3
NovoLog
®
(insulin aspart [rDNA origin] injection)
A double-blind, randomized, two-way cross-over study in 16 patients with
type 1 diabetes demonstrated that intravenous infusion of NovoLog
®
resulted
in a blood glucose profile that was similar to that after intravenous infusion
with regular human insulin. NovoLog
®
or human insulin was infused until
the patient’s blood glucose decreased to 36 mg/dL, or until the patient
demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating),
defined as the time of autonomic reaction (R) (see Figure 3).
180
162
144
126
108
90
72
54
36
18
0
0
10
R–20
R
R+40 R+50 R+60
Time (min)
Mean Blood Glucose (mg/dL)
R–10
R+10 R+20 R+30
Note: The slashes on the mean profile indicate a jump on the time axis
Figure 3. Mean blood glucose profiles following intravenous
infusion of NovoLog
®
(hatched curve) and regular human insulin
(solid curve) in 16 patients with type 1 diabetes. R represents the
time of autonomic reaction.
12.3 Pharmacokinetics
The single substitution of the amino acid proline with aspartic acid at position
B28 in NovoLog
®
reduces the molecule’s tendency to form hexamers as
observed with regular human insulin. NovoLog
®
is, therefore, more rapidly
absorbed after subcutaneous injection compared to regular human insulin.
In a randomized, double-blind, crossover study 17 healthy Caucasian male
subjects between 18 and 40 years of age received an intravenous infusion of
either NovoLog
®
or regular human insulin at 1.5 mU/kg/min for 120 minutes.
The mean insulin clearance was similar for the two groups with mean values
of 1.2 l/h/kg for the NovoLog
®
group and 1.2 l/h/kg for the regular human
insulin group.
Bioavailability and Absorption
- NovoLog
®
has a faster absorption, a faster
onset of action, and a shorter duration of action than regular human insulin
after subcutaneous injection (see Figure 2 and Figure 4). The relative
bioavailability of NovoLog
®
compared to regular human insulin indicates that
the two insulins are absorbed to a similar extent.
80
60
40
20
0
0
1
2
3
4
5
6
Time (h)
Free serum insulin (mU/L)
Figure 4. Serial mean serum free insulin concentration collected
up to 6 hours following a single pre-meal dose of NovoLog
®
(solid curve) or regular human insulin (hatched curve) injected
immediately before a meal in 22 patients with type 1 diabetes.
In studies in healthy volunteers (total n=107) and patients with type 1 diabetes
(total n=40), NovoLog
®
consistently reached peak serum concentrations
approximately twice as fast as regular human insulin. The median time to
maximum concentration in these trials was 40 to 50 minutes for NovoLog
®
versus 80 to 120 minutes for regular human insulin. In a clinical trial in patients
with type 1 diabetes, NovoLog
®
and regular human insulin, both administered
subcutaneously at a dose of 0.15 U/kg body weight, reached mean
maximum concentrations of 82 and 36 mU/L, respectively. Pharmacokinetic/
pharmacodynamic characteristics of insulin aspart have not been established
in patients with type 2 diabetes.
The intra-individual variability in time to maximum serum insulin concentration
for healthy male volunteers was significantly less for NovoLog
®
than for
regular human insulin. The clinical significance of this observation has not
been established.
In a clinical study in healthy non-obese subjects, the pharmacokinetic
differences between NovoLog
®
and regular human insulin described above,
were observed independent of the site of injection (abdomen, thigh, or upper
arm).
Distribution and Elimination
- NovoLog
®
has low binding to plasma proteins
(<10%), similar to that seen with regular human insulin. After subcutaneous
administration in normal male volunteers (n=24), NovoLog
®
was more rapidly
eliminated than regular human insulin with an average apparent half-life of 81
minutes compared to 141 minutes for regular human insulin.
Specific Populations
Children and Adolescents
- The pharmacokinetic and pharmacodynamic
properties of NovoLog
®
and regular human insulin were evaluated in a
single dose study in 18 children (6-12 years, n=9) and adolescents (13-17
years [Tanner grade
≥
2], n=9) with type 1 diabetes. The relative differences
in pharmacokinetics and pharmacodynamics in children and adolescents with
type 1 diabetes between NovoLog
®
and regular human insulin were similar to
those in healthy adult subjects and adults with type 1 diabetes.
Gender
- In healthy volunteers, no difference in insulin aspart levels was
seen between men and women when body weight differences were taken into
8.3 Nursing Mothers
It is unknown whether insulin aspart is excreted in human milk. Use of
NovoLog
®
is compatible with breastfeeding, but women with diabetes who are
lactating may require adjustments of their insulin doses.
8.4 Pediatric Use
NovoLog
®
is approved for use in children for subcutaneous daily injections
and for subcutaneous continuous infusion by external insulin pump.
NovoLog
®
has not been studied in pediatric patients younger than 2 years of
age. NovoLog
®
has not been studied in pediatric patients with type 2 diabetes.
Please see
Section 14
CLINICAL STUDIES
for summaries of clinical studies.
8.5 Geriatric Use
Of the total number of patients (n= 1,375) treated with NovoLog
®
in 3 controlled
clinical studies, 2.6% (n=36) were 65 years of age or over. One-half of these
patients had type 1 diabetes (18/1285) and the other half had type 2 diabetes
(18/90). The HbA
1c
response to NovoLog
®
, as compared to human insulin, did
not differ by age, particularly in patients with type 2 diabetes. Additional studies
in larger populations of patients 65 years of age or over are needed to permit
conclusions regarding the safety of NovoLog
®
in elderly compared to younger
patients. Pharmacokinetic/pharmacodynamic studies to assess the effect of
age on the onset of NovoLog
®
action have not been performed.
10 OVERDOSAGE
Excess insulin administration may cause hypoglycemia and, particularly when
given intravenously, hypokalemia. Mild episodes of hypoglycemia usually
can be treated with oral glucose. Adjustments in drug dosage, meal patterns,
or exercise, may be needed. More severe episodes with coma, seizure, or
neurologic impairment may be treated with intramuscular/subcutaneous
glucagon or concentrated intravenous glucose. Sustained carbohydrate intake
and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery. Hypokalemia must be corrected appropriately.
11 DESCRIPTION
NovoLog
®
(insulin aspart [rDNA origin] injection) is a rapid-acting human
insulin analog used to lower blood glucose. NovoLog
®
is homologous with
regular human insulin with the exception of a single substitution of the amino
acid proline by aspartic acid in position B28, and is produced by recombinant
DNA technology utilizing
Saccharomyces cerevisiae
(baker’s yeast). Insulin
aspart has the empirical formula C
256
H
381
N
65
0
79
S
6
and a molecular weight
of 5825.8.
Figure 1. Structural formula of insulin aspart.
NovoLog
®
is a sterile, aqueous, clear, and colorless solution, that contains
insulin aspart 100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL,
metacresol 1.72 mg/mL, zinc 19.6 mcg/mL, disodium hydrogen phosphate
dihydrate 1.25 mg/mL, sodium chloride 0.58 mg/mL and water for injection.
NovoLog
®
has a pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium
hydroxide 10% may be added to adjust pH.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The primary activity of NovoLog
®
is the regulation of glucose metabolism.
Insulins, including NovoLog
®
, bind to the insulin receptors on muscle and fat
cells and lower blood glucose by facilitating the cellular uptake of glucose and
simultaneously inhibiting the output of glucose from the liver.
12.2 Pharmacodynamics
Studies in normal volunteers and patients with diabetes demonstrated that
subcutaneous administration of NovoLog
®
has a more rapid onset of action
than regular human insulin.
In a study in patients with type 1 diabetes (n=22), the maximum glucose-
lowering effect of NovoLog
®
occurred between 1 and 3 hours after
subcutaneous injection (see Figure 2). The duration of action for NovoLog
®
is 3 to 5 hours. The time course of action of insulin and insulin analogs such
as NovoLog
®
may vary considerably in different individuals or within the same
individual. The parameters of NovoLog
®
activity (time of onset, peak time and
duration) as designated in Figure 2 should be considered only as general
guidelines. The rate of insulin absorption and onset of activity is affected by the
site of injection, exercise, and other variables [
see Warnings and Precautions
(5.1)
].
300
200
100
50
0
0
1
2
3
4
5
6
Time (h)
Serum glucose (mg/dL)
250
150
Figure 2. Serial mean serum glucose collected up to 6 hours
following a single pre-meal dose of NovoLog
®
(solid curve) or
regular human insulin (hatched curve) injected immediately
before a meal in 22 patients with type 1 diabetes.
Table 2: Treatment-Emergent Adverse Events in Patients with
Type 2 Diabetes Mellitus (except for hypoglycemia, adverse
events with frequency
≥
5% and occurring more frequently with
NovoLog
®
compared to human regular insulin are listed)
NovoLog
®
+ NPH
N= 91
Human Regular I NPH
N= 91
N
(%)
N
(%)
Hypoglycemia*
25
27%
33
36%
Hyporeflexia
10
11%
6
7%
Onychomycosis
9
10%
5
5%
Sensory disturbance
8
9%
6
7%
Urinary tract infection
7
8%
6
7%
Chest pain
5
5%
3
3%
Headache
5
5%
3
3%
Skin disorder
5
5%
2
2%
Abdominal pain
5
5%
1
1%
Sinusitis
5
5%
1
1%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL,
with or without symptoms. See Section 14 for the incidence of serious hypoglycemia in
the individual clinical trials.
Postmarketing Data
The following additional adverse reactions have been identified during
postapproval use of NovoLog
®
. Because these adverse reactions are reported
voluntarily from a population of uncertain size, it is generally not possible to
reliably estimate their frequency. Medication errors in which other insulins
have been accidentally substituted for NovoLog
®
have been identified during
postapproval use [
see Patient Counseling Information (17)
].
7
DRUG INTERACTIONS
A number of substances affect glucose metabolism and may require insulin
dose adjustment and particularly close monitoring.
• The following are examples of substances that may increase the
blood-glucose-lowering effect and susceptibility to hypoglycemia:
oral antidiabetic products, pramlintide, ACE inhibitors, disopyramide,
fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene,
salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics.
• The following are examples of substances that may reduce the blood-
glucose-lowering effect: corticosteroids, niacin, danazol, diuretics,
sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline),
isoniazid, phenothiazine derivatives, somatropin, thyroid hormones,
estrogens, progestogens (e.g., in oral contraceptives), atypical
antipsychotics.
• Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or
weaken the blood-glucose-lowering effect of insulin.
• Pentamidine may cause hypoglycemia, which may sometimes be followed
by hyperglycemia.
• The signs of hypoglycemia may be reduced or absent in patients taking
sympatholytic products such as beta-blockers, clonidine, guanethidine,
and reserpine.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B. All pregnancies have a background risk of birth
defects, loss, or other adverse outcome regardless of drug exposure. This
background risk is increased in pregnancies complicated by hyperglycemia
and may be decreased with good metabolic control. It is essential for patients
with diabetes or history of gestational diabetes to maintain good metabolic
control before conception and throughout pregnancy. Insulin requirements
may decrease during the first trimester, generally increase during the second
and third trimesters, and rapidly decline after delivery. Careful monitoring of
glucose control is essential in these patients. Therefore, female patients should
be advised to tell their physician if they intend to become, or if they become
pregnant while taking NovoLog
®
.
An open-label, randomized study compared the safety and efficacy of
NovoLog
®
(n=157) versus regular human insulin (n=165) in 322 pregnant
women with type 1 diabetes. Two-thirds of the enrolled patients were already
pregnant when they entered the study. Because only one-third of the patients
enrolled before conception, the study was not large enough to evaluate the risk
of congenital malformations. Both groups achieved a mean HbA
1c
of ~ 6%
during pregnancy, and there was no significant difference in the incidence of
maternal hypoglycemia.
Subcutaneous reproduction and teratology studies have been performed
with NovoLog
®
and regular human insulin in rats and rabbits. In these
studies, NovoLog
®
was given to female rats before mating, during mating,
and throughout pregnancy, and to rabbits during organogenesis. The effects
of NovoLog
®
did not differ from those observed with subcutaneous regular
human insulin. NovoLog
®
, like human insulin, caused pre- and post-
implantation losses and visceral/skeletal abnormalities in rats at a dose of 200
U/kg/day (approximately 32 times the human subcutaneous dose of 1.0 U/
kg/day, based on U/body surface area) and in rabbits at a dose of 10 U/kg/
day (approximately three times the human subcutaneous dose of 1.0 U/kg/day,
based on U/body surface area). The effects are probably secondary to maternal
hypoglycemia at high doses. No significant effects were observed in rats at a
dose of 50 U/kg/day and in rabbits at a dose of 3 U/kg/day. These doses are
approximately 8 times the human subcutaneous dose of 1.0 U/kg/day for rats
and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits, based
on U/body surface area.
