Novo Nordisk NovoLog Instruction Manual

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use NovoLog prescribing information for NovoLog

NovoLog

(insulin aspart [rDNA origin] injection)

safely and effectively. See full

solution for subcutaneous use Initial U.S. Approval: 2000

——— INDICATIONS AND USAGE ———

• NovoLog

is an insulin analog indicated to improve glycemic

control in adults and children with diabetes mellitus (1.1).

——— DOSAGE AND ADMINISTRATION ———

• The dosage of NovoLog® must be individualized.

•

Subcutaneous injection:

NovoLog

should generally be given immediately (within 5-10 minutes) prior to the start of a meal (2.2).

•

Use in pumps:

Change the NovoLog every 6 days, change the infusion set, and the infusion set insertion site at least every 3 days. NovoLog

in the reservoir at least

should not be mixed with other insulins or with a diluent when it is used in the pump (2.3).

•

Intravenous use:

from 0.05 U/mL to 1.0 U/mL insulin aspart in infusion systems using polypropylene infusion bags. NovoLog

NovoLog

should be used at concentrations

has been shown to be stable in infusion ﬂuids such as 0.9% sodium chloride (2.4).

——— DOSAGE FORMS AND STRENGTHS ———

Each presentation contains 100 Units of insulin aspart per mL (U-100)

•

10 mL vials (3)

• 3 mL PenFill® cartridges for the 3 mL PenFill® cartridge device (3)

• 3 mL NovoLog® FlexPen® (3)

•

3 mL NovoLog

FlexTouch® (3)

——— CONTRAINDICATIONS ———

•

Do not use during episodes of hypoglycemia (4). Do not use in patients with hypersensitivity to NovoLog

•

or one

of its excipients.

——— WARNINGS AND PRECAUTIONS ———

•

Hypoglycemia is the most common adverse effect of insulin therapy. Glucose monitoring is recommended for all patients with diabetes. Any change of insulin dose should be made cautiously and only under medical supervision (5.1, 5.2).

•

Insulin, particularly when given intravenously or in settings of poor glycemic control, can cause hypokalemia. Use caution in patients predisposed to hypokalemia (5.3).

Like all insulins, NovoLog

•

requirements may be reduced in

patients with renal impairment or hepatic impairment (5.4, 5.5). Severe, life-threatening, generalized allergy

• anaphylaxis, may occur with insulin products, including

NovoLog

(5.6).

•

Fluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including NovoLog

, including

(5.10).

——— ADVERSE REACTIONS ———

Adverse reactions observed with NovoLog

include hypoglycemia, allergic reactions, local injection site reactions, lipodystrophy, rash and pruritus (6).

To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800FDA-1088 or www.fda.gov/medwatch.

——— DRUG INTERACTIONS ———

•

The following may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral antidiabetic products, pramlintide, ACE inhibitors, disopyramide, ﬁbrates, ﬂuoxetine, monoamine oxidase inhibitors, propoxyphene, salicylates, somatostatin analogs, sulfonamide antibiotics (7).

•

The following 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 (7).

•

Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin (7).

•

Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia (7).

The signs of hypoglycemia may be reduced or absent in patients

• taking sympatholytic products such as beta-blockers, clonidine, guanethidine, and reserpine (7).

——— USE IN SPECIFIC POPULATIONS ———

•

Pediatric: Has not been studied in children with type 2 diabetes. Has not been studied in children with type 1 diabetes <2 years of age (8.4).

See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling.

Revised: 4/2014

FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE

1.1 Treatment of Diabetes Mellitus

2 DOSAGE AND ADMINISTRATION

2.1 Dosing

2.2 Subcutaneous Injection

2.3 Continuous Subcutaneous Insulin Infusion (CSII) by External Pump

2.4 Intravenous Use

3 DOSAGE FORMS AND STRENGTHS 4

CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Administration

5.2

Hypoglycemia

5.3

Hypokalemia

5.4 Renal Impairment

5.5 Hepatic Impairment

5.6 Hypersensitivity and Allergic Reactions

5.7 Antibody Production

5.8 Mixing of Insulins

5.9

5.10

Continuous Subcutaneous Insulin Infusion by External Fluid retention and heart failure with concomitant use of

PPAR-gamma agonists

ADVERSE REACTIONS

Pump

7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULA

8.1

Pregnancy

TIONS

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

OVERDOSAGE

11 DESCRIPTION

CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2

Pharmacodynamics

12.3

Pharmacokinetics

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal T

CLINICAL STUDIES

oxicology and/or Pharmacology

14.1 Subcutaneous Daily Injections

14.2

14.3 Intravenous Administration of NovoLog

Continuous Subcutaneous Insulin Infusion (CSII) by External Pump

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Recommended Storage

17 PATIENT COUNSELING INFORMATION

17.1 Physician Instructions

17.2 Patients Using Pumps

17.3 FDA Approved Patient Labeling * Sections or subsections omitted from the full prescribing information are

not listed.

NovoLog® (insulin aspart [rDNA origin] injection)

FULL PRESCRIBING INFORMATION

INDICA

1.1 Treatment of Diabetes Mellitus

NovoLog and children with diabetes mellitus.

2.1 Dosing

NovoLog human insulin. The dosage of 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 mealrelated subcutaneous injection treatment regimen, 50 to 70% of total insulin requirements may be provided by NovoLog by an intermediate-acting or long-acting insulin. Because of NovoLog 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 regular insulin.

Do not use NovoLog clear and colorless. NovoLog date.

2.2 Subcutaneous Injection

NovoLog region, buttocks, thigh, or upper arm. Because NovoLog 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 the dose, injection site, blood ﬂow, temperature, and level of physical activity.

NovoLog subcutaneous injection. Diluting one part NovoLog yield a concentration one-tenth that of NovoLog one part NovoLog of NovoLog

2.3

NovoLog [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 regular insulin, pre-meal boluses of NovoLog (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

the NovoLog infusion sets and the infusion set insertion site at least every 3 days.

The following insulin pumps studies conducted by Novo Nordisk, the manufacturer of NovoLog

• Medtronic Paradigm

• MiniMed 508

• Disetronic

Before using a different insulin pump with NovoLog®, read the pump label to make sure the pump has been evaluated with NovoLog

2.4

NovoLog 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 shown to be stable in infusion ﬂuids such as 0.9% sodium chloride.

Inspect NovoLog administration.

NovoLog contains 100 units of insulin aspart per mL (U-100).

• 10 mL vials

• 3 mL PenFill cartridges for the 3 mL PenFill

• 3 mL NovoLog

• 3 mL NovoLog® FlexTouch

4 CONTRAINDICATIONS

NovoLog

• during episodes of hypoglycemia

• in patients with hypersensitivity to NovoLog

TIONS AND USAGE

is an insulin analog indicated to improve glycemic control in adults

DOSAGE AND ADMINISTRA

is an insulin analog with an earlier onset of action than regular

that is viscous (thickened) or cloudy; use only if it is

should be administered by subcutaneous injection in the abdominal

may be diluted with Insulin Diluting Medium for NovoLog® for

to one part diluent will yield a concentration one-half that

(equivalent to U-50).

TION

must be individualized. NovoLog®

and the remainder provided

than when using human

should not be used after the printed expiration

has a more rapid

will vary according to

to nine parts diluent will

(equivalent to U-10). Diluting

Continuous Subcutaneous Insulin Infusion (CSII) by External Pump

can also be infused subcutaneously by an external insulin pump

has a more rapid onset and a shorter duration of activity than human

and the remainder is given as a basal infusion. Change

in the reservoir at least every 6 days, change the

†

have been used in NovoLog® clinical or in vitro

512 and 712

D-TRON® and H-TRON

Intravenous Use

can be administered intravenously under medical supervision for

for particulate matter and discoloration prior to parenteral

DOSAGE FORMS AND STRENGTHS

is available in the following package sizes: each presentation

(with or without the addition of a NovoPen disposable needles

FlexPen

is contraindicated

should be infused immediately

cartridge delivery device

3 PenMate®) with NovoFine®

or one of its excipients.

has been

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 followed by a meal within 5-10 minutes. Because of NovoLog

should immediately be

’s short duration

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 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

’s

be shared.

5.2 Hypoglycemia

Hypoglycemia is the most common adverse effect of all insulin therapies, including NovoLog 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 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 patients with renal impairment [see Clinical Pharmacology (12.3)].

5.5 Hepatic Impairment

As with other insulins, the dose requirements for NovoLog 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 usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation of NovoLog

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 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 (0.1%) NovoLog

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 in anti-insulin antibodies are observed more frequently with NovoLog 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.

action may vary in different

FlexPen® and NovoLog® FlexTouch® must not

. Severe hypoglycemia may lead to unconsciousness and/

, cause a shift in potassium from the

may be reduced in

injection. These reactions

. In some instances, these reactions may

have been reported post-approval.

. In controlled and uncontrolled clinical trials, 3 of 2341

-treated patients discontinued due to allergic reactions.

. Increases

5.8 Mixing of Insulins

• Mixing NovoLog attenuates the peak concentration of NovoLog affecting the time to peak concentration or total bioavailability of NovoLog If NovoLog into the syringe ﬁrst, and the mixture should be injected immediately after mixing.

• The efﬁcacy and safety of mixing NovoLog produced by other manufacturers have not been studied.

Insulin mixtures should not be administered intravenously

•

5.9 When used in an external subcutaneous insulin infusion pump,

NovoLog

When using NovoLog information should be followed (e.g., in-use time, frequency of changing infusion sets) because NovoLog 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

NovoLog 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

with NPH human insulin immediately before injection

is mixed with NPH human insulin, NovoLog® should be drawn

, without signiﬁcantly

with insulin preparations

Continuous Subcutaneous Insulin Infusion by External Pump

should not be mixed with any other insulin or diluent.

in an external insulin pump, the NovoLog®-speciﬁc

-speciﬁc information may differ from general

should not be exposed to temperatures greater than 37°C (98.6°F).

that will be used in a pump should not be mixed with

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.

ADVERSE REACTIONS

rial Experience

Clinical T

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 obser

using insulin, including NovoLog

• 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

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

eight 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

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 regular insulin are listed)

NovoLog® + NPH

Preferred Term N (%) N (%)

than

N= 596

ved adverse reaction in patients

[see Warnings and Precautions (5)].

, can cause lipodystrophy at

clinical trials

compared to human

Human Regular Insulin + NPH

N= 286

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.

NovoLog® (insulin aspart [rDNA origin] injection)

180

162

144

126

108

R+60

Mean Blood Glucose (mg/dL)

Note: The slashes on the mean profile indicate a jump on the time axis

Time (h)

Free serum insulin (mU/L)

300

Time (h)

Serum glucose (mg/dL)

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

compared to human regular insulin are listed)

NovoLog

NovoLog® + NPH

N= 91

Human Regular Insulin + 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 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 postapproval use [see Patient Counseling Information (17)].

. Because these adverse reactions are reported

have been identiﬁed during

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 bloodglucose-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.

USE IN SPECIFIC POPULA

TIONS

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

(n=157) versus regular human insulin (n=165) in 322 pregnant

NovoLog 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 during pregnancy, and there was no signiﬁcant difference in the incidence of maternal hypoglycemia.

Subcutaneous reproduction and teratology studies have been performed with NovoLog studies, NovoLog and throughout pregnancy, and to rabbits during organogenesis. The effects of NovoLog human insulin. NovoLog 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.

and regular human insulin in rats and rabbits. In these

did not differ from those observed with subcutaneous regular

of ~ 6%

was given to female rats before mating, during mating,

, like human insulin, caused pre- and post-

Nursing Mothers

8.3

is unknown whether insulin aspart is excreted in human milk. Use of

is compatible with breastfeeding, but women with diabetes who are

NovoLog lactating may require adjustments of their insulin doses.

Pediatric Use

8.4

NovoLog

is approved for use in children for subcutaneous daily injections

and for subcutaneous continuous infusion by external insulin pump.

has not been studied in pediatric patients younger than 2 years of

NovoLog age. NovoLog Please see Section 14 CLINICAL STUDIES for summaries of clinical studies.

8.5

Of the total number of patients (n= 1,375) treated with NovoLog 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 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 patients. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of NovoLog

has not been studied in pediatric patients with type 2 diabetes.

Geriatric Use

response to NovoLog®, as compared to human insulin, did

in elderly compared to younger

action have not been performed.

in 3 controlled

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

(insulin aspart [rDNA origin] injection) is a rapid-acting human

NovoLog insulin analog used to lower blood glucose. NovoLog 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 of 5825.8.

Figure 1. Structural formula of insulin aspart.

is a sterile, aqueous, clear, and colorless solution, that contains

NovoLog 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.

has a pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium

NovoLog hydroxide 10% may be added to adjust pH.

CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The primar

y activity of NovoLog Insulins, including NovoLog cells and lower blood glucose by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose from the liver.

256H381N65079S6

is the regulation of glucose metabolism.

, bind to the insulin receptors on muscle and fat

is homologous with

and a molecular weight

12.2 Pharmacodynamics

Studies in normal volunteers and patients with diabetes demonstrated that subcutaneous administration of NovoLog than regular human insulin.

In a study in patients with type 1 diabetes (n=22), the maximum glucoselowering effect of NovoLog 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 individual. The parameters of NovoLog 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)].

Figure 2. Serial mean serum glucose collected up to 6 hours following a single pre-meal dose of NovoLog regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes.

may vary considerably in different individuals or within the same

250

200

150

100

0 12345

has a more rapid onset of action

occurred between 1 and 3 hours after

activity (time of onset, peak time and

(solid curve) or

A double-blind, randomized, two-way cross-over study in 16 patients with type 1 diabetes demonstrated that intravenous infusion of NovoLog in a blood glucose proﬁle that was similar to that after intravenous infusion with regular human insulin. NovoLog 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).

0 10 R–20 R R+40 R+50

Figure 3. Mean blood glucose proﬁles following intravenous infusion of NovoLog (solid curve) in 16 patients with type 1 diabetes. R represents the time of autonomic reaction.

R–10 R+10 R+20 R+30

(hatched curve) and regular human insulin

or human insulin was infused until

Time (min)

resulted

12.3 Pharmacokinetics

The single substitution of the amino acid proline with aspartic acid at position B28 in NovoLog observed with regular human insulin. NovoLog 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 The mean insulin clearance was similar for the two groups with mean values of 1.2 l/h/kg for the NovoLog insulin group.

Bioavailability and Absorption - NovoLog 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 the two insulins are absorbed to a similar extent.

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 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 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 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 were observed independent of the site of injection (abdomen, thigh, or upper arm).

Distribution and Elimination - NovoLog (<10%), similar to that seen with regular human insulin. After subcutaneous administration in normal male volunteers (n=24), NovoLog eliminated than regular human insulin with an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.

reduces the molecule’s tendency to form hexamers as

or regular human insulin at 1.5 mU/kg/min for 120 minutes.

group and 1.2 l/h/kg for the regular human

compared to regular human insulin indicates that

012345

consistently reached peak serum concentrations

and regular human insulin, both administered

and regular human insulin described above,

is, therefore, more rapidly

has a faster absorption, a faster

has low binding to plasma proteins

than for

was more rapidly

Speciﬁc Populations

Children and Adolescents - The pharmacokinetic and pharmacodynamic properties of NovoLog 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 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

and regular human insulin were evaluated in a

and regular human insulin were similar to

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