ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
NovoRapid 100 U/ml solution for injection in vial.
2.
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.
*Insulin aspart is produced by recombinant DNA technology in
Saccharomyces cerevisiae
.
For a full list of excipients, see section 6.1.
3.
Solution for injection in vial.
Clear, colourless, aqueous solution.
4.
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.
2
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
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.
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.
3
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.
A number of medicinal products are known to interact with the glucose metabolism.
The following substances may reduce the patient's insulin requirements:
4
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);
5
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).
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 disorders
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 temporary 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 (pain, redness, hives, inflammation,
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.
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.
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
6
•
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.
5.
5.1 Pharmacodynamic properties
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.
Time (h)
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.
7
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.
5.2 Pharmacokinetic properties
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),
8
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.
5.3 Preclinical safety data
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.
6.
6.1 List of excipients
Glycerol
Phenol
Metacresol
Zinc chloride
Disodium phosphate dihydrate
Sodium chloride
Hydrochloric acid (for pH adjustment)
Sodium hydroxide (for pH adjustment)
Water for injections
6.2 Incompatibilities
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.
6.3 Shelf life
30 months.
After first opening: A maximum of 4 weeks when stored below 30°C.
6.4 Special precautions for storage
9
Store in a refrigerator (2°C - 8°C). Keep away from the cooling element. Do not freeze.
Keep the vial in the outer carton 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.
6.5 Nature and contents of container
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.
6.6 Special precautions for disposal and other handling
NovoRapid vials are for use with insulin syringes with the corresponding unit scale.
NovoRapid must not be used if it does not appear clear and colourless.
NovoRapid which has been frozen must not be used.
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.
7.
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd
Denmark
8.
EU/1/99/119/001
EU/1/99/119/008
EU/1/99/119/015
9.
Date of first authorisation: 7 September 1999
Date of last renewal: 30 April 2009
10
1.
NovoRapid Penfill 100 U/ml solution for injection in cartridge.
2.
1 ml of the solution contains 100 U of insulin aspart* (equivialent to 3.5mg). 1 cartridge 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.
3.
Solution for injection in cartridge. Penfill.
Clear, colourless, aqueous solution.
4.
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.
11
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
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 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.
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.
12
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.
13
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 duringbreast-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.
14
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).
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 disorders
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 temporary 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 (pain, redness, hives, inflammation,
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.
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.
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:
15
•
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.
5.
5.1 Pharmacodynamic properties
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.
Time (h)
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
16
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.
5.2 Pharmacokinetic properties
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
17
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.
5.3 Preclinical safety data
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.
6.
6.1 List of excipients
Glycerol
Phenol
Metacresol
Zinc chloride
Disodium phosphate dihydrate
Sodium chloride
Hydrochloric acid (for pH adjustment)
Sodium hydroxide (for pH adjustment)
Water for injections
6.2 Incompatibilities
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 (Neu-
tral Protamine Hagedorn) insulin and infusion fluids as described in section 4.2.
6.3 Shelf life
30 months.
After first opening: A maximum of 4 weeks when stored below 30°C.
18
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C). Keep away from the cooling element. Do not freeze.
Keep the cartridge in the outer carton 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.
6.5 Nature and contents of container
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.
6.6 Special precautions for disposal and other handling
NovoRapid Penfill 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.
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.
7.
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd
Denmark
8.
EU/1/99/119/003
EU/1/99/119/006
9.
Date of first authorisation: 7 September 1999
Date of last renewal: 30 April 2009
19
1.
NovoRapid NovoLet 100 U/ml solution for injection in pre-filled pen.
2.
1 ml of the solution contains 100 U of insulin aspart* (equivialent to 3.5mg). 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.
3.
Solution for injection in pre-filled pen. NovoLet.
Clear, colourless, aqueous solution.
4.
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.
20
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
Administration with NovoLet
:
NovoRapid NovoLet are pre-filled pens designed to be used with NovoFine needles.
NovoLet delivers 2-78 units in increments of 2 units.
NovoRapid NovoLet is accompanied by a package leaflet with detailed instructions 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.
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.
21
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.
22
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.
23
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).
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 disorders
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 temporary 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 (pain, redness, hives, inflammation,
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.
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.
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:
24
•
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.
5.
5.1 Pharmacodynamic properties
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.
Time (h)
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
25
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.
5.2 Pharmacokinetic properties
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
26
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.
5.3 Preclinical safety data
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.
6.
6.1 List of excipients
Glycerol
Phenol
Metacresol
Zinc chloride
Disodium phosphate dihydrate
Sodium chloride
Hydrochloric acid (for pH adjustment)
Sodium hydroxide (for pH adjustment)
Water for injections
6.2 Incompatibilities
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.
6.3 Shelf life
30 months.
After first opening: A maximum of 4 weeks when stored below 30°C.
27
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C). Keep away from the cooling element. Do not freeze.
Keep the cap on NovoLet 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.
6.5 Nature and contents of container
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 5 and 10 pre-filled pens. Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
NovoRapid NovoLet 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.
In case of emergency in current NovoRapid users (hospitalisation or insulin pen malfunction),
NovoRapid can be withdrawn with an U100 insulin syringe from a NovoLet.
7.
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd
Denmark
8.
EU/1/99/119/005
EU/1/99/119/007
9.
Date of first authorisation: 7 September 1999
Date of last renewal: 30 April 2009
28
1.
FURTHER INFORMATION
What NovoRapid contains
–
The active substance is insulin aspart. Each ml contains 100 U of insulin aspart. Each pre-filled
pen contains 300 U insulin aspart in 3 ml solution for injection
–
The other ingredients are: glycerol, phenol, metacresol, zinc chloride, disodium phosphate
dihydrate, sodium chloride, hydrochloric acid, sodium hydroxide and water for injections.
What NovoRapid looks like and contents of the pack
NovoRapid comes as a clear, colourless, aqueous solution.
Pack sizes of 1, 5 and 10 pre-filled pens of 3 ml. Not all packs may be marketed.
Marketing authorisation holder
and manufacturer:
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd, Denmark
Now turn over for information on how to use your InnoLet.
This leaflet was last approved in
110
NOVORAPID solution for injection in a pre-filled pen. InnoLet. INSTSTRUCTIONS FOR USE
Please read the following instructions carefully before using your NovoRapid InnoLet.
NovoRapid InnoLet is a simple, compact pre-filled pen able to deliver 1 to 50 units in increments of
1 unit. NovoRapid InnoLet is designed to be used with NovoFine needles of 8 mm or shorter in length.
As a precautionary measure, always carry a spare insulin delivery device in case your InnoLet is lost
or damaged.
Push-
button
Dose
selector
dial
Residual
scale
Dose
scale
Compartment
for needles
Insulin
cartridge
Rubber
membrane
Needle
Pen cap
Protective
tab
Inner
needle
cap
Big
outer
needle
cap
Getting started
Check the label to be sure that your NovoRapid InnoLet contains the correct type of insulin.
Take off the cap (as shown by the arrow).
•
Always use a new needle for each injection to prevent contamination
•
Remove the protective tab from a NovoFine needle
•
Screw the needle straight and tightly onto NovoRapid InnoLet (picture
1A
)
•
Pull off the big outer needle cap and the inner needle cap. You may want to store the big outer
needle cap in the compartment.
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•
Disinfect the rubber membrane with a medicinal swab
1A
Priming to expel air
prior to each injection
Small amounts of air may collect in the needle and cartridge during normal use.
To avoid injection of air and ensure proper dosing:
•
Hold NovoRapid InnoLet with the needle upwards and tap the cartridge gently with your finger
a few times
to make any air bubbles collect at the top of the cartridge
•
A drop of insulin should appear at the needle tip (picture
1B
). If not, change the needle and
repeat the procedure no more than 6 times.
If a drop of insulin still does not appear, the device is defective and must not be used.
1B
Setting the dose
•
Dial the number of units required by turning the dose selector clockwise (picture
2
). Do not use
the residual scale to measure your dose of insulin
•
You will hear a click for every single unit dialled. The dose can be corrected by turning the dial
either way.
You cannot set a dose larger than the number of units remaining in the cartridge.
112
•
Dial 2 units by turning the dose selector clockwise
•
Keeping the needle upwards, press the push-button and the dose selector returns to zero
•
Always check that the push-button is fully depressed and the dose selector is set to zero
2
Injecting the insulin
•
Insert the needle into your skin. Use the injection technique advised by your doctor
•
Deliver the dose by pressing the push-button fully down
(picture
3
).
You will hear clicks as the
dose selector returns to zero
•
After the injection, the needle must remain under the skin for at least 6 seconds to ensure that
the full dose has been delivered
•
Make sure not to block the dose selector while injecting, as the dose selector must be allowed to
return to zero when you press the push-button.
3
Removing the needle
•
Replace the big outer needle cap and unscrew the needle (picture
4
). Dispose of it carefully.
113
4
Use a new needle for each injection.
Remove and discard the needle after each injection and store NovoRapid InnoLet without the needle
attached. Otherwise, the liquid may leak out which can cause inaccurate dosing.
Health care professionals, relatives and other carers must follow general precautionary measures for
removal and disposal of needles to eliminate the risk of unintended needle penetration.
Dispose of your used NovoRapid InnoLet carefully without the needle attached.
Maintenance
Your NovoRapid InnoLet is designed to work accurately and safely. It must be handled with care.
You can clean your NovoRapid InnoLet with a medicinal swab. Do not soak it, wash or lubricate it as
this may damage the mechanism.
Do not refill NovoRapid InnoLet.
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Source: European Medicines Agency
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