.

Hepatic impairment