NovoMix 30 (Insulin Aspart)

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

NovoMix 30 (Insulin Aspart) 30 is indicated for treatment of diabetes mellitus in adults, adolescents and children aged 10 years 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.

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.

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. 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. 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.

NovoRapid Penfill

Administration with an insulin delivery system

NovoRapid Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist needles. NovoRapid Penfill is only suitable for subcutaneous injections from a reusable 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 NovoRapid PumpCart should be used.

NovoMix 30 (Insulin Aspart)

Administration with FlexPen

NovoMix 30 (Insulin Aspart) is a pre-filled pen (colour-coded) designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm. FlexPen delivers 1-60 units in increments of 1 unit. NovoMix 30 (Insulin Aspart) 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 NovoRapid PumpCart should be used.

NovoRapid FlexTouch

Administration with FlexTouch

NovoRapid FlexTouch is a pre-filled pen (colour-coded) designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm. FlexTouch delivers 1-80 units in increments of 1 unit. NovoRapid FlexTouch 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 NovoRapid PumpCart should be used.

NovoRapid PumpCart

Administration via Continuous Subcutaneous Insulin Infusion (CSII)

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.

CSII should be administered in the abdominal wall. Infusion sites should be rotated. NovoRapid 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.

For detailed user instructions, please refer to the package leaflet.

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 (Insulin Aspart) 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 (Insulin Aspart) 30 can be given as monotherapy. NovoMix 30 (Insulin Aspart) 30 can also be given in combination with oral antidiabetic medicinal products if the patient's blood glucose is inadequately controlled with oral antidiabetic medicinal products alone. For patients with type 2 diabetes, the recommended starting dose of NovoMix 30 (Insulin Aspart) 30 is 6 units at breakfast and 6 units at dinner (evening meal). NovoMix 30 (Insulin Aspart) 30 can also be initiated once daily with 12 units at dinner (evening meal). When using NovoMix 30 (Insulin Aspart) 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 (Insulin Aspart) 30 results in recurrent daytime hypoglycaemic episodes, the morning dose can be split into morning and lunchtime doses (thrice daily dosing).

The following titration guideline is recommended for dose adjustments:

The lowest of the three previous days' pre-meal blood glucose levels should be used. The dose should not be increased if hypoglycaemia occurred within these days. Dose adjustments can be made once a week until target HbA_1c is reached. Pre-meal blood glucose levels should be used to evaluate the adequacy of the preceding dose.

In patients with type 1 diabetes, the individual insulin requirement is usually between 0.5 and 1.0 unit/kg/day. NovoMix 30 (Insulin Aspart) 30 may fully or partially meet this requirement.

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)

NovoMix 30 (Insulin Aspart) 30 can be used in elderly patients; however there is limited experience with the use of NovoMix 30 (Insulin Aspart) 30 in combination with oral antidiabetic medicinal products in patients older than 75 years.

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

NovoMix 30 (Insulin Aspart) 30 can be used in adolescents and children aged 10 years and above when premixed insulin is preferred. There is limited clinical experience with NovoMix 30 (Insulin Aspart) 30 in children aged 6-9 years.

No data are available for NovoMix 30 (Insulin Aspart) 30 in children below 6 years of age.

Transfer from other insulin medicinal products

When transferring a patient from biphasic human insulin to NovoMix 30 (Insulin Aspart) 30, start with the same dose and regimen. Then titrate according to individual needs (see the titration guideline in the table above).

Close glucose monitoring is recommended during the transfer and in the initial weeks thereafter.

Method of administration

NovoMix 30 (Insulin Aspart) 30 is a biphasic suspension of the insulin analogue, insulin aspart. The suspension contains rapid-acting and intermediate-acting insulin aspart in the ratio 30/70.

NovoMix 30 (Insulin Aspart) 30 is for subcutaneous administration only.

NovoMix 30 (Insulin Aspart) 30 is administered subcutaneously by injection 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 the absorption of NovoMix 30 (Insulin Aspart) 30 has not been investigated. The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

NovoMix 30 (Insulin Aspart) 30 has a faster onset of action than biphasic human insulin and should generally be given immediately before a meal. When necessary, NovoMix 30 (Insulin Aspart) 30 can be given soon after a meal.

For detailed user instructions, please refer to the package leaflet.

NovoMix 30 (Insulin Aspart) 30 Penfill

Administration with an insulin delivery system

NovoMix 30 (Insulin Aspart) 30 Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist needles. NovoMix 30 (Insulin Aspart) 30 Penfill is only suitable for subcutaneous injections from a reusable pen. If administration by syringe is necessary, a vial should be used.

NovoMix 30 (Insulin Aspart) 30 FlexPen

Administration with FlexPen

NovoMix 30 (Insulin Aspart) 30 FlexPen is a pre-filled pen (colour-coded) designed to be used with NovoFine or NovoTwist needles. FlexPen delivers 1-60 units in increments of 1 unit. NovoMix 30 (Insulin Aspart) 30 FlexPen is only suitable for subcutaneous injections. If administration by syringe is necessary, a vial should be used.

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

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.

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.

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.

NovoMix 30 (Insulin Aspart) 30 must not be administered intravenously, as it may result in severe hypoglycaemia. Intramuscular administration should be avoided. NovoMix 30 (Insulin Aspart) 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 30 (Insulin Aspart) must not be injected. After stabilisation of the patient's blood glucose, adjustment of the dose should be considered.

Compared with biphasic human insulin, NovoMix 30 (Insulin Aspart) 30 may have a more pronounced glucose lowering effect up to 6 hours after injection. This may have to be compensated for in the individual patient through adjustment of insulin dose and/or food intake.

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.

Since NovoMix 30 (Insulin Aspart) 30 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 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 NovoMix 30 (Insulin Aspart) 30 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 NovoMix 30 (Insulin Aspart) 30.

Combination of NovoMix 30 (Insulin Aspart) 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 NovoMix 30 (Insulin Aspart) 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 NovoMix 30 (Insulin Aspart) 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.

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.

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.

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.).

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).

* see section 4.8, Description of selected adverse reactions.

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.

Lipodystrophy:

Lipodystrophy (including lipohypertrophy, lipoatrophy) may occur at the injection site. Continuous rotation of the injection site within the particular injection area reduces the risk of developing these reactions.

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:

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple store

Summary of the safety profile

Adverse reactions observed in patients using NovoMix 30 (Insulin Aspart) 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).

* see Description of selected adverse reactions

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 concentrating, 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.

Lipodystrophy:

Lipodystrophy (including lipohypertrophy, lipoatrophy) may occur at the injection site. Continuous rotation of the injection site within the particular area reduces the risk of developing these reactions.

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 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

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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.

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.

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 (GIR_max,AUC_{GIR, 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.

The efficacy and safety of NovoRapid given as bolus insulin in combination with either insulin detemir or insulin degludec as basal insulin has been studied for up to 12 months, in two randomised controlled clinical trials in adolescents and children aged 1 to less than 18 years (n=712). The trials included 167 children aged 1-5 years, 260 aged 6-11 and 285 aged 12-17. The observed improvements in HbA1c and the safety profiles were comparable between all age groups.

Pregnancy

A clinical trial comparing safety and efficacy of insulin aspart vs. human insulin in the treatment of pregnant women with type 1 diabetes (322 exposed pregnancies (insulin aspart: 157; human insulin: 165)) did not indicate any adverse effect of insulin aspart on pregnancy or on the health of the foetus/newborn.

In addition the data from a clinical trial including 27 women with gestational diabetes randomised to treatment with insulin aspart vs. human insulin (insulin aspart: 14; human insulin: 13) showed similar safety profiles between treatments.

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

NovoMix 30 (Insulin Aspart) 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 (Insulin Aspart) 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 (Insulin Aspart) 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).

Figure 1: Activity profile of NovoMix 30 (Insulin Aspart) 30 (^___) and biphasic human insulin 30 (---) in healthy subjects.

Clinical efficacy and safety

In a 3 month trial in patients with type 1 and type 2 diabetes, NovoMix 30 (Insulin Aspart) 30 showed equal control of glycosylated haemoglobin compared to treatment with biphasic human insulin 30. Insulin aspart is equipotent to human insulin on a molar basis. Compared to biphasic human insulin 30, administration of NovoMix 30 (Insulin Aspart) 30 before breakfast and dinner resulted in lower postprandial blood glucose after both meals (breakfast and dinner).

A meta-analysis including nine trials in patients with type 1 and type 2 diabetes showed that fasting blood glucose was higher in patients treated with NovoMix 30 (Insulin Aspart) 30, than in patients treated with biphasic human insulin 30.

In one study, 341 patients with type 2 diabetes were randomised to treatment with NovoMix 30 (Insulin Aspart) 30 either alone or in combination with metformin, or to metformin together with sulfonylurea. The primary efficacy variable - HbA_1c after 16 weeks of treatment - did not differ between patients with NovoMix 30 (Insulin Aspart) 30 combined with metformin and patients with metformin plus sulfonylurea. In this trial, 57% of the patients had baseline HbA_1c above 9%; in these patients, treatment with NovoMix 30 (Insulin Aspart) 30 in combination with metformin resulted in significantly lower HbA_1c than metformin in combination with sulfonylurea.

In one study, patients with type 2 diabetes, insufficiently controlled on oral hypoglycaemic agents alone, were randomised to treatment with twice daily NovoMix 30 (Insulin Aspart) 30 (117 patients) or once daily insulin glargine (116 patients)._1c was 2.8% with NovoMix 30 (Insulin Aspart) 30 (mean at baseline = 9.7%). With NovoMix 30 (Insulin Aspart) 30, 66% and 42% of the patients reached HbA_1c levels below 7% and 6.5%, respectively, and mean FPG was reduced by about 7 mmol/l (from 14.0 mmol/l at baseline to 7.1 mmol/l).

In patients with type 2 diabetes, a meta-analysis showed a reduced risk of overall nocturnal hypoglycaemic episodes and major hypoglycaemia with NovoMix 30 (Insulin Aspart) 30 compared to biphasic human insulin 30. The risk of overall daytime hypoglycaemic episodes was increased in patients treated with NovoMix 30 (Insulin Aspart) 30.

Paediatric population

A 16-week clinical trial comparing postprandial glycaemic control of meal-related NovoMix 30 (Insulin Aspart) 30 with meal-related human insulin/biphasic human insulin 30 and bedtime NPH insulin was performed in 167 patients aged 10 to 18 years. Mean HbA_1c remained similar to baseline throughout the trial in both treatment groups, and there was no difference in hypoglycaemia rate with NovoMix 30 (Insulin Aspart) 30 or biphasic human insulin 30.

In a smaller (54 patients) and younger (age range 6 to 12 years) population, treated in a double-blind, cross-over trial (12 weeks on each treatment), the rate of hypoglycaemic episodes and the postprandial glucose increase were significantly lower with NovoMix 30 (Insulin Aspart) 30 compared to biphasic human insulin 30. Final HbA_1c was significantly lower in the biphasic human insulin 30 treated group compared with NovoMix 30 (Insulin Aspart) 30.

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 C_max (352±240 pmol/l) and later t_max (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 C_max 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 t_max (82 (interquartile range: 60-120) minutes), whereas C_max was similar to that observed in younger patients with type 2 diabetes and slightly lower than in patients with type 1 diabetes.

Hepatic impairment

A single dose pharmacokinetic study of insulin aspart was performed in 24 subjects with hepatic function ranging from normal to severely impaired. In patients with hepatic impairment, absorption rate was decreased and more variable, resulting in delayed t_max from about 50 min in subjects with normal hepatic function to about 85 min in patients with moderate and severe hepatic impairment. AUC, C_max and CL/F were similar in patients with reduced hepatic function compared with subjects with normal hepatic function.

Renal impairment

A single dose pharmacokinetic study of insulin aspart in 18 subjects with renal function ranging from normal to severely impaired was performed. No apparent effect of creatinine clearance values on AUC, C_max, CL/F and t_max of insulin aspart was found. Data were limited in patients with moderate and severe renal impairment. Patients with renal failure necessitating dialysis treatment were not investigated.

Paediatric population

The pharmacokinetic and pharmacodynamic properties of NovoRapid were 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 t_max as in adults. However, C_max differed between the age groups, stressing the importance of the individual titration of NovoRapid.

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 (Insulin Aspart) 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 (Insulin Aspart) 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 (t_½) of NovoMix 30 (Insulin Aspart) 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 (Insulin Aspart) 30 have not been investigated in elderly patients or in patients with renal or hepatic impairment.

Paediatric population

The pharmacokinetics of NovoMix 30 (Insulin Aspart) 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 t_max as in adults. However, C_max differed between the age groups, stressing the importance of the individual titration of insulin aspart.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.

In in vitro tests, including binding to insulin and IGF-1 receptor sites and effects on cell growth, insulin aspart behaved in a manner that closely resembled human insulin. Studies also demonstrate that the dissociation of binding to the insulin receptor of insulin aspart is equivalent to human insulin.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.

In in vitro tests, including binding to insulin and IGF-1 receptor sites and effects on cell growth, insulin aspart behaved in a manner that closely resembled human insulin. Studies also demonstrate that the dissociation of binding to the insulin receptor of insulin aspart is equivalent to human insulin.

Substances added to NovoRapid may cause degradation of insulin aspart.

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

Do not use this medicinal product if you notice that the solution is not clear, colourless and aqueous.

NovoRapid which has been frozen must not be used.

The patient should be advised to discard the needle after each injection.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Needles, syringes, cartridges, pre-filled pens and infusion sets must not be shared.

The cartridge must not be refilled.

NovoRapid vial

Tubings in which the inner surface materials are made of polyethylene or polyolefin have been evaluated and found compatible with pump use.

NovoRapid PumpCart

NovoRapid PumpCart is a pre-filled cartridge ready for use directly in the pump. Please refer to the package leaflet where detailed instructions for use are provided.

To ensure correct dosing, NovoRapid PumpCart must not be used in an insulin pen.

NovoRapid PumpCart is only for use with an insulin infusion pump system designed to be used with this cartridge, such as the Accu- Tubings in which the inner surface materials are made of polyethylene or polyolefin have been evaluated and found compatible with pump use.

After removing NovoMix 30 (Insulin Aspart) 30 Penfill or NovoMix 30 (Insulin Aspart) 30 FlexPen from the refrigerator, it is recommended to allow NovoMix 30 (Insulin Aspart) 30 Penfill or NovoMix 30 (Insulin Aspart) 30 FlexPen to reach room temperature before resuspending the insulin as instructed for first time use.

Do not use this medicinal product if you notice that the resuspended liquid is not uniformly white, cloudy and aqueous.

The necessity of resuspending the NovoMix 30 (Insulin Aspart) 30 suspension immediately before use is to be stressed to the patient.

NovoMix 30 (Insulin Aspart) 30 which has been frozen must not be used.

The patient should be advised to discard the needle after each injection.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Needles, cartridges and pre-filled pens must not be shared.

The cartridge must not be refilled.