Data Sheet
NOVORAPID®
Insulin Aspart 100 Units/ml NOVO NORDISK
Recombinant DNA origin: Saccharomyces cerevisiae
Presentation
NovoRapid is a sterile, clear, colourless, aqueous, neutral solution of insulin aspart (B28 Asp), human insulin analogue for subcutaneous injection/infusion or intravenous injection. One unit of insulin aspart corresponds to 6 nmol or 0.035mg salt-free anhydrous insulin aspart per ml.
Uses
Actions
Pharmacotherapeutic group: insulins and analogues, fast acting. ATC code A10A B05.
The blood glucose lowering effect of insulin occurs when the molecules facilitate the uptake of glucose by binding to insulin receptors on muscle and fat cells and simultaneously inhibit the output of glucose 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 10-20 minutes of injection. The maximum effect is exerted between 1 and 3 hours after injection. The duration of action is 3 to 5 hours.
Children and adolescents: 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 thos four were younger than 4 years old) and a single dose PK/PD trial was performed in children (6 to 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.
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.
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 as well as a significant improvement in post prandial glucose control in the insulin aspart treated group.
Insulin aspart is equipotent to soluble human insulin on a molar basis.
Pharmacokinetics
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 429±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 resulting in a lower Cmax (352±240 pmol/l) and later tmax (60 (interquartile range 50-90) minutes). The intra-individual variability in time to maximum concentration is significantly less for NovoRapid than for soluble human insulin, whereas the intra-individual variability in Cmax for NovoRapid is larger.
Reduced renal or hepatic function does not alter the pharmacokinetics of NovoRapid.
Children and adolescents: 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 tmax as in adults. However, Cmax differed between the age groups, stressing the importance of the individual titration of NovoRapid
Indications
NovoRapid is indicated for the treatment of patients with insulin-requiring diabetes mellitus.
Dosage and Administration
NovoRapid has a faster onset and a shorter duration of action than soluble human insulin. Due to the faster onset of action, NovoRapid should generally be given immediately before a meal. When necessary NovoRapid may be given soon after a meal.
Due to the shorter duration, NovoRapid has a lower risk of causing nocturnal hypoglycaemic episodes.
Dosage of NovoRapid is individual and determined on the basis of the physician's advice 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.
The individual insulin requirement is usually between 0.5 and 1.0 U/kg/day in adults and children over 2 years of age. In a meal-related treatment 50-70% of this requirement may be provided by NovoRapid and the remainder by intermediate-acting or long-acting insulin. The daily insulin requirement may be higher in patients with insulin resistance (e.g. due to obesity), and lower in patients with residual endogenous insulin production.
NovoRapid can be used during pregnancy.
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 infusion pump NovoRapid should not be mixed with any other insulin.
Patients using CSII should be comprehensively instructed in the use of the pump system, and use of the correct reservoir and tubing.
Patients administering NovoRapid by CSII must have alternative insulin available in case of pump system failure.
NovoRapid is administered subcutaneously by injection in the abdominal wall, the thigh, the deltoid region or the gluteal region or by infusion in the abdominal wall. Injection sites should be rotated within the same region. If necessary NovoRapid may also be administered intravenously which should be carried out by healthcare professionals.
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. As with all insulins, the duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity. As with all insulins, subcutaneous injection in the abdominal wall will ensure a faster absorption than other injection sites. However, the faster onset of action compared to soluble insulin is maintained regardless of injection site.
Vials are for use with insulin syringes with corresponding unit scale. Draw air corresponding to insulin to be injected and expel air from the syringe before injection.
Vial and FlexPen; the needle should be kept under the skin for at least 6 seconds to make sure the entire dose is injected.
Penfill; after the injection the needle should remain under the skin for at least 6 seconds. Keep the push button fully depressed until the needle has been withdrawn from the skin. This will ensure correct delivery and limit possible flow of blood into the needle or insulin reservoir.
Renal or hepatic impairment may reduce the patients insulin requirements.
NovoRapid can be used in children in preference to soluble insulin when a fast onset of action might be beneficial, for example, in the timing of injections in relation to meals.
Contraindications
- Hypoglycaemia
- Hypersensitivity to insulin aspart or any of the excipients
Warnings and Precautions
Inadequate dosing or discontinuation of treatment may, especially in Type 1 diabetes (insulin-dependent diabetes mellitus), lead to hyperglycaemia and diabetic ketoacidosis; which are are potentially lethal.
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. A consequence of the pharmacodynamics of rapidly acting insulin analogues is that if hypoglycaemia occurs, it may occur earlier after an injection when compared with soluble human insulin.
NovoRapid should be administered in immediate relation to a meal. The rapid onset of action should therefore be considered in patients with concomitant diseases or medication where a delayed absorption of food might be expected.
Concomitant illness, especially infections, usually increases the patient's insulin requirements.
Transferring a patient to a new type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type (animal, human, human insulin analogue) and/or method of manufacture may result in a change in dosage. Adjustment of dosage may also be necessary if patients undertake increased physical activity or change their usual diet. Exercise immediately after a meal may increase the risk of hypoglycaemia. Patients taking NovoRapid 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 several weeks or months.
Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.
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
Use during pregnancy and lactation
NovoRapid can be used in pregnancy. Data from two randomised controlled clinical trials (322 and 27 exposed pregnancies respectively) do not indicate any adverse effect of insulin aspart on pregnancy or on the health of the foetus/newborn when compared to insulin human (see Actions).
Intensified blood glucose control and monitoring of pregnant women with diabetes (type 1 diabetes, Type 2 diabetes or gestational diabetes) are recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimesters. After delivery, insulin requirements return rapidly to pre-pregnant levels.
There are no restrictions on treatment with NovoRapid during lactation. Insulin treatment of the nursing mother presents no risk to the baby. However, the NovoRapid dosage may need to be adjusted.
Effects on ability to drive and use machines
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 (eg. driving a car or operating machinery).
Patients should be advised to take precautions in order to avoid hypoglycaemia whilst 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 Effects
Adverse drug reactions observed in patients using NovoRapid are mainly dose-dependent and due to the pharmacologic effect of insulin. As for other insulin products, hypoglycaemia, in general is the most frequently occurring 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.
Frequencies of adverse drug reactions from clinical trials, which by an overall judgement are considered related to NovoRapid are listed below. The frequencies are defined as: Uncommon (>1/1,000, < 1/100) and rare (>1/10,000, < 1/1,000). Isolated spontaneous cases are presented as very rare defined as (< 1/10,000).
Immune system disorders
Uncommon - Urticaria, rash, eruptions
Very rare - Anaphylactic reactions
Symptoms of generalised hypersensitivity may include generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulties in breathing, palpitation and reduction in blood pressure. Generalised hypersensitivity reactions are potentially life threatening.
Nervous system disorders
Rare - Peripheral neuropathy
Fast improvement in blood glucose control may be associated with a condition termed acute painful neuropathy, which is usually reversible.
Eye disorders
Uncommon - Refraction disorder
Refraction anomalies may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature.
Uncommon - Diabetic retinopathy
Long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy. However, intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with worsening of diabetic retinopathy.
Skin and subcutaneous tissue disorders
Uncommon - Lipodystrophy
Lipodystrophy may occur at the injection site as a consequence of failure to rotate injection sites within an area.
Uncommon - Local hypersensitivity
Local hypersensitivity reactions (redness, swelling and itching at the injection site) may occur during treatment with insulin. These reactions are usually transitory and normally they disappear during continued treatment.
General disorders and administration site conditions
Uncommon - Oedema
Oedema may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature.
Interactions
A number of medicines are known to interact with the glucose metabolism.
The following substances may reduce the patient's insulin requirements: Oral hypoglycaemic agents (OHAs), octreotide, monoamine oxidase inhibitors (MAOIs), non-selective beta-adrenergic blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol, anabolic steroids and sulphonamides.
The following substances may increase the patient's insulin requirements:
Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics and danazol.
Beta-blocking agents may mask the symptoms of hypoglycaemia.
Alcohol may intensify and prolong the hypoglycaemic effect of insulin.
Overdosage
- A specific overdose for insulin cannot be defined however hypoglycaemia may develop over sequential stages, if too high doses relative to the patient's requirements are administered.
- Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient constantly carries some sugar lumps or a source of sugar eg. a few biscuits.
- 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 glucose given intravenously by a medical 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 carbohydrate is recommended for the patient in order to prevent relapse.
Pharmaceutical Precautions
Nature and content of container
NovoRapid Penfill® cartridge 3.0 ml is made of glass, containing a rubber piston and closed with a rubber disc. The cartridge is packed in a carton.
NovoRapid FlexPen prefilled syringe comprises of a pen injector with a 3.0 ml cartridge. The cartridge is made of glass, contains a rubber piston and is closed with a rubber disc. The prefilled syringe is packed in a carton. The pen injector is made of plastic. The prefilled multidose syringe is disposable.
NovoRapid vial of 10 ml is made of glass. The vial is closed with a rubber disc and packed in a carton.
Not all presentations may be marketed.
Instructions for use and handling
The carton contains a package leaflet with instructions for use and handling.
NovoRapid Penfill
For NovoRapid Penfill, the leaflet carries a reference to the instructions for using the accompanying Novo Nordisk insulin delivery system.
NovoRapid Penfill is for use by one person only. The container must not be refilled.
NovoRapid Penfill cartridges are designed to be used with the Novo Nordisk insulin delivery system and NovoFine® needles.
NovoRapid FlexPen
NovoRapid FlexPen is for use by one person only. The container must not be refilled.
NovoRapid FlexPen prefilled syringes are designed to be used with NovoFine® needles.
NovoRapid
NovoRapid vials are for use with insulin syringes with the corresponding unit scale and for use with an infusion pump system.
Incompatibilities
Substances added to the insulin may cause degradation of the insulin, e.g. if the medicinal product contains thiol or sulphites.
Shelf-life
The in-use time is 4 weeks for cartridges and 6 weeks for vials.
Special precautions for storage
NovoRapid should be stored between 2°C and 8°C. Do not freeze.
Cartridges in use or carried as a spare should be kept at ambient temperature (below 30°C) for up to 4 weeks but should not be exposed to excessive heat or sunlight. 10 ml vials may be kept at room temperature (below 30°C) for up to 6 weeks.
Medicine Classification
Prescription Medicine
Package Quantities
NovoRapid Penfill cartridges 3.0 ml
NovoRapid FlexPen prefilled syringe 3.0 ml (not marketed)
NovoRapid vial 10 ml
Further Information
Preclinical safety data
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 demonstrated that the dissociation of binding to the insulin receptor of insulin aspart is equivalent to human insulin. Acute, one month and twelve month toxicity studies produced no toxicity findings of clinical relevance.
Animal reproduction studies have not revealed any differences between insulin aspart and insulin human regarding embryotoxicity or teratogenicity.
List of excipients
Glycerol
Phenol
Metacresol
Zinc (as chloride)
Disodium Phosphate dihydrate
Sodium chloride
Hydrochloric acid/Sodium hydroxide (for pH adjustment)
Water for injection
Trademarks
NovoRapid, Penfill, FlexPen and NovoFine are registered trademarks owned by Novo Nordisk A/S
Name and Address
Novo Nordisk Pharmaceuticals Ltd.
PO Box 51-268
Pakuranga
Auckland
Tel: (09) 916 5590
Fax: (09) 916 5595
Date of Preparation
5 October 2006
SPC 6.1.06