2
NovoLog
®
(insulin aspart [rDNA origin] injection)
5.8 Mixing of Insulins
• Mixing NovoLog
®
with NPH human insulin immediately before injection
attenuates the peak concentration of NovoLog
®
, without significantly
affecting the time to peak concentration or total bioavailability of NovoLog
®
.
If NovoLog
®
is mixed with NPH human insulin, NovoLog
®
should be drawn
into the syringe first, and the mixture should be injected immediately after
mixing.
• The efficacy and safety of mixing NovoLog
®
with insulin preparations
produced by other manufacturers have not been studied.
• Insulin mixtures should not be administered intravenously.
5.9 Continuous Subcutaneous Insulin Infusion by External Pump
When used in an external subcutaneous insulin infusion pump,
NovoLog
®
should not be mixed with any other insulin or diluent.
When using NovoLog
®
in an external insulin pump, the NovoLog
®
-specific
information should be followed (e.g., in-use time, frequency of changing
infusion sets) because NovoLog
®
-specific information may differ from general
pump manual instructions.
Pump or infusion set malfunctions or insulin degradation can lead to a rapid
onset of hyperglycemia and ketosis because of the small subcutaneous depot
of insulin. This is especially pertinent for rapid-acting insulin analogs that are
more rapidly absorbed through skin and have a shorter duration of action.
Prompt identification and correction of the cause of hyperglycemia or ketosis
is necessary. Interim therapy with subcutaneous injection may be required [
see
Dosage and Administration (2.3), Warnings and Precautions (5.8, 5.9), How
Supplied/Storage and Handling (16.2), and Patient Counseling Information
(17.2)
].
NovoLog
®
should not be exposed to temperatures greater than 37°C (98.6°F).
NovoLog
®
that will be used in a pump should not be mixed with
other insulin or with a diluent
[
see Dosage and Administration (2.3),
Warnings and Precautions (5.8, 5.9), How Supplied/Storage and Handling
(16.2), and Patient Counseling Information (17.2)
].
5.10 Fluid retention and heart failure with concomitant use of
PPAR-gamma agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated
receptor (PPAR)-gamma agonists, can cause dose-related fluid retention,
particularly when used in combination with insulin. Fluid retention may lead to
or exacerbate heart failure. Patients treated with insulin, including NovoLog
®
,
and a PPAR-gamma agonist should be observed for signs and symptoms
of heart failure. If heart failure develops, it should be managed according
to current standards of care, and discontinuation or dose reduction of the
PPAR-gamma agonist must be considered.
6
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying designs, the adverse
reaction rates reported in one clinical trial may not be easily compared to those
rates reported in another clinical trial, and may not reflect the rates actually
observed in clinical practice.
•
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients
using insulin, including NovoLog
®
[
see Warnings and Precautions (5)
].
•
Insulin initiation and glucose control intensification
Intensification or rapid improvement in glucose control has been
associated with a transitory, reversible ophthalmologic refraction disorder,
worsening of diabetic retinopathy, and acute painful peripheral neuropathy.
However, long-term glycemic control decreases the risk of diabetic
retinopathy and neuropathy.
•
Lipodystrophy
Long-term use of insulin, including NovoLog
®
, can cause lipodystrophy at
the site of repeated insulin injections or infusion. Lipodystrophy includes
lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of
adipose tissue), and may affect insulin absorption. Rotate insulin injection
or infusion sites within the same region to reduce the risk of lipodystrophy.
•
Weight gain
Weight gain can occur with some insulin therapies, including NovoLog
®
,
and has been attributed to the anabolic effects of insulin and the decrease
in glucosuria.
•
Peripheral Edema
Insulin may cause sodium retention and edema, particularly if previously
poor metabolic control is improved by intensified insulin therapy.
•
Frequencies of adverse drug reactions
The frequencies of adverse drug reactions during NovoLog
®
clinical trials
in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are
listed in the tables below.
Table 1: Treatment-Emergent Adverse Events in Patients with Type
1 Diabetes Mellitus (Adverse events with frequency
≥
5% and
occurring more frequently with NovoLog
®
compared to human
regular insulin are listed)
NovoLog
®
+ NPH
N= 596
Human Regular I NPH
N= 286
Preferred Term
N
(%)
N
(%)
Hypoglycemia*
448
75%
205
72%
Headache
70
12%
28
10%
Injury accidental
65
11%
29
10%
Nausea
43
7%
13
5%
Diarrhea
28
5%
9
3%
*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.
of action, a longer acting insulin should also be used in patients with type 1
diabetes and may also be needed in patients with type 2 diabetes. Glucose
monitoring is recommended for all patients with diabetes and is particularly
important for patients using external pump infusion therapy.
Any change of insulin dose should be made cautiously and only under medical
supervision. Changing from one insulin product to another or changing the
insulin strength may result in the need for a change in dosage. As with all
insulin preparations, the time course of NovoLog
®
action may vary in different
individuals or at different times in the same individual and is dependent on many
conditions, including the site of injection, local blood supply, temperature, and
physical activity. Patients who change their level of physical activity or meal
plan may require adjustment of insulin dosages. Insulin requirements may be
altered during illness, emotional disturbances, or other stresses.
Patients using continuous subcutaneous insulin infusion pump therapy must
be trained to administer insulin by injection and have alternate insulin therapy
available in case of pump failure.
Needles, NovoLog
®
FlexPen
®
and NovoLog
®
FlexTouch
®
must not
be shared.
5.2 Hypoglycemia
Hypoglycemia is the most common adverse effect of all insulin therapies,
including NovoLog
®
. Severe hypoglycemia may lead to unconsciousness and/
or convulsions and may result in temporary or permanent impairment of brain
function or death. Severe hypoglycemia requiring the assistance of another
person and/or parenteral glucose infusion or glucagon administration has
been observed in clinical trials with insulin, including trials with NovoLog
®
.
The timing of hypoglycemia usually reflects the time-action profile of the
administered insulin formulations [
see Clinical Pharmacology (12)
]. Other
factors such as changes in food intake (e.g., amount of food or timing of
meals), injection site, exercise, and concomitant medications may also alter
the risk of hypoglycemia [
see Drug Interactions (7)
]. As with all insulins, use
caution in patients with hypoglycemia unawareness and in patients who may
be predisposed to hypoglycemia (e.g., patients who are fasting or have erratic
food intake). The patient’s ability to concentrate and react may be impaired as
a result of hypoglycemia. This may present a risk in situations where these
abilities are especially important, such as driving or operating other machinery.
Rapid changes in serum glucose levels may induce symptoms of
hypoglycemia in persons with diabetes, regardless of the glucose value. Early
warning symptoms of hypoglycemia may be different or less pronounced under
certain conditions, such as longstanding diabetes, diabetic nerve disease, use
of medications such as beta-blockers, or intensified diabetes control [
see
Drug Interactions (7)
]. These situations may result in severe hypoglycemia
(and, possibly, loss of consciousness) prior to the patient’s awareness of
hypoglycemia. Intravenously administered insulin has a more rapid onset
of action than subcutaneously administered insulin, requiring more close
monitoring for hypoglycemia.
5.3 Hypokalemia
All insulin products, including NovoLog
®
, cause a shift in potassium from the
extracellular to intracellular space, possibly leading to hypokalemia that, if left
untreated, may cause respiratory paralysis, ventricular arrhythmia, and death.
Use caution in patients who may be at risk for hypokalemia (e.g., patients using
potassium-lowering medications, patients taking medications sensitive to serum
potassium concentrations, and patients receiving intravenously administered
insulin).
5.4 Renal Impairment
As with other insulins, the dose requirements for NovoLog
®
may be reduced in
patients with renal impairment [
see Clinical Pharmacology (12.3)
].
5.5 Hepatic Impairment
As with other insulins, the dose requirements for NovoLog
®
may be reduced in
patients with hepatic impairment [
see Clinical Pharmacology (12.3)
].
5.6 Hypersensitivity and Allergic Reactions
Local Reactions
- As with other insulin therapy, patients may experience
redness, swelling, or itching at the site of NovoLog
®
injection. These reactions
usually resolve in a few days to a few weeks, but in some occasions, may
require discontinuation of NovoLog
®
. In some instances, these reactions may
be related to factors other than insulin, such as irritants in a skin cleansing
agent or poor injection technique. Localized reactions and generalized
myalgias have been reported with injected metacresol, which is an excipient
in NovoLog
®
.
Systemic Reactions
- Severe, life-threatening, generalized allergy, including
anaphylaxis, may occur with any insulin product, including NovoLog
®
.
Anaphylactic reactions with NovoLog
®
have been reported post-approval.
Generalized allergy to insulin may also cause whole body rash (including
pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In
controlled clinical trials, allergic reactions were reported in 3 of 735 patients
(0.4%) treated with regular human insulin and 10 of 1394 patients (0.7%)
treated with NovoLog
®
. In controlled and uncontrolled clinical trials, 3 of 2341
(0.1%) NovoLog
®
-treated patients discontinued due to allergic reactions.
5.7 Antibody Production
Increases in anti-insulin antibody titers that react with both human insulin and
insulin aspart have been observed in patients treated with NovoLog
®
. Increases
in anti-insulin antibodies are observed more frequently with NovoLog
®
than
with regular human insulin. Data from a 12-month controlled trial in patients
with type 1 diabetes suggest that the increase in these antibodies is transient,
and the differences in antibody levels between the regular human insulin and
insulin aspart treatment groups observed at 3 and 6 months were no longer
evident at 12 months. In this study these antibodies did not appear to cause
deterioration in glycemic control or necessitate increases in insulin dose.
In rare cases, the presence of such insulin antibodies may necessitate
adjustment of the insulin dose in order to correct a tendency towards
hyperglycemia or hypoglycemia.
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1 Treatment of Diabetes Mellitus
NovoLog
®
is an insulin analog indicated to improve glycemic control in adults
and children with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
NovoLog
®
is an insulin analog with an earlier onset of action than regular
human insulin. The dosage of NovoLog
®
must be individualized. NovoLog
®
given by subcutaneous injection should generally be used in regimens with an
intermediate or long-acting insulin [
see Warnings and Precautions (5), How
Supplied/Storage and Handling (16.2)
]. The total daily insulin requirement
may vary and is usually between 0.5 to 1.0 units/kg/day. When used in a meal-
related subcutaneous injection treatment regimen, 50 to 70% of total insulin
requirements may be provided by NovoLog
®
and the remainder provided
by an intermediate-acting or long-acting insulin. Because of NovoLog
®
’s
comparatively rapid onset and short duration of glucose lowering activity,
some patients may require more basal insulin and more total insulin to prevent
pre-meal hyperglycemia when using NovoLog
®
than when using human
regular insulin.
Do not use NovoLog
®
that is viscous (thickened) or cloudy; use only if it is
clear and colorless. NovoLog
®
should not be used after the printed expiration
date.
2.2 Subcutaneous Injection
NovoLog
®
should be administered by subcutaneous injection in the abdominal
region, buttocks, thigh, or upper arm. Because NovoLog
®
has a more rapid
onset and a shorter duration of activity than human regular insulin, it should
be injected immediately (within 5-10 minutes) before a meal. Injection sites
should be rotated within the same region to reduce the risk of lipodystrophy.
As with all insulins, the duration of action of NovoLog
®
will vary according to
the dose, injection site, blood flow, temperature, and level of physical activity.
NovoLog
®
may be diluted with Insulin Diluting Medium for NovoLog
®
for
subcutaneous injection. Diluting one part NovoLog
®
to nine parts diluent will
yield a concentration one-tenth that of NovoLog
®
(equivalent to U-10). Diluting
one part NovoLog
®
to one part diluent will yield a concentration one-half that
of NovoLog
®
(equivalent to U-50).
2.3 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
NovoLog
®
can also be infused subcutaneously by an external insulin pump
[
see Warnings and Precautions (5.8, 5.9), How Supplied/Storage and Handling
(16.2)
]. Diluted insulin should not be used in external insulin pumps. Because
NovoLog
®
has a more rapid onset and a shorter duration of activity than human
regular insulin, pre-meal boluses of NovoLog
®
should be infused immediately
(within 5-10 minutes) before a meal. Infusion sites should be rotated within
the same region to reduce the risk of lipodystrophy. The initial programming
of the external insulin infusion pump should be based on the total daily
insulin dose of the previous regimen. Although there is significant interpatient
variability, approximately 50% of the total dose is usually given as meal-related
boluses of NovoLog
®
and the remainder is given as a basal infusion.
Change
the NovoLog
®
in the reservoir at least every 6 days, change the
infusion sets and the infusion set insertion site at least every 3
days.
The following insulin pumps
†
have been used in NovoLog
®
clinical or
in vitro
studies conducted by Novo Nordisk, the manufacturer of NovoLog
®
:
• Medtronic Paradigm
®
512 and 712
• MiniMed 508
• Disetronic
®
D-TRON
®
and H-TRON
®
Before using a different insulin pump with NovoLog
®
, read the pump label to
make sure the pump has been evaluated with NovoLog
®
.
2.4 Intravenous Use
NovoLog
®
can be administered intravenously under medical supervision for
glycemic control with close monitoring of blood glucose and potassium levels
to avoid hypoglycemia and hypokalemia [
see Warnings and Precautions (5),
How Supplied/Storage and Handling (16.2)
]. For intravenous use, NovoLog
®
should be used at concentrations from 0.05 U/mL to 1.0 U/mL insulin aspart
in infusion systems using polypropylene infusion bags. NovoLog
®
has been
shown to be stable in infusion fluids such as 0.9% sodium chloride.
Inspect NovoLog
®
for particulate matter and discoloration prior to parenteral
administration.
3
DOSAGE FORMS AND STRENGTHS
NovoLog
®
is available in the following package sizes: each presentation
contains 100 units of insulin aspart per mL (U-100).
• 10 mL vials
• 3 mL PenFill cartridges for the 3 mL PenFill
®
cartridge delivery device
(with or without the addition of a NovoPen
®
3 PenMate
®
) with NovoFine
®
disposable needles
• 3 mL NovoLog
®
FlexPen
®
• 3 mL NovoLog
®
FlexTouch
®
4 CONTRAINDICATIONS
NovoLog
®
is contraindicated
• during episodes of hypoglycemia
• in patients with hypersensitivity to NovoLog
®
or one of its excipients.
5
WARNINGS AND PRECAUTIONS
5.1 Administration
NovoLog
®
has a more rapid onset of action and a shorter duration of activity
than regular human insulin. An injection of NovoLog
®
should immediately be
followed by a meal within 5-10 minutes. Because of NovoLog
®
’s short duration
