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. The safety of NOVOLOG was evaluated in two treat-to-target trials of 6 months duration, conducted in patients with type 1 diabetes or type 2 diabetes

The data in Table 1 reflect the exposure of 596 patients with type 1 diabetes to NOVOLOG in one clinical trial with a mean exposure duration to NOVOLOG of 24 weeks. The mean age was 39 years. Fifty-one percent were male, 94% were Caucasian, 2% were Black and 4% were other races. The mean body mass index (BMI) was 25.6 kg/m

The data in Table 2 reflect the exposure of 91 patients with type 2 diabetes to NOVOLOG in one clinical trial with a mean exposure duration to NOVOLOG of 24 weeks. The mean age was 57 years. Sixty-three percent were male, 76% were Caucasian, 9% were Black and 15% were other races. The mean BMI was 29.7 kg/m

Common adverse reactions were defined as events that occurred in ≥5%, excluding hypoglycemia, of the population studied. Common adverse events that occurred at the same rate or greater for NOVOLOG-treated patients than in comparator-treated patients during clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus (other than hypoglycemia) are listed in Table 1 and Table 2, respectively.

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including NOVOLOG

Severe hypoglycemia was defined as hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization. The incidence of severe hypoglycemia in:

No severe hypoglycemic episodes were reported in adult patients with type 2 diabetes mellitus receiving NOVOLOG via continuous subcutaneous insulin infusion by external pump at 16 weeks.

Some patients taking insulin, including NOVOLOG have experienced erythema, local edema, and pruritus at the site of injection. These conditions were usually self-limiting. Severe cases of generalized allergy (anaphylaxis) have been reported

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.

Administration of insulin, including NOVOLOG, subcutaneously and via subcutaneous insulin infusion by external pump, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients

Insulins, including NOVOLOG, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Weight gain has occurred with insulins, including NOVOLOG, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to NOVOLOG in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In a 6-month study with a 6-month extension in adult subjects with type 1 diabetes, 99.8% of patients who received NOVOLOG were positive for anti-insulin antibodies (AIA) at least once during the study, including 97.2% that were positive at baseline. A total of 92.1% of patients who received NOVOLOG were positive for anti-drug antibodies (ADA) at least once during the study, including 64.6% that were positive at baseline.

In a phase 3 type 1 diabetes clinical trial of NOVOLOG, initial increase in titers of antibodies to insulin, followed by a decrease to baseline values, was observed in regular human insulin and insulin aspart treatment groups with similar incidences. These antibodies did not cause deterioration in glycemic control or necessitate increases in insulin dose.

The following adverse reactions have been identified during post-approval 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 or establish a causal relationship to drug exposure.

Medication errors have been reported in which other insulins have been accidentally substituted for NOVOLOG.

Localized cutaneous amyloidosis at the injection site has occurred with insulin aspart. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.