Insulin Glargine Yfgn Drug Information

Insulin Glargine-yfgn is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. Limitations of Use Insulin Glargine-yfgn is not recommended for the treatment of diabetic ketoacidosis. Insulin Glargine-yfgn is a long-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus.

Limitations of Use Not recommended for the treatment of diabetic ketoacidosis.

Important

Administration Instructions Always check insulin labels before administration. This product is Insulin Glargine-yfgn. Visually inspect Insulin Glargine-yfgn vials and prefilled pens for particulate matter and discoloration prior to administration.

Only use if the solution is clear and colorless with no visible particles. Administer Insulin Glargine-yfgn subcutaneously into the abdominal area, thigh, or deltoid, and rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis.

During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring. Do not administer intravenously or via an insulin pump. Do not dilute or mix Insulin Glargine-yfgn with any other insulin or solution.

The Insulin Glargine-yfgn prefilled pen dials in 1-unit increments. Use the Insulin Glargine-yfgn prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.

General Dosing Instructions Administer Insulin Glargine-yfgn subcutaneously once daily at any time

of day but at the same time every day. Individualize and adjust the dosage of Insulin Glargine-yfgn based on the patient’s metabolic needs, blood glucose monitoring results and glycemic control goal. Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), during acute illness, or changes in renal or hepatic function.

Dosage adjustments should only be made under medical supervision with appropriate glucose monitoring. In patients with type 1 diabetes, Insulin Glargine-yfgn must be used concomitantly with short-acting insulin.

Initiation of Insulin Glargine-yfgn Therapy Recommended Starting Dosage in Patients with Type

1 Diabetes The recommended starting dosage of Insulin Glargine-yfgn in patients with type 1 diabetes is approximately one-third of the total daily insulin requirements. Use short-acting, premeal insulin to satisfy the remainder of the daily insulin requirements Recommended Starting Dosage in Patients with Type 2 Diabetes The recommended starting dosage of Insulin Glargine-yfgn in patients with type 2 diabetes who are not currently treated with insulin is 0.2 units/kg or up to 10 units once daily.

Switching to Insulin Glargine-yfgn from Other Insulin Therapies Dosage adjustments are recommended

to lower the risk of hypoglycemia when switching patients to Insulin Glargine-yfgn from other insulin therapies. When switching from: Once-daily insulin glargine 300 units/mL to once-daily Insulin Glargine-yfgn (100 units/mL), the recommended starting Insulin Glargine-yfgn dosage is 80% of the insulin glargine, 300 units/mL dosage that is being discontinued. Once-daily NPH insulin to once-daily Insulin Glargine-yfgn, the recommended starting Insulin Glargine-yfgn dosage is the same as the dosage of NPH that is being discontinued.

Twice-daily NPH insulin to once-daily Insulin Glargine-yfgn, the recommended starting Insulin Glargine-yfgn dosage is 80% of the total NPH dosage that is being discontinued.

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 the 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 in studies 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 the 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 = 1,257) NPH,% (n = 1,070) Upper respiratory tract infection 22.4

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

5.5

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

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

Cataract 18.1 15.9 Bronchitis 15.2 14.1 Arthralgia 14.2 16.1 Pain in extremity

13.0

Back pain 12.8 12.3 Cough 12.1 7.4 Urinary tract infection 10.7 10.1

Diarrhea 10.7

Depression 10.5 9.7 Headache 10.3 9.3 Table 4: Adverse Reactions Occurring ≥5%

in a 28-Week Clinical Study in Pediatric Patients with Type 1 Diabetes Insulin Glargine, % (n = 174) NPH,% (n = 175) Infection Body system not specified 13.8

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

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

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 Median duration of follow-up: 6.2 years Insulin Glargine n = 6231 Standard Care n = 6273 Percent of patients 5.6

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 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 occurred with insulin, including insulin glargine products and may be life threatening.

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.

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.

Table 8 includes clinically significant drug interactions with Insulin Glargine-yfgn. Table 8: Clinically Significant Drug Interactions with Insulin Glargine-yfgn Drugs that May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors. Intervention: Dosage reductions and increased frequency of glucose monitoring may be required when Insulin Glargine-yfgn is coadministered with these drugs.

Drugs that May Decrease the Blood Glucose Lowering Effect of Insulin Glargine-yfgn Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dosage increases and increased frequency of glucose monitoring may be required when Insulin Glargine-yfgn is coadministered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Glargine-yfgn Drugs: Alcohol, beta-blockers, clonidine, and lithium salts.

Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dosage adjustment and increased frequency of glucose monitoring may be required when Insulin Glargine-yfgn is coadministered with these drugs. Drugs that May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine.

Intervention: Increased frequency of glucose monitoring may be required when Insulin Glargine-yfgn is coadministered with these drugs. Drugs that Affect Glucose Metabolism : Adjustment of insulin dosage may be needed. Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product.

Biosimilarity of Insulin Glargine-yfgn has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information.

Pregnancy Risk Summary Published studies with use of insulin glargine products during pregnancy have not reported a clear association with insulin glargine products and adverse developmental outcomes (see Data ). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations ). Rats and rabbits were exposed to insulin glargine in animal reproduction studies during organogenesis, respectively 50 times and 10 times the human subcutaneous dosage of 0.2 units/kg/day. Overall, the effects of insulin glargine did not generally differ from those observed with regular human insulin (see Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20% to 25% in women with a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown.

Clinical Considerations Disease-Associated Maternal and/or Embryo-fetal Risk Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

Data Human Data Published data do not report a clear association with insulin glargine products and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some lacking comparator groups. Animal Data Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits.

Insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 50 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day (0.007 mg/kg/day), on a mg/kg basis. In rabbits, doses of 0.072 mg/kg/day, which is approximately 10 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day on a mg/kg basis, were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits.

However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic development appeared normal.

Pediatric Use The safety and effectiveness of Insulin Glargine-yfgn to improve glycemic control in pediatric patients with diabetes mellitus have been established. Use of Insulin Glargine-yfgn for this indication is supported by Insulin Glargine-yfgn's approval as a biosimilar to insulin glargine and evidence from an adequate and well-controlled study (Study D) in 174 insulin glargine-treated pediatric patients aged 6 to 15 years with type 1 diabetes mellitus and from adequate and well-controlled studies of insulin glargine in adults with diabetes mellitus . In the pediatric clinical study, pediatric patients with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia compared to the adults in studies with type 1 diabetes.

Insulin Glargine-yfgn is contraindicated: During episodes of hypoglycemia. In patients with hypersensitivity to insulin glargine products or any of the excipients in Insulin Glargine-yfgn. During episodes of hypoglycemia Hypersensitivity to insulin glargine products or any excipient in Insulin Glargine-yfgn

Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia can usually be treated with oral carbohydrates. Lowering the insulin dosage, and adjustments in meal patterns or exercise may be needed.

More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with glucagon for emergency use or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia must be corrected appropriately.