1 INDICATIONS AND USAGE APIDRA is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus.

APIDRA is a rapid-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus.

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6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: Hypoglycemia [see Warnings and Precautions (5.3) ] Hypoglycemia Due to Medication Errors [see Warnings and Precautions (5.4) ] Hypokalemia [see Warnings and Precautions (5.5) ] Hypersensitivity Reactions [see Warnings and Precautions (5.6) ] Adverse reactions commonly associated with APIDRA include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, and weight gain.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials 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.

The data in Table 1 reflect the exposure of 1591 patients with type 1 diabetes to APIDRA or comparators [see Clinical Studies (14.1) ] .

The type 1 diabetes population had the following characteristics: Mean age was 39.74 years.

54.5 % were male, 95.5% were Caucasian, 1.5% were Black or African American.

The data in Table 2 reflect the exposure of 1766 patients with type 2 diabetes to APIDRA or comparators [see Clinical Studies (14.2) ] .

The type 2 diabetes population had the following characteristics: Mean age was 59.08 years.

51.2% were male, 88.5% were Caucasian, 7.2% were Black or African American.

The frequencies of adverse drug reactions during APIDRA clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.

Table 1: Adverse Reactions Occurring ≥5% in Pooled Studies of Adults with Type 1 Diabetes APIDRA, % (n=950) All Comparators Insulin lispro, regular human insulin, insulin aspart , % (n=641) Nasopharyngitis 10.6 12.9 Hypoglycemia Only severe symptomatic hypoglycemia 6.8 6.7 Upper respiratory tract infection 6.6 5.6 Influenza 4.0 5.0 Table 2: Adverse Reactions Occurring ≥5% in Pooled Studies of Adults with Type 2 Diabetes APIDRA, % (n=883) Regular Human Insulin, % (n=883) Upper respiratory tract infection 10.5 7.7 Nasopharyngitis 7.6 8.2 Edema peripheral 7.5 7.8 Influenza 6.2 4.2 Arthralgia 5.9 6.3 Hypertension 3.9 5.3 Pediatrics Table 3 summarizes the adverse reactions occurring with frequency higher than 5% in a clinical study in pediatric patients with type 1 diabetes treated with APIDRA (n=277) or insulin lispro (n=295).

Table 3: Adverse Reactions Occurring ≥5% in Pediatric Patients with Type 1 Diabetes APIDRA, % (n=277) Insulin Lispro, % (n=295) Nasopharyngitis 9.0 9.5 Upper respiratory tract infection 8.3 10.8 Headache 6.9 11.2 Hypoglycemic seizure 6.1 4.7 Severe Symptomatic Hypoglycemia Hypoglycemia was the most commonly observed adverse reaction in patients treated with insulin, including APIDRA.

The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors.

For these reasons, comparing rates of hypoglycemia in clinical trials for APIDRA with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that occur in clinical practice.

The rates and incidence of severe symptomatic hypoglycemia, defined as hypoglycemia requiring intervention from a third party are presented in Table 4.

In the clinical trials, children and adolescents with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to adults with type 1 diabetes (see Table 4 ) [see Clinical Studies (14) ] .

Table 4: Severe Symptomatic Hypoglycemia Severe symptomatic hypoglycemia defined as a hypoglycemic event requiring the assistance of another person that met one of the following criteria: the event was associated with a whole blood referenced blood glucose <36 mg/dL or the event was associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration.

Type 1 Diabetes Adults 12 weeks with insulin glargine Type 1 Diabetes Adults 26 weeks with insulin glargine Type 2 Diabetes Adults 26 weeks with NPH human insulin Type 1 Diabetes Pediatrics 26 weeks APIDRA Pre meal APIDRA Post meal Regular Human Insulin APIDRA Insulin Lispro APIDRA Regular Human Insulin APIDRA Insulin Lispro Events per month per patient 0.05 0.05 0.13 0.02 0.02 0.00 0.00 0.09 0.08 Percent of patients (n/total N) 8.4% (24/286) 8.4% (25/296) 10.1% (28/278) 4.8% (16/339) 4.0% (13/333) 1.4% (6/416) 1.2% (5/420) 16.2% (45/277) 19.3% (57/295) Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII) In a 12-week randomized study in patients with type 1 diabetes (n=59), the rates of catheter occlusions and infusion site reactions were similar for APIDRA and insulin aspart–treated patients (see Table 5 ).

Table 5: Catheter Occlusions and Infusion Site Reactions APIDRA (n=29) Insulin Aspart (n=30) Catheter occlusions/month 0.08 0.15 Infusion site reactions 10.3% (3/29) 13.3% (4/30) Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including APIDRA.

Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.

In controlled clinical trials up to 12 months duration, potential systemic allergic reactions were reported in 79 of 1833 patients (4.3%) who received APIDRA and 58 of 1524 patients (3.8%) who received the comparator short-acting insulins.

During these trials, treatment with APIDRA was permanently discontinued in 1 of 1833 patients due to a potential systemic allergic reaction.

Injection Site Reactions As with any insulin, patients taking APIDRA may experience redness, swelling, or itching at the site of injection.

These minor reactions usually resolve in a few days to a few weeks, but on some occasions may require discontinuation of APIDRA.

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.

Insulin Initiation and Intensification of Glucose Control 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 APIDRA, 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 [see Dosage and Administration (2.2) ] .

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

Weight Gain Weight gain can occur with insulins, including APIDRA, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

6.2 Immunogenicity 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 medication, and underlying disease.

For these reasons, comparison of the incidence of antibodies to APIDRA in the studies described below with the incidence of antibodies in other studies or to other insulin products may be misleading.

In a study in patients with type 1 diabetes (n=333), the concentrations of insulin antibodies that react with both human insulin and insulin glulisine (cross-reactive insulin antibodies) remained near baseline during the first 6 months of the study in the patients treated with APIDRA.

A decrease in antibody concentration was observed during the following 6 months of the study.

In a study in patients with type 2 diabetes (n=411), a similar increase in cross-reactive insulin antibody concentration was observed in the patients treated with APIDRA and in the patients treated with human insulin during the first 9 months of the study.

Thereafter the concentration of antibodies decreased in the APIDRA patients and remained stable in the human insulin patients.

There was no correlation between cross-reactive insulin antibody concentration and changes in HbA1c, insulin doses, or incidence of hypoglycemia.

APIDRA did not elicit a significant antibody response in a study of pediatric patients with type 1 diabetes.

6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of APIDRA.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.

Medication errors have been reported in which other insulins, particularly long-acting insulins, have been accidentally administered instead of APIDRA.

Localized cutaneous amyloidosis at the injection site has occurred.

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.