NOVORAPID FLEXPEN 100U / ml injectible solution medication leaflet

NovoRapid 100 units/ml solution for injection in vial

NovoRapid Penfill 100 units/ml solution for injection in cartridge

NovoRapid FlexPen 100 units/ml solution for injection in pre-filled pen

NovoRapid InnoLet 100 units/ml solution for injection in pre-filled pen

NovoRapid FlexTouch 100 units/ml solution for injection in pre-filled pen

NovoRapid PumpCart 100 units/ml solution for injection in cartridge

NovoRapid vial1 vial contains 10 ml equivalent to 1,000 units.1 ml solution contains 100 units insulin aspart*(equivalent to 3.5 mg).

NovoRapid Penfill1 cartridge contains 3 ml equivalent to 300 units.1 ml solution contains 100 units insulin aspart*(equivalent to 3.5 mg).

NovoRapid FlexPen/NovoRapid InnoLet/NovoRapid FlexTouch1 pre-filled pen contains 3 ml equivalent to 300 units.1 ml solution contains 100 units insulin aspart*(equivalent to 3.5 mg).

NovoRapid PumpCart1 cartridge contains 1.6 ml equivalent to 160 units.1 ml solution contains 100 units insulin aspart*(equivalent to 3.5 mg).

*Insulin aspart is produced in Saccharomyces cerevisiae by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection.

The solution is clear, colourless and aqueous.

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

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

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

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

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

Blood glucose monitoring and insulin dose adjustments are recommended to achieve optimalglycaemic 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 andthe remainder by intermediate-acting or long-acting insulin.

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

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 anindividual basis.

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 insulinaspart dose adjusted on an individual basis.

NovoRapid can be used in children and adolescents aged 1 year and above in preference to solublehuman insulin when a rapid onset of action might be beneficial, for example, in the timing of theinjections 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 thedose of the basal insulin may be necessary. NovoRapid has a faster onset and a shorter duration ofaction than soluble human insulin. When injected subcutaneously into the abdominal wall, the onset ofaction will occur within 10-20 minutes of injection. The maximum effect is exerted between 1 and3 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 (seesection 4.4).

NovoRapid is a rapid-acting insulin analogue.

NovoRapid is administered subcutaneously by injection in the abdominal wall, the thigh, the upperarm, the deltoid region or the gluteal region. Injection sites should always be rotated within the sameregion in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see sections 4.4 and4.8). Subcutaneous injection in the abdominal wall ensures a faster absorption than other injectionsites. Compared to soluble human insulin the faster onset of action of NovoRapid is maintainedregardless 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 beadministered in the abdominal wall. Infusion sites should be rotated.

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

Patients using CSII should be comprehensively instructed in the use of the pump system and use thecorrect 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 theinfusion set.

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

NovoRapid vial

If necessary, NovoRapid can be administered intravenously which should be carried out by physiciansor other healthcare staff.

For intravenous use, infusion systems with NovoRapid 100 units/ml at concentrations from0.05 unit/ml to 1.0 unit/ml insulin aspart in the infusion fluids 0.9% sodium chloride, 5% dextrose or10% dextrose including 40 mmol/l potassium chloride using polypropylene infusion bags, are stable atroom temperature for 24 hours.

Although stable over time, a certain amount of insulin will be initially adsorbed to the material of theinfusion 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 forsubcutaneous use. When NovoRapid is mixed with NPH insulin, NovoRapid should be drawn into thesyringe first, and the mixture should be injected immediately after mixing. Insulin mixtures should notbe 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 section6.2.

NovoRapid Penfill

Administration with an insulin delivery system

NovoRapid Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFineor NovoTwist needles. NovoRapid Penfill is only suitable for subcutaneous injections from a reusablepen. If administration by syringe or intravenous injection is necessary, a vial should be used. Ifadministration by infusion pump is necessary, a vial or NovoRapid PumpCart should be used.

NovoRapid FlexPen

Administration with FlexPen

NovoRapid FlexPen 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 of1 unit. NovoRapid FlexPen is only suitable for subcutaneous injections. If administration by syringe orintravenous injection is necessary, a vial should be used. If administration by infusion pump isnecessary, a vial or NovoRapid PumpCart should be used.

NovoRapid InnoLet

Administration with InnoLet

NovoRapid InnoLet is a pre-filled pen designed to be used with NovoFine or NovoTwist disposableneedles up to a length of 8 mm. InnoLet delivers 1-50 units in increments of 1 unit. NovoRapid

InnoLet is only suitable for subcutaneous injections. If administration by syringe or intravenousinjection 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 of1 unit. NovoRapid FlexTouch is only suitable for subcutaneous injections. If administration by syringeor intravenous injection is necessary, a vial should be used. If administration by infusion pump isnecessary, 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 withthis 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 bysyringe or intravenous injection is necessary, a vial should be used.

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

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

Before travelling between different time zones, the patient should seek the doctor’s advice since thismay 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 withthis cartridge, such as the Accu-Chek Insight and YpsoPump insulin pumps. It must not be used withother devices not designed for NovoRapid PumpCart, as this may result in incorrect insulin dosing andsubsequent hyper- or hypoglycaemia.

Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead tohyperglycaemia and diabetic ketoacidosis. Usually the first symptoms of hyperglycaemia developgradually 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 ispotentially lethal.

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 ofhypoglycaemia.

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

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

A consequence of the pharmacodynamics of rapid-acting insulin analogues is that if hypoglycaemiaoccurs, 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 actionshould be considered in patients with concomitant diseases or treatment where a delayed absorption offood might be expected.

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

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

Transfer from other insulin medicinal products

Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. Changes in strength, brand (manufacturer), type, origin (animal, human insulin or humaninsulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) mayresult in the need for a change in dose. Patients transferred to NovoRapid from another type of insulinmay require an increased number of daily injections or a change in dose from that used with theirusual insulin medicinal products. If an adjustment is needed, it may occur with the first dose or duringthe first few weeks or months.

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 givenarea reduces the risk of developing these reactions. Reactions usually resolve in a few days to a fewweeks. On rare occasions, injection site reactions may require discontinuation of NovoRapid.

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk ofdeveloping lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulinabsorption and worsened glycaemic control following insulin injections at sites with these reactions. Asudden 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 anunaffected 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 inmind if treatment with the combination of pioglitazone and NovoRapid is considered. If thecombination is used, patients should be observed for signs and symptoms of heart failure, weight gainand 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 accidentalmix-ups between NovoRapid and other insulin products.

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

In order to improve the traceability of biological medicinal products, the name and the batch number ofthe 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, angiotensinconverting 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 hormoneand 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.

NovoRapid (insulin aspart) can be used in pregnancy. Data from two randomised controlled clinicaltrials (322 and 27 exposed pregnancies) do not indicate any adverse effect of insulin aspart onpregnancy 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 whencontemplating pregnancy. Insulin requirements usually fall in the first trimester and increasesubsequently during the second and third trimester. After delivery, insulin requirements normallyreturn rapidly to pre-pregnancy values.

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

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 mayconstitute a risk in situations where these abilities are of special importance (e.g. driving a car oroperating machinery).

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

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

The most frequently reported adverse reaction during treatment is hypoglycaemia. The frequencies ofhypoglycaemia vary with patient population, dose regimens and level of glycaemic control (seesection 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 beassociated with acute painful neuropathy, which is usually reversible. Intensification of insulin therapywith abrupt improvement in glycaemic control may be associated with temporary worsening ofdiabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression ofdiabetic retinopathy.

Adverse reactions listed below are based on clinical trial data and classified according to MedDRAfrequency and System Organ Class. Frequency categories are defined according to the followingconvention: 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 theavailable data).

Immune system disorders Uncommon - Urticaria, rash, eruptions

Very rare - Anaphylactic reactions*

Metabolism and nutrition Very common - Hypoglycaemia*disorders

Nervous system disorders Rare - Peripheral neuropathy (painful neuropathy)

Eye disorders Uncommon - Refraction disorders

Uncommon - Diabetic retinopathy

Skin and subcutaneous tissue Uncommon - Lipodystrophy*disorders

Not known - Cutaneous amyloidosis*†

General disorders and Uncommon - Injection site reactionsadministration siteconditions Uncommon - Oedema

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

Anaphylactic reactions:

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

The most frequently reported adverse reaction is hypoglycaemia. It may occur if the insulin dose is toohigh in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/orconvulsions 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 paleskin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficultyin concentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation.

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

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

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

Based on post-marketing sources and clinical trials, the frequency, type and severity of adversereactions observed in the elderly patients and in patients with renal or hepatic impairment do notindicate any differences to the broader experience in the general population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop oversequential 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 sugaryproducts. It is therefore recommended that the diabetic patient always carries sugar-containingproducts.

* Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated withglucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or withglucose given intravenously by physicians or other healthcare staff. Glucose must be givenintravenously, if the patient does not respond to glucagon within 10 to 15 minutes. Uponregaining consciousness, administration of oral carbohydrates is recommended for the patient inorder 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 followingbinding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucoseoutput from the liver.

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

Fig. I. Blood glucose concentrations following a single pre-meal dose of NovoRapid injectedimmediately before a meal (solid curve) or soluble human insulin administered 30 minutes before ameal (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 ofinjection. The maximum effect is exerted between 1 and 3 hours after injection. The duration of actionis 3 to 5 hours.

Clinical trials in patients with type 1 diabetes have demonstrated a lower postprandial blood glucosewith NovoRapid compared to soluble human insulin (Fig. I). In two long-term open label trials inpatients with type 1 diabetes comprising 1070 and 884 patients, respectively, NovoRapid reducedglycated 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 nocturnalhypoglycaemia with insulin aspart compared with soluble human insulin. The risk of daytimehypoglycaemia was not significantly increased.

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

Elderly (≥ 65 years old)

A randomised, double-blind cross-over PK/PD trial comparing insulin aspart with soluble humaninsulin was performed in elderly patients with type 2 diabetes (19 patients aged 65-83 years, mean age70 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 healthysubjects and in younger patients with diabetes.

A clinical trial comparing preprandial soluble human insulin with postprandial insulin aspart wasperformed in small children (20 patients aged 2 to less than 6 years, studied for 12 weeks, among thosefour 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 childrenwas similar to that seen in adults.

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

A clinical trial comparing safety and efficacy of insulin aspart vs. human insulin in the treatment ofpregnant 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 thefoetus/newborn.

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

Absorption, distribution and elimination

In NovoRapid substitution of amino acid proline with aspartic acid at position B28 reduces thetendency to form hexamers as observed with soluble human insulin. NovoRapid is therefore morerapidly 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 meanmaximum 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 insulinconcentrations returned to baseline about 4 to 6 hours after dose. The absorption rate was somewhatslower 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 maximumconcentration is significantly less for NovoRapid than for soluble human insulin, whereas the intra-individual variability in Cmax for NovoRapid is larger.

Elderly (≥ 65 years old)

The relative differences in pharmacokinetic properties between insulin aspart and soluble humaninsulin in elderly patients (65-83 years, mean age 70 years) with type 2 diabetes were similar to thoseobserved in healthy subjects and in younger patients with diabetes. A decreased absorption rate wasobserved 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 lowerthan in patients with type 1 diabetes.

A single dose pharmacokinetic study of insulin aspart was performed in 24 subjects with hepaticfunction ranging from normal to severely impaired. In patients with hepatic impairment, absorptionrate was decreased and more variable, resulting in delayed tmax from about 50 min in subjects withnormal hepatic function to about 85 min in patients with moderate and severe hepatic impairment.

AUC, Cmax and CL/F were similar in patients with reduced hepatic function compared with subjectswith normal hepatic function.

A single dose pharmacokinetic study of insulin aspart in 18 subjects with renal function ranging fromnormal to severely impaired was performed. No apparent effect of creatinine clearance values on

AUC, Cmax, CL/F and tmax of insulin aspart was found. Data were limited in patients with moderate andsevere renal impairment. Patients with renal failure necessitating dialysis treatment were notinvestigated.

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 absorbedin both age groups, with similar tmax as in adults. However, Cmax differed between the age groups,stressing the importance of the individual titration of NovoRapid.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, 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 thatthe dissociation of binding to the insulin receptor of insulin aspart is equivalent to human insulin.

Glycerol

Phenol

Metacresol

Zinc chloride

Disodium phosphate dihydrate

Sodium chloride

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

Substances added to NovoRapid may cause degradation of insulin aspart.

This medicinal product must not be diluted or mixed with other medicinal products except for mixingwith NPH (Neutral Protamine Hagedorn) insulin in a syringe for subcutaneous use, or with infusionfluids as described in section 4.2.

Before opening: 30 months.

NovoRapid vial/NovoRapid Penfill/NovoRapid FlexPen/NovoRapid InnoLet/NovoRapid FlexTouch

During use or when carried as a spare: The product must be stored for a maximum of 4 weeks. Storebelow 30°C.

NovoRapid PumpCart

During use or when carried as a spare: NovoRapid PumpCart carried as a spare can be kept for up to2 weeks below 30°C. Thereafter it can be used for up to 7 days below 37°C in an insulin infusionpump system designed to be used with this cartridge, such as the Accu-Chek Insight and YpsoPumpinsulin pumps.

For storage conditions of the medicinal product, see section 6.3.

Before opening: Store in a refrigerator (2°C - 8°C). Do not freeze.

NovoRapid vial/NovoRapid Penfill

During use or when carried as a spare: Store below 30°C. Do not refrigerate. Do not freeze.

Keep the vial/cartridge in the outer carton in order to protect from light.

NovoRapid FlexPen/NovoRapid FlexTouch

During use or when carried as a spare: Store below 30˚C. Can be stored in a refrigerator (2˚C - 8˚C).

Do not freeze.

Keep the pen cap on the pen in order to protect from light.

NovoRapid InnoLet

During use or when carried as a spare: Store below 30°C. Do not refrigerate. Do not freeze.

Keep the pen cap on the pen in order to protect from light.

NovoRapid PumpCart

During use or when carried as a spare: Store below 37°C (in use) or store below 30°C (carried as aspare). Do not refrigerate. Do not freeze.

Keep the cartridge in the outer carton in order to protect from light.

NovoRapid vial10 ml solution in vial (type 1 glass) closed with a disc (bromobutyl/polyisoprene rubber) and aprotective tamper-proof plastic cap.

Pack sizes of 1 or 5 vials of 10 ml or a multipack containing 5 packs of 1 x 10 ml vial. Not all packsizes may be marketed.

NovoRapid Penfill3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure(bromobutyl/polyisoprene).

Pack sizes of 5 and 10 cartridges. Not all pack sizes may be marketed.

NovoRapid FlexPen3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure(bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene.

Pack sizes of 1 (with or without needles), 5 (without needles) and 10 (without needles) pre-filled pens.

Not all pack sizes may be marketed.

NovoRapid InnoLet3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure(bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene.

Pack sizes of 1, 5 and 10 pre-filled pens. Not all pack sizes may be marketed.

NovoRapid FlexTouch3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure(bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene.

Pack sizes of 1 (with or without needles), 5 (without needles) or a multipack with 2 x 5 (withoutneedles) pre-filled pens of 3 ml. Not all pack sizes may be marketed.

NovoRapid PumpCart1.6 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure(bromobutyl/polyisoprene).

Pack size of 5 cartridges and a multipack containing 25 (5 packs of 5) cartridges. Not all pack sizesmay be marketed.

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 localrequirements.

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

The cartridge must not be refilled.

NovoRapid vial

NovoRapid may be used in an infusion pump system (CSII) as described in section 4.2. Tubings inwhich the inner surface materials are made of polyethylene or polyolefin have been evaluated andfound compatible with pump use.

NovoRapid PumpCart

NovoRapid PumpCart is a pre-filled cartridge ready for use directly in the pump. Please refer to thepackage 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 withthis cartridge, such as the Accu-Chek Insight and YpsoPump insulin pumps, as described in section4.2. Tubings in which the inner surface materials are made of polyethylene or polyolefin have beenevaluated and found compatible with pump use.

Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark

NovoRapid vial

EU/1/99/119/001

EU/1/99/119/008

EU/1/99/119/015

NovoRapid Penfill

EU/1/99/119/003

EU/1/99/119/006

NovoRapid FlexPen

EU/1/99/119/009

EU/1/99/119/010

EU/1/99/119/011

EU/1/99/119/017

EU/1/99/119/018

NovoRapid InnoLet

EU/1/99/119/012

EU/1/99/119/013

EU/1/99/119/014

NovoRapid FlexTouch

EU/1/99/119/019

EU/1/99/119/020

EU/1/99/119/021

EU/1/99/119/022

EU/1/99/119/023

NovoRapid PumpCart

EU/1/99/119/024

EU/1/99/119/025

Date of first authorisation: 7 September 1999

Date of last renewal: 30 April 2009

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.