NovoRapid 100 U/ml solution for injection in vial.

NovoRapid Penfill 100 U/ml solution for injection in cartridge.

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

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

1 ml of the solution contains 100 U of insulin aspart* (equivialent to 3.5mg).

1 vial contains 10 ml equivalent to 1,000 U.

1 cartridge contains 3 ml equivalent to 300 U.

1 pre-filled pen contains 3 ml equivalent to 300 U.

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

For a full list of excipients, see section 6.1.

Solution for injection in vial.

Solution for injection in cartridge. Penfill.

Solution for injection in pre-filled pen. FlexPen.

Solution for injection in pre-filled pen. FlexTouch.

Clear, colourless, aqueous solution.

Treatment of diabetes mellitus in adults and adolescents and children aged 2 to 17 years.

NovoRapid is a rapid-acting insulin analogue.

Posology

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 given at least once a day. 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 U/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 dosage may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.

Special population

As with all insulin products, in elderly patients and patients with renal or hepatic impairment, glucose monitoring should be intensified and insulin aspart dosage adjusted on an individual basis.

Paediatric use

No studies have been performed in children below the age of 2 years. NovoRapid should only be used in this age group under careful medical supervision.

NovoRapid can be used in children in preference to soluble human insulin when a rapid onset of action might be beneficial (see section 5.1 and 5.2). For example, in the timing of the injections in relation to meals.

Transfer from other insulin products

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.

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. The faster onset of action compared to soluble human insulin is maintained regardless of injection site. When transferring from other insulin products, adjustment of the NovoRapid dose and the dose of the basal insulin may be necessary.

Method of administration

NovoRapid vial and FlexPen:

Administration with a syringe:

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 therefore always be rotated within the same region. As with all insulin products, subcutaneous injection in the abdominal wall ensures a faster absorption than other injection sites. The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

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 accompanied by a package leaflet with detailed instruction for use to be followed.

NovoRapid FlexPen:

Administration with FlexPen:

NovoRapid FlexPen are pre-filled pens designed to be used with NovoFine or NovoTwist needles. FlexPen delivers 1-60 units in increments of 1 unit.

NovoRapid FlexPen is colour coded and accompanied by a package leaflet with detailed instruction for use to be followed.

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 therefore always be rotated within the same region. As with all insulin products, subcutaneous injection in the abdominal wall ensures a faster absorption than other injection sites. The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

NovoRapid FlexTouch:

Administration with FlexTouch:

NovoRapid FlexTouch are pre-filled pens designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm.

The patient should be advised not to use any counterfeit needles.

FlexTouch delivers 1-80 units in increments of 1 unit.

NovoRapid FlexTouch is colour coded and accompanied by a package leaflet with detailed instruction for use to be followed.

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 therefore always be rotated within the same region. As with all insulin products, subcutaneous injection in the abdominal wall ensures a faster absorption than other injection sites. The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

NovoRapid vial, Penfill, FlexPen and FlexTouch:

Continuous Subcutaneous Insulin Infusion (CSII):

NovoRapid may be used for Continuous Subcutaneous Insulin Infusion (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 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 alternative insulin available in case of pump system failure.

Intravenous use:

If necessary, NovoRapid can be administered intravenously which should be carried out by health care professionals.

For intravenous use, infusion systems with NovoRapid 100 U/ml at concentrations from 0.05 U/ml to 1.0 U/ml insulin aspart in the infusion fluids 0.9% sodium chloride, 5% dextrose or 10% dextrose inclusive 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.

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

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.

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.

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 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 medication where a delayed absorption of food might be expected.

Concomitant illness, especially infections and feverish conditions, usually increases the patient's insulin requirements.

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

Transfer from other insulin 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, human insulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in the need for a change in dosage. Patients transferred to NovoRapid from another type of insulin may require an increased number of daily injections or a change in dosage from that used with their usual insulins. 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, swelling and itching. Continuous rotation of the injection site within a given area may help to reduce or prevent 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.

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-blocking agents may mask the symptoms of hypoglycaemia.

Octreotide/lanreotide may both increase or decrease 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 dosage may need to be adjusted.

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.

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

Hypoglycaemia is a common undesirable effect. 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.

In clinical trials and during marketed use the frequency varies with patient population and dose regimens therefore no specific frequency can be presented. During clinical trials the overall rates of hypoglycaemia did not differ between patients treated with insulin aspart compared to human insulin.

Adverse reactions listed below are classified according to 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 fromthe available data).

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 by glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or by glucose given intravenously by a health care professional. Glucose must also 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: Insulins and analogues for injection, fast-acting: ATC code A10AB05.

Mechanism of action

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.

Adults

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 glycosylated 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 doubtful clinical significance.

Elderly

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 human insulin in elderly were similar to those seen in healthy subjects and in younger subjects with diabetes.

Children and adolescent

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.

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.

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.

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

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 U/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.

Children and adolescent

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.

Elderly

The relative differences in pharmacokinetic properties between insulin aspart and soluble human insulin in elderly subjects (65-83 years, mean age 70 years) with type 2 diabetes were similar to those observed in healthy subjects and in younger subjects with diabetes. A decreased absorption rate was observed in elderly subjects, resulting in a later t_max (82 (interquartile range: 60-120) minutes), whereas C_max was similar to that observed in younger subjects with type 2 diabetes and slightly lower than in subjects 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 subjects 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 subjects with moderate and severe hepatic impairment. AUC, C_max and CL/F were similar in subjects 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 subjects with moderate and severe renal impairment. Subjects with renal failure necessitating dialysis treatment were not investigated.

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

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.

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, e.g. if the medicinal product contains thiols or sulphites.

This medicinal product must not be mixed with other medicinal products. Exceptions are NPH (Neutral Protamine Hagedorn) insulin and infusion fluids as described in section 4.2.

30 months.

After first opening: A maximum of 4 weeks when stored below 30°C.

Store in a refrigerator (2°C - 8°C). Keep away from the cooling element. Do not freeze.

NovoRapid vial:

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

NovoRapid Penfill:

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

NovoRapid FlexPen:

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

NovoRapid FlexTouch:

Keep the cap on FlexTouch Pen in order to protect from light.

After first opening or carried as a spare: Do not refrigerate. Store below 30°C.

NovoRapid must be protected from excessive heat and light.

NovoRapid vial:

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

Pack sizes of 1 and 5 vials and a multipack with 5 x (1 x 10 ml) vials. Not all pack sizes may be marketed.

NovoRapid Penfill:

3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a stopper (bromobutyl/polyisoprene) in a carton.

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

NovoRapid FlexPen:

3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a stopper (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 FlexTouch:

3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a stopper (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 a multipack with 2 x 5 (without needles) pre-filled pens of 3 ml. Not all pack sizes may be marketed.

NovoRapid vials are for use with insulin syringes with the corresponding unit scale.

NovoRapid Penfill is for use by one person only. The cartridge must not be refilled.

NovoRapid FlexPen is for use by one person only. The cartridge must not be refilled.

NovoRapid FlexTouch is for use by one person only. The cartridge must not be refilled.

NovoRapid must not be used if it does not appear clear and colourless.

NovoRapid which has been frozen must not be used.

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

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

NovoRapid Penfill:

In case of emergency in current NovoRapid users (hospitalisation or insulin pen malfunction), NovoRapid can be withdrawn with an U100 insulin syringe from the cartridge.

NovoRapid FlexPen:

In case of emergency in current NovoRapid users (hospitalisation or insulin pen malfunction), NovoRapid can be withdrawn with an U100 insulin syringe from the FlexPen.

NovoRapid FlexTouch:

In case of emergency in current NovoRapid users (hospitalisation or insulin pen malfunction), NovoRapid can be withdrawn with an U100 insulin syringe from a FlexTouch Pen.

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

EU/1/99/119/001

EU/1/99/119/003

EU/1/99/119/009

EU/1/99/119/020

Date of first authorisation: 7 September 1999

Date of last renewal: 30 April 2009

07/2011