Insulinside effects

The following adverse reactions are discussed elsewhere: Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Hypoglycemia Hypoglycemia Due to Medication Errors Hypersensitivity Reactions Hypokalemia Adverse reactions commonly associated with insulin glargine products include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema and weight gain. To report SUSPECTED ADVERSE REACTIONS, contact Biocon Biologics at 1-833-986-1468 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 conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice. The data in Table 1 reflect the exposure of 2,327 patients with type 1 diabetes to insulin glargine or NPH in Studies A, B, C, and D. The type 1 diabetes population had the following characteristics: the mean age was 39 years. 54% were male, and mean body mass index (BMI) was 25.1 Kg/m 2. Ninety-seven percent were White, 2% were Black or African American and less than 1% were Asian. Approximately 3% of the patients instudies B and C were Hispanic. The data in Table 2 reflect the exposure of 1,563 patients with type 2 diabetes to insulin glargine or NPH in Studies E, F, and G. The type 2 diabetes population had the following characteristics: the mean age was 59 years, 58% were male, and mean BMI was 29.2 kg/m 2. Eighty-seven percent were white, 8% were Black or African American and 3% were Asian. Approximately 9% of patients in Study F were Hispanic. The frequencies of adverse reactions during insulin glargine clinical studies in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below (Tables 1, 2, 3, and 4).

Table 1: Adverse Reactions Occurring≥5% in Pooled Clinical Studies up to 28 Weeks Duration in Adults with Type 1 Diabetes Insulin Glargine, % (n = 1257) NPH,% (n = 1070) Upper respiratory tract infection 22.4

23.1 Infection

Body system not specified 9.4 10.3 Accidental injury 5.7 6.4 Headache 5.5

4.7 Table 2:

Adverse Reactions Occurring≥5% in Pooled Clinical Studies up to 1 Year Duration in Adults with Type 2 Diabetes Insulin Glargine, % (n = 849) NPH,% (n = 714) Upper respiratory tract infection 11.4

13.3 Infection

Body system not specified 10.4 11.6 Retinal vascular disorder 5.8

7.4 Table 3:

Adverse Reactions Occurring≥10% in a 5 Year Study of Adults with Type 2 Diabetes Insulin Glargine, % (n = 514) NPH,% (n = 503) Upper respiratory tract infection 29.0 33.6 Edema peripheral 20.0 22.7 Hypertension 19.6 18.9 Influenza 18.7 19.5 Sinusitis 18.5 17.9 Cataract 18.1 15.9 Bronchitis 15.2 14.1 Arthralgia 14.2 16.1 Pain in extremity 13.0 13.1 Back pain 12.8 12.3 Cough 12.1 7.4 Urinary tract infection 10.7 10.1 Diarrhea 10.7 10.3 Depression 10.5 9.7 Headache 10.3

9.3 Table 4:

Adverse Reactions Occurring≥5% in a 28-Week Clinical Study in Peadiatric Patients with Type 1 Diabetes Insulin Glargine, % (n = 174) NPH,% (n = 175) Infection Body system not specified 13.8 17.7 Upper respiratory tract infection 13.8 16.0 Pharyngitis 7.5 8.6 Rhinitis 5.2

5.1 Severe Hypoglycemia

Hypoglycemia was the most commonly observed adverse reaction in patients treated with insulin glargine. Tables 5, 6, and 7 summarize the incidence of severe hypoglycemia in the insulin glargine clinical Studies. Severe symptomatic hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose below 50 mg/dL (≤ 56 mg/dL in the 5-year study and ≤ 36 mg/dL in the ORIGIN study) or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. Percentages of insulin glargine-treated adult patients who experienced severe symptomatic hypoglycemia in the insulin glargine clinical studies were comparable to percentages of NPH-treated patients for all treatment regimens (see Tables 5 and 6). In the pediatric clinical study, pediatric patients with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to the adult studies with type 1 diabetes.

Table 5: Severe Symptomatic Hypoglycemia in Patients with Type 1 Diabetes Study A Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study B Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study C Type 1 Diabetes Adults 16 weeks In combination with insulin lispro Study D Type 1 Diabetes Pediatrics 26 weeks In combination with regular insulin Insulin Glargine n = 292 NPH n = 293 Insulin Glargine n = 264 NPH n = 270 Insulin Glargine n = 310 NPH n = 309 Insulin Glargine n = 174 NPH n = 175 Percent of patients 10.6 15.0 8.7 10.4 6.5 5.2 23.0

28.6 Table 6:

Severe Symptomatic Hypoglycemia in Patients with Type 2 Diabetes Study E Type 2 Diabetes Adults 52 weeks In combination with oral agents Study F Type 2 Diabetes Adults 28 weeks In combination with regular insulin Study G Type 2 Diabetes Adults 5 years In combination with regular insulin Insulin Glargine n = 289 NPH n = 281 Insulin Glargine n = 259 NPH n = 259 Insulin Glargine n = 513 NPH n = 504 Percent of patients 1.7 1.1 0.4 2.3 7.8 11.9 Table 7 displays the proportion of patients who experienced severe symptomatic hypoglycemia in the insulin glargine and Standard Care groups in the ORIGIN study.

Table 7: Severe Symptomatic Hypoglycemia in the ORIGIN Study ORIGIN Study Medium duration of follow-up: 6.2 years Insulin Glargine n = 6231 Standard Care n = 6273 Percent of patients 5.6

1.8 Peripheral

Edema Some patients taking insulin glargine products have experienced sodium retention and edema, particularly if previously poor metabolic control was improved by intensified insulin therapy. Lipodystrophy Administration of insulin subcutaneously, including insulin glargine products, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients. 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. Weight Gain Weight gain has occurred with insulin including insulin glargine products and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Hypersensitivity Reactions Local Reactions Patients taking insulin glargine experienced injection site reactions, including redness, pain, itching, urticaria, edema, and inflammation. In clinical studies in adult patients, there was a higher incidence of treatment-emergent injection site pain in insulin glargine-treated patients (2.7%) compared to NPH insulin-treated patients (0.7%). The reports of pain at the injection site did not result in discontinuation of therapy. Systemic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock have occured with insulin, including insulin glargine products and may be life threatening.

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 medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other insulin glargine products may be misleading. All insulin products can elicit the formation of insulin antibodies. The presence of such insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In clinical studies of insulin glargine, increases in titers of antibodies to insulin were observed in NPH insulin and insulin glargine treatment groups with similar incidences.

6.3 Postmarketing

Experience The following adverse reactions have been identified during postapproval use of insulin glargine products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Medication errors have been reported in which rapid-acting insulins and other insulins have been accidentally administered instead of insulin glargine products. 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.