4
NovoLog
®
(insulin aspart [rDNA origin] injection)
account. There was no significant difference in efficacy noted (as assessed by
HbA
1c
) between genders in a trial in patients with type 1 diabetes.
Obesity
- A single subcutaneous dose of 0.1 U/kg NovoLog
®
was administered
in a study of 23 patients with type 1 diabetes and a wide range of body mass
index (BMI, 22-39 kg/m
2
). The pharmacokinetic parameters, AUC and C
max
,
of NovoLog
®
were generally unaffected by BMI in the different groups – BMI
19-23 kg/m
2
(N=4); BMI 23-27 kg/m
2
(N=7); BMI 27-32 kg/m
2
(N=6) and BMI
>32 kg/m
2
(N=6). Clearance of NovoLog
®
was reduced by 28% in patients with
BMI >32 kg/m
2
compared to patients with BMI <23 kg/m
2
.
Renal Impairment
- Some studies with human insulin have shown increased
circulating levels of insulin in patients with renal failure. A single subcutaneous
dose of 0.08 U/kg NovoLog
®
was administered in a study to subjects with
either normal (N=6) creatinine clearance (CLcr) (>80 ml/min) or mild (N=7;
CLcr = 50-80 ml/min), moderate (N=3; CLcr = 30-50 ml/min) or severe (but
not requiring hemodialysis) (N=2; CLcr = <30 ml/min) renal impairment. In
this small study, there was no apparent effect of creatinine clearance values
on AUC and C
max
of NovoLog
®
. Careful glucose monitoring and dose
adjustments of insulin, including NovoLog
®
, may be necessary in patients
with renal dysfunction [
see Warnings and Precautions (5.4)
].
Hepatic Impairment
- Some studies with human insulin have shown increased
circulating levels of insulin in patients with liver failure. A single subcutaneous
dose of 0.06 U/kg NovoLog
®
was administered in an open-label, single-dose
study of 24 subjects (N=6/group) with different degree of hepatic impairment
(mild, moderate and severe) having Child-Pugh Scores ranging from 0
(healthy volunteers) to 12 (severe hepatic impairment). In this small study,
there was no correlation between the degree of hepatic failure and any
NovoLog
®
pharmacokinetic parameter. Careful glucose monitoring and dose
adjustments of insulin, including NovoLog
®
, may be necessary in patients with
hepatic dysfunction [
see Warnings and Precautions (5.5)
].
The effect of age, ethnic origin, pregnancy and smoking on the pharmacokinetics
and pharmacodynamics of NovoLog
®
has not been studied.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to
evaluate the carcinogenic potential of NovoLog
®
. In 52-week studies, Sprague-
Dawley rats were dosed subcutaneously with NovoLog
®
at 10, 50, and 200 U/
kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of
1.0 U/kg/day, based on U/body surface area, respectively). At a dose of 200
U/kg/day, NovoLog
®
increased the incidence of mammary gland tumors in
females when compared to untreated controls. The incidence of mammary
tumors for NovoLog
®
was not significantly different than for regular human
insulin. The relevance of these findings to humans is not known. NovoLog
®
was not genotoxic in the following tests: Ames test, mouse lymphoma cell
forward gene mutation test, human peripheral blood lymphocyte chromosome
aberration test,
in vivo
micronucleus test in mice, and in
ex vivo
UDS test in rat
liver hepatocytes. In fertility studies in male and female rats, at subcutaneous
doses up to 200 U/kg/day (approximately 32 times the human subcutaneous
dose, based on U/body surface area), no direct adverse effects on male and
female fertility, or general reproductive performance of animals was observed.
13.2 Animal Toxicology and/or Pharmacology
In standard biological assays in mice and rabbits, one unit of NovoLog
®
has the same glucose-lowering effect as one unit of regular human insulin.
In humans, the effect of NovoLog
®
is more rapid in onset and of shorter
duration, compared to regular human insulin, due to its faster absorption after
subcutaneous injection (see
Section 12 CLINICAL PHARMACOLOGY
Figure
2 and Figure 4).
14 CLINICAL STUDIES
14.1 Subcutaneous Daily Injections
Two six-month, open-label, active-controlled studies were conducted to
compare the safety and efficacy of NovoLog
®
to Novolin
®
R in adult patients
with type 1 diabetes. Because the two study designs and results were similar,
data are shown for only one study (see Table 3). NovoLog
®
was administered
by subcutaneous injection immediately prior to meals and regular human
insulin was administered by subcutaneous injection 30 minutes before meals.
NPH insulin was administered as the basal insulin in either single or divided
daily doses. Changes in HbA
1c
and the incidence rates of severe hypoglycemia
(as determined from the number of events requiring intervention from a third
party) were comparable for the two treatment regimens in this study (Table 3)
as well as in the other clinical studies that are cited in this section. Diabetic
ketoacidosis was not reported in any of the adult studies in either treatment
group.
Table 3. Subcutaneous NovoLog
®
Administration in Type 1
Diabetes
(24 weeks; n=882)
NovoLog
®
+ NPH Novolin
®
R + NPH
N
596
286
Baseline HbA
1c
(%)*
7.9 ± 1.1
8.0 ± 1.2
Change from Baseline HbA
1c
(%)
-0.1 ± 0.8
0.0 ± 0.8
Treatment Difference in HbA
1c
, Mean
(95% confidence interval)
-0.2 (-0.3, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
104 (17%)
54 (19%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
75.3 ± 14.5
0.5 ± 3.3
75.9 ± 13.1
0.9 ± 2.9
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system
symptoms and requiring the intervention of another person or hospitalization.
A 24-week, parallel-group study of children and adolescents with type 1
diabetes (n = 283) aged 6 to 18 years compared two subcutaneous multiple-
dose treatment regimens: NovoLog
®
(n = 187) or Novolin
®
R (n = 96). NPH
insulin was administered as the basal insulin. NovoLog
®
achieved glycemic
control comparable to Novolin
®
R, as measured by change in HbA
1c
(Table 4)
and both treatment groups had a comparable incidence of hypoglycemia.
Subcutaneous administration of NovoLog
®
and regular human insulin have
also been compared in children with type 1 diabetes (n=26) aged 2 to 6 years
with similar effects on HbA
1c
and hypoglycemia.
Table 4. Pediatric Subcutaneous Administration of NovoLog
®
in
Type 1 Diabetes
(24 weeks; n=283)
NovoLog
®
+ NPH Novolin
®
R + NPH
N
187
96
Baseline HbA
1c
(%)*
8.3 ± 1.2
8.3 ± 1.3
Change from Baseline HbA
1c
(%)
0.1 ± 1.0
0.1 ± 1.1
Treatment Difference in HbA
1c
, Mean
(95% confidence interval)
0.1 (-0.5, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
11 (6%)
9 (9%)
Diabetic ketoacidosis (n, %)
10 (5%)
2 (2%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
50.6 ± 19.6
2.7 ± 3.5
48.7 ± 15.8
2.4 ± 2.6
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system
symptoms and requiring the intervention of another person or hospitalization.
One six-month, open-label, active-controlled study was conducted to compare
the safety and efficacy of NovoLog
®
to Novolin
®
R in patients with type 2
diabetes (Table 5). NovoLog
®
was administered by subcutaneous injection
immediately prior to meals and regular human insulin was administered
by subcutaneous injection 30 minutes before meals. NPH insulin was
administered as the basal insulin in either single or divided daily doses.
Changes in HbA
1c
and the rates of severe hypoglycemia (as determined from
the number of events requiring intervention from a third party) were comparable
for the two treatment regimens.
Table 5. Subcutaneous NovoLog
®
Administration in Type 2
Diabetes
(6 months; n=176)
NovoLog
®
+ NPH Novolin
®
R + NPH
N
90
86
Baseline HbA
1c
(%)*
8.1 ± 1.2
7.8 ± 1.1
Change from Baseline HbA
1c
(%)
-0.3 ± 1.0
-0.1 ± 0.8
Treatment Difference in HbA
1c
, Mean
(95% confidence interval)
-0.1 (-0.4, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.6 ± 0.3
0.6 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.7 ± 0.3
Patients with severe hypoglycemia (n, %)**
9 (10%)
5 (8%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
88.4 ± 13.3
1.2 ± 3.0
85.8 ± 14.8
0.4 ± 3.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system
symptoms and requiring the intervention of another person or hospitalization.
14.2 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
Two open-label, parallel design studies (6 weeks [n=29] and 16 weeks
[n=118]) compared NovoLog
®
to buffered regular human insulin (Velosulin) in
adults with type 1 diabetes receiving a subcutaneous infusion with an external
insulin pump. The two treatment regimens had comparable changes in HbA
1c
and rates of severe hypoglycemia.
Table 6. Adult Insulin Pump Study in Type 1 Diabetes
(16 weeks;
n=118)
NovoLog
®
Buffered human insulin
N
59
59
Baseline HbA
1c
(%)*
7.3 ± 0.7
7.5 ± 0.8
Change from Baseline HbA
1c
(%)
0.0 ± 0.5
0.2 ± 0.6
Treatment Difference in HbA
1c
, Mean
(95% confidence interval)
0.3 (-0.1, 0.4)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.8
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)* 0.7 ± 0.7
0.6 ± 0.2
Patients with severe hypoglycemia (n, %)**
1 (2%)
2 (3%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
77.4 ± 16.1
0.1 ± 3.5
74.8 ± 13.8
-0.0 ± 1.7
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system
symptoms and requiring the intervention of another person or hospitalization.
A randomized, 16-week, open-label, parallel design study of children and
adolescents with type 1 diabetes (n=298) aged 4-18 years compared two
subcutaneous infusion regimens administered via an external insulin pump:
NovoLog
®
(n=198) or insulin lispro (n=100). These two treatments resulted
in comparable changes from baseline in HbA
1c
and comparable rates of
hypoglycemia after 16 weeks of treatment (see Table 7).
Table 7. Pediatric Insulin Pump Study in Type 1 Diabetes
(16
weeks; n=298)
NovoLog
®
Lispro
N
198
100
Baseline HbA
1c
(%)*
8.0 ± 0.9
8.2 ± 0.8
Change from Baseline HbA
1c
(%)
-0.1 ± 0.8
-0.1 ± 0.7
Treatment Difference in HbA
1c
, Mean
(95% confidence interval)
-0.1 (-0.3, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.9 ± 0.3
0.9 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.2
0.9 ± 0.2
Patients with severe hypoglycemia (n, %)**
19 (10%)
8 (8%)
Diabetic ketoacidosis (n, %)
1 (0.5%)
0 (0)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
54.1 ± 19.7
1.8 ± 2.1
55.5 ± 19.0
1.6 ± 2.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system
symptoms and requiring the intervention of another person or hospitalization.
An open-label, 16-week parallel design trial compared pre-prandial NovoLog
®
injection in conjunction with NPH injections to NovoLog
®
administered
by continuous subcutaneous infusion in 127 adults with type 2 diabetes.
The two treatment groups had similar reductions in HbA
1c
and rates of
severe hypoglycemia (Table 8) [
see Indications and Usage (1), Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage
and Handling (16.2)
].
Table 8. Pump Therapy in Type 2 Diabetes
(16 weeks; n=127)
NovoLog
®
pump NovoLog
®
+ NPH
N
66
61
Baseline HbA
1c
(%)*
8.2 ± 1.4
8.0 ± 1.1
Change from Baseline HbA
1c
(%)
-0.6 ± 1.1
-0.5 ± 0.9
Treatment Difference in HbA
1c
, Mean
(95% confidence interval)
0.1 (0.4, 0.3)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.8 ± 0.5
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.4
0.9 ± 0.5
Baseline body weight (kg)*
Weight Change from baseline (kg)*
96.4 ± 17.0
1.7 ± 3.7
96.9 ± 17.9
0.7 ± 4.1
*Values are Mean ± SD
14.3 Intravenous Administration of NovoLog
®
See Section 12.2 CLINICAL PHARMACOLOGY/Pharmacodynamics.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
NovoLog
®
is available in the following package sizes: each presentation
containing 100 Units of insulin aspart per mL (U-100).
10 mL vials
NDC 0169-7501-11
3 mL PenFill
®
cartridges*
NDC 0169-3303-12
3 mL NovoLog
®
FlexPen
®
NDC 0169-6339-10
3 mL NovoLog
®
FlexTouch
®
NDC 0169-6338-10
*NovoLog
®
PenFill
®
cartridges are designed for use with Novo Nordisk 3 mL
PenFill
®
cartridge compatible insulin delivery devices (with or without the
addition of a NovoPen
®
3 PenMate
®
) with NovoFine
®
disposable needles.
FlexPen
®
and FlexTouch
®
can be used with NovoFine
®
or NovoTwist
®
disposable needles.
16.2 Recommended Storage
Unused NovoLog
®
should be stored in a refrigerator between 2° and 8°C
(36° to 46°F). Do not store in the freezer or directly adjacent to the refrigerator
cooling element.
Do not freeze NovoLog
®
and do not use NovoLog
®
if it has been frozen.
NovoLog
®
should not be drawn into a syringe and
stored for later use.
Vials:
After initial use a vial may be kept at temperatures below 30°C (86°F)
for up to 28 days, but should not be exposed to excessive heat or light. Opened
vials may be refrigerated.
Unpunctured vials can be used until the expiration date printed on the label if
they are stored in a refrigerator. Keep unused vials in the carton so they will stay
clean and protected from light.
PenFill cartridges or NovoLog
®
FlexPen
®
and NovoLog
®
FlexTouch
®
:
Once a cartridge or NovoLog
®
FlexPen
®
or NovoLog
®
FlexTouch
®
is
punctured, it should be kept at temperatures below 30°C (86°F) for up to 28
days, but should not be exposed to excessive heat or sunlight. A NovoLog
®
FlexPen
®
or NovoLog
®
FlexTouch
®
or cartridge in use must NOT be stored
in the refrigerator. Keep the NovoLog
®
FlexPen
®
or NovoLog
®
FlexTouch
®
and all PenFill cartridges away from direct heat and sunlight. Unpunctured
NovoLog
®
FlexPen
®
or NovoLog
®
FlexTouch
®
and PenFill cartridges can
be used until the expiration date printed on the label if they are stored in a
refrigerator. Keep unused NovoLog
®
FlexPen
®
or NovoLog
®
FlexTouch
®
and
PenFill cartridges in the carton so they will stay clean and protected from light.
Always remove the needle after each injection and store the 3
mL PenFill cartridge delivery device or NovoLog
®
FlexPen
®
or
NovoLog
®
FlexTouch
®
without a needle attached. This prevents
contamination and/or infection, or leakage of insulin, and will
ensure accurate dosing. Always use a new needle for each
injection to prevent contamination.
