Included as part of the PRECAUTIONS section.
Subcutaneous injection of
Novolin R should be followed by a meal. Patients should wait approximately 30
minutes after injection before starting the meal [see DOSAGE AND
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 Novolin R action may vary in different individuals or at different times in
the same individual and is dependent on many conditions, including dosage, 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.
Hypoglycemia is the most common
adverse reaction of all insulin therapies, including Novolin R. Severe
hypoglycemia may lead to unconsciousness, convulsions, temporary or permanent
impairment of brain function or death. Severe hypoglycemia requiring the
assistance of another person, parenteral glucose infusion, and glucagon
administration has been observed in clinical trials with insulin, including
trials with Novolin R.
The timing of hypoglycemia
usually reflects the time-action profile of the administered insulin formulations
[see CLINICAL PHARMACOLOGY]. 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]. 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, pediatric
patients, and the elderly). 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
Rapid changes in serum glucose
concentrations may induce symptoms of hypoglycemia in patients 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 neuropathy, use of medications such as beta-blockers, or
intensified glycemic control [see DRUG INTERACTIONS]. 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.
All insulins, including Novolin
R, 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
and patients taking medications sensitive to serum potassium concentrations).
Monitor glucose and potassium frequently when Novolin R is administered
Ketoacidosis, And Hyperosmolar Hyperglycemic Non-Ketotic Syndrome
ketoacidosis, or hyperosmolar hyperglycemic non-ketotic syndrome may develop in
patients who take less insulin than needed to control blood glucose. These
conditions can be precipitated by illness, infection, dietary indiscretion, or
omission or improper administration of the prescribed insulin dose.
Renal Or Hepatic Impairment
As with other insulins, the
dose requirements for Novolin R may be reduced in patients with renal or
Hypersensitivity And Allergic
As with other insulins, patients
may experience redness, swelling, or itching at the site of injection of
Novolin R. These reactions usually resolve in a few days to a few weeks, but in
some occasions, may require discontinuation of Novolin R. 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 the use of metacresol, which is an
excipient in Novolin R.
generalized allergy, including anaphylaxis may occur with any insulin,
including Novolin R. Generalized allergy to insulin may manifest as a whole
body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or
Mixing Of Insulins
If Novolin R is mixed with NPH
human insulin, Novolin R should be drawn into the syringe first and the mixture
should be injected immediately after mixing. Insulin mixtures should not be
Increases in titers of
anti-insulin antibodies that react with human insulin have been observed in
patients treated with Novolin R. Data from a 12-month controlled trial in
patients with type 1 diabetes suggest that the increase in these antibodies is
transient. The clinical significance of these antibodies is not known but does
not appear to cause deterioration in glycemic control or necessitate increases
in insulin dose.
Fluid Retention And Heart Failure With Concomitant Use Of
Thiazolidinediones (TZDs), which are peroxisome
proliferator-activated receptor (PPAR) gamma agonists, can cause dose-related
fluid retention, particularly when used in combination with Â insulin. Fluid
retention may lead to or exacerbate heart failure. Patients treated with
insulin, including NOVOLIN R, 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.
Patient Counseling Information
See FDA-Approved Patient
Labeling (Patient Information and Instructions for Use)
Instructions For All Patients
Maintenance of normal or
near-normal glucose control is a treatment goal in diabetes mellitus and has
been associated with a reduction in some diabetic complications. Patients
should be informed about potential risks and benefits of Novolin R therapy including
possible adverse reactions. Patients should also be offered continued education
and advice on insulin therapies, injection technique, lifestyle management,
regular glucose monitoring, periodic glycosylated hemoglobin testing,
recognition and management of hypo-and hyperglycemia, adherence to meal
planning, complications of insulin therapy, timing of dose, instruction
in the use of injection devices, and proper storage of insulin. Patients should
be informed that frequent, patient-performed blood glucose measurements are
needed to achieve optimal glycemic control and avoid both hyper-and
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. Patients who have frequent hypoglycemia or reduced or absent
warning signs of hypoglycemia should be advised to use caution when driving or
operating machinery. Female patients should be advised to tell their physician
if they intend to become, or if they become pregnant.
Patients should be instructed to always carefully check
that they are administering the correct insulin to avoid medication errors
between Novolin R and other insulins. Patients should check the label for the
drug name Novolin R, the enlarged R letter, and the blue horizontal bar. If a
prescription for Novolin R is needed, it should be written clearly to avoid
confusion with other insulin products.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Standard 2-year carcinogenicity studies in animals have
not been performed to evaluate the carcinogenic potential of Novolin R.
Novolin R is not mutagenic in the following in vitro tests:
The chromosomal aberration assay in human lymphocytes, the micronucleus assay
in mouse polychromatic erythrocytes, and the mutation frequency assay in
Chinese hamster cells.
Standard reproduction and teratology studies in animals,
including fertility assessments have not been conducted with Novolin R.
Use In Specific Populations
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 glycemic control. It is essential
for patients with diabetes or a history of gestational diabetes to maintain
good glycemic 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 important during pregnancy in patients with diabetes.
Therefore, women should be advised to tell their healthcare provider if they
intend to become, or if they become, pregnant while taking Novolin R.
No reproductive toxicity studies have been performed with
It is unknown whether Novolin R is excreted in breast
milk. Small amounts of human insulin are secreted into breast milk, the
significance of which is not known. Use of Novolin R is compatible with breastfeeding,
but insulin doses may need to be adjusted because lactation can reduce insulin requirements.
The safety and effectiveness of subcutaneous injections
of Novolin R have been established in pediatric patients (ages 2 to18 years)
with type 1 diabetes [see Clinical Studies]. Novolin R has not been
studied in pediatric patients younger than 2 years of age. Novolin R has not
been studied in pediatric patients with type 2 diabetes.
In general, pediatric patients with type 1 diabetes are
more susceptible to hypoglycemia than adult patients with type 1 diabetes. As
in adults, the dosage of Novolin R must be individualized in pediatric patients
based on metabolic needs and frequent monitoring of blood glucose [see
DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
In 3 controlled clinical trials 18 of 1285 patients
(1.4%) with type 1 diabetes treated with Novolin R and insulin aspart were
≥ 65 years of age. In 4 controlled clinical trials 151 of 635 patients (24%)
with type 2 diabetes were ≥ 65 years of age. Therefore, conclusions are
limited regarding the efficacy and safety of Novolin R in patients ≥ 65
years of age, particularly in patients with type 1 diabetes.
Pharmacokinetic/pharmacodynamic studies to assess the effect of age on Novolin
R have not been performed.
Use caution in patients with advanced age, due to the
potential for decreased renal function in this population [see WARNINGS AND