SEMGLEE- insulin glargine-yfgn_injection, solution

The primary activity of insulin, including insulin glargine products, is regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis. In clinical studies, the glucose-lowering effect on a molar basis (i. , when given at the same doses) of intravenous insulin glargine is approximately the same as that for human insulin. Figure 1 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24 hours after subcutaneous injection of insulin glargine or NPH insulin. The median time between subcutaneous injection and the end of pharmacological effect was 14. 5 hours (range: 9. 3 hours) for NPH insulin, and 24 hours (range: 10. 8 to > 24 hours) (24 hours was the end of the observation period) for insulin glargine. Figure 1: Glucose-Lowering Effect Over 24 Hours in Patients with Type 1 Diabetes * Determined as amount of glucose infused to maintain constant plasma glucose levels The duration of action after abdominal, deltoid, or thigh subcutaneous administration of insulin glargine was similar. The time course of action of insulins, including insulin glargine products, may vary between patients and within the same patient. Figure 1: Glucose-Lowering Effect Over 24 Hours in Patients with Type 1 Diabetes After subcutaneous injection of insulin glargine in healthy subjects and in patients with diabetes, the insulin serum concentrations indicated a slower, more prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to NPH insulin. Metabolism A metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of human insulin, M1 (21 A A B Specific Populations Age, Race, Body Mass Index, and Gender Effect of age, race, body mass index (BMI), and gender on the pharmacokinetics of insulin glargine products has not been evaluated. However, in controlled clinical studies in adults (n = 3,890) and a controlled clinical study in pediatric patients (n = 349), subgroup analyses based on age, race, BMI, and gender did not show differences in safety and efficacy between insulin glargine and NPH insulin [see Clinical Studies (14).

SEMGLEE is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. Limitations of Use SEMGLEE is not recommended for the treatment of diabetic ketoacidosis. SEMGLEE is a long-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. ( 1 Limitations of Use Not recommended for the treatment of diabetic ketoacidosis.

DOSAGE AND ADMINISTRATION
4 [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 2) Adverse Reactions (6) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 2) Recommended Starting Dosage in Patients with Type 1 Diabetes The recommended starting dosage of SEMGLEE 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 SEMGLEE 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. Dosage adjustments are recommended to lower the risk of hypoglycemia when switching patients to SEMGLEE from other insulin therapies [see Warnings and Precautions (5. 3) When switching from: .
INSTRUCTIONS FOR USE
SEMGLEEregistered (Sehm-GLEE) These Instructions for Use contain information on how to inject SEMGLEE using the vial. Read these Instructions for Use before you start taking SEMGLEE and each time you get a new SEMGLEE vial. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Do not share your SEMGLEE syringes with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. Supplies Needed to Give Your Injection: “Disposing of used needles and syringes” Preparing to Inject SEMGLEE: Do not Do not Always use a syringe that is marked for U-100 insulin. Always use a new syringe and a new needle for each injection to help prevent infections and prevent blocked needles. Step 1: If you are using a new SEMGLEE vial, remove the protective cap. Do not Step 2: Wipe the top of the vial with an alcohol swab. You do not have to shake the vial of SEMGLEE before use. Step 3: Draw air into the syringe equal to your SEMGLEE dose. Put the needle through the rubber top of the vial and push the plunger to inject the air into the vial. Step 4: Leave the syringe in the vial and turn both upside down. Hold the syringe and vial firmly in one hand. Make sure the tip of the needle is in the SEMGLEE solution. With your free hand, pull the plunger to withdraw the correct dose into the syringe. Step 5: Before you take the needle out of the vial, check the syringe for air bubbles. If bubbles are in the syringe, hold the syringe straight up and tap the side of the syringe until the bubbles float to the top. Push the bubbles out with the plunger and draw insulin back in until you have the correct dose. Step 6: Remove the needle from the vial. Do not let the needle touch anything. You are now ready to inject. Injecting SEMGLEE: Step 7: Choose your injection site: Change (rotate) your injection sites within the area you choose for each dose Do not Do not Step 8: 10 Step 9: Do not Do not Disposing of Used Needles and Syringes Do not o o o o o Do not Do not Storing and Disposing SEMGLEE? Unopened (not in-use) SEMGLEE vials Do not After SEMGLEE vials have been opened (in-use) 28 days Do not 28 This Instructions for Use has been approved by the U. Food and Drug Administration. Revised: 05/2023 Manufactured by: Mylan Pharmaceuticals Inc. Manufactured for: Mylan Specialty L. Product of Malaysia SEMGLEE is a registered trademark of Mylan Pharmaceuticals Inc. , a Viatris Company. MA:B:IFUV:INGLIJK:RX7 Step 1 Step 2 Step 3 Step 4 Step 5 Step 7 A Step 7 B Step 8.
INSTRUCTIONS FOR USE
SEMGLEEregistered (Sehm-GLEE) (insulin glargine-yfgn) 3 mL Single-Patient-Use PREFILLED PEN: 100 units/mL (U-100) Read these Instructions for Use before you start taking the SEMGLEE pen and each time you get a new SEMGLEE pen. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Do not share your SEMGLEE pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. People who are blind or have vision problems should not use the SEMGLEE prefilled pen without help from a person trained to use the SEMGLEE prefilled pen. SEMGLEE is a disposable prefilled pen used to inject SEMGLEE. Each SEMGLEE pen has 300 units of insulin which can be used for multiple injections. You can select doses from 1 to 80 units in steps of 1 unit. The pen plunger moves with each dose. The plunger will only move to the end of the cartridge when 300 units of SEMGLEE have been given. Important Information You Need to Know Before Injecting SEMGLEE: Learn to Inject Need Help? If you have any questions about your pen or about diabetes, ask your healthcare provider, or call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). Extra Items You Will Need Places to inject Inject your insulin exactly as your healthcare provider has shown you. Inject your insulin under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen). Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Get to know your pen Step 1: Check your pen Take a new pen out of the refrigerator at least 1 hour before you inject. Cold insulin is more painful to inject. 1A Check the name and expiration date on the label of your pen. Do not 1B Pull off the pen cap 1C Check that the insulin is clear Do not 1D Wipe the rubber seal with an alcohol swab If you have other injector pens: Step 2: Attach a new needle Do not Only use needles that are compatible for use with SEMGLEE, such as BD Ultra Fineregistered 2A Take a new needle and peel off the protective seal 2B Keep the needle straight and screw it onto the pen until fixed. Do not over-tighten 2C Pull off the outer needle cap Keep this for later. 2D Pull off the inner needle cap and throw away Handling needles Step 3: Do a safety test Always do a safety test before each injection to: 3A Select 2 units by turning the dose selector until the dose pointer is at the 2 mark 3B Press the injection button all the way in When insulin comes out of the needle tip, your pen is working correctly. If no insulin appears: - Step 6 Step 2 - Step 3 Do not Do not If you see air bubbles: Step 4: Select the dose Do not 4A Make sure a needle is attached and the dose is set to “0” 4B Turn the dose selector until the dose pointer lines up with your dose How to read the dose window Even numbers are shown in line with dose pointer (See Figure n). Odd numbers are shown as a line between even numbers (See Figure o). Units of SEMGLEE in your pen: 300 1 80 1 Step 5: Injecting Your SEMGLEE Dose If you find it hard to press the injection button in, do not force it as this may break your pen. See the section below for help. 5A Choose a place to inject as shown in the section “Places to Inject” 5B Push the needle into your skin as shown by your healthcare provider Do not touch the injection button yet. 5C Place your thumb on the injection button. Then press all the way in and hold 5D Keep the injection button held in and when you see “0” in the dose window, slowly count to 10 5E After holding and slowly counting to 10, release the injection button. Then remove the needle from your skin. If you find it hard to press the button in: Step 6 Step 2 Step 3 Do not Step 6: Remove the needle Do not 6A Grip the widest part of the outer needle cap. Keep the needle straight and guide it into the outer needle cap. Then push firmly on 6B Grip and squeeze the widest part of the outer needle cap. Turn your pen several times with your other hand to remove the needle 6C Throw away the used needle in a puncture-resistant container (see “Throwing your pen away” at the end of this Instructions for Use). 6D Put your pen cap back on Do not Storing the SEMGLEE Pen Before first use: 36°F to 46°F (2°C to 8°C). Do not Do not After first use: 86°F (30°C) Do not Do not Keep out of the reach of children. up to 28 days Caring for Your SEMGLEE Pen Handle your pen with care Protect your pen from dust and dirt You can clean the outside of your pen by wiping it with a damp cloth (water only). Do not soak, wash or lubricate your pen. This may damage it. Disposing SEMGLEE Pen Do not - - - - - http://www. gov/safesharpsdisposal Do not Do not This Instructions for Use has been approved by the U. Food and Drug Administration. Revised: 05/2023 Manufactured by: Mylan Pharmaceuticals Inc. Manufactured for: Mylan Specialty L. Product of Malaysia BD is a registered trademark of Becton, Dickinson, and Company. MA:B:IFUP:INGLIJK:RX9 Places to inject Get to know your pen Figure a Figure b Figure c Figure d Figure e Figure f Figure g Figure h Figure i Figure j Figure k Figure l Figure m Figure n Figure o Figure p Figure q Figure r Figure s Figure t Figure u Figure v.

ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere: [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 6) Adverse reactions commonly associated with insulin glargine products include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain. 1 To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 [see Clinical Studies (14. 2) 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 [see Clinical Studies (14. 3) 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. 1 Infection Body system not specified 9. 3 Accidental injury 5. 4 Headache 5. 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. 3 Infection Body system not specified 10. 6 Retinal vascular disorder 5. 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. 6 Edema peripheral 20. 7 Hypertension 19. 9 Influenza 18. 5 Sinusitis 18. 9 Cataract 18. 9 Bronchitis 15. 1 Arthralgia 14. 1 Pain in extremity 13. 1 Back pain 12. 4 Urinary tract infection 10. 1 Diarrhea 10. 3 Depression 10. 7 Headache 10. 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. 7 Upper respiratory tract infection 13. 0 Pharyngitis 7. 6 Rhinitis 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 [see Clinical Studies (14) 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 10. 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 Study G Type 2 Diabetes Adults 5 years In combination with Insulin Glargine N = 289 NPH N = 281 Insulin Glargine N = 259 NPH N = 259 Insulin Glargine N = 513 NPH N = 504 Percent of 1. 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 [see Clinical Studies (14) 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. 8 Some patients taking insulin glargine products have experienced sodium retention and edema, particularly if previously poor metabolic control was improved by intensified insulin therapy. 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 [see Dosage and Administration (2. 2) 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 has occurred with insulin including insulin glargine products and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. 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. The reports of pain at the injection site did not result in discontinuation of therapy. 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. 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. 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.
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.

SEMGLEE is contraindicated: [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 5) 4 4.

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 (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. 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. Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pregestational 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. 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. 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. There are either no or only limited data on the presence of insulin glargine products in human milk, the effects on breastfed infant, or the effects on milk production. Endogenous insulin is present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SEMGLEE, and any potential adverse effects on the breastfed child from SEMGLEE or from the underlying maternal condition. The safety and effectiveness of insulin glargine products to improve glycemic control in pediatric patients with diabetes mellitus have been established. Use of insulin glargine for this indication is supported by 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 [see Clinical Pharmacology (12. 3) Clinical Studies (14. 2) 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 [see Adverse Reactions (6. 1) Of the total number of subjects in controlled clinical studies of patients with type 1 and type 2 diabetes who were treated with insulin glargine, 15% (n = 316) were >= 65 years of age and 2% (n = 42) were >= 75 years of age. No overall differences in safety or effectiveness of insulin glargine have been observed between patients 65 years of age and older and younger adult patients. Nevertheless, caution should be exercised when SEMGLEE is administered to geriatric patients. In geriatric patients with diabetes, the initial dosing, dosage increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in geriatric patients. The effect of kidney impairment on the pharmacokinetics of insulin glargine products has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with kidney failure. Frequent glucose monitoring and dosage adjustment may be necessary for SEMGLEE in patients with kidney impairment [see Warnings and Precautions (5. 3) The effect of hepatic impairment on the pharmacokinetics of insulin glargine products has not been studied. Frequent glucose monitoring and dosage adjustment may be necessary for SEMGLEE in patients with hepatic impairment [see Warnings and Precautions (5.

Table 8 includes clinically significant drug interactions with SEMGLEE. Table 8: Clinically Significant Drug Interactions with SEMGLEE 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. , 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 SEMGLEE is coadministered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of SEMGLEE Drugs: Atypical antipsychotics (e. , olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e. , in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e. , albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dosage increases and increased frequency of glucose monitoring may be required when SEMGLEE is coadministered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of SEMGLEE 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 SEMGLEE 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 SEMGLEE is coadministered with these drugs. Drugs that Affect Glucose Metabolism: 7 Antiadrenergic Drugs 5. 3 7 * An interchangeable product (IP) is a biological product that is approved based on data demonstrating that it is highly similar to an FDA-approved reference product (RP) and that there are no clinically meaningful differences between the products; it can be expected to produce the same clinical result as the RP in any given patient; and if administered more than once to a patient, the risk in terms of safety or diminished efficacy from alternating or switching between use of the RP and IP is not greater than that from the RP without such alternation or switch. Interchangeability of SEMGLEE has been demonstrated for the condition(s) of use, strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information.

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.
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3 5.6) 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.
NONCLINICAL TOXICOLOGY
In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at doses up to 0.455 mg/kg, which was for the rat approximately 65 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day (0.007 mg/kg/day) on a mg/kg basis. Histiocytomas were found at injection sites in male rats and mice in acid vehicle containing groups and are considered a response to chronic tissue irritation and inflammation in rodents. These tumors were not found in female animals, in saline control, or insulin comparator groups using a different vehicle. Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames and HGPRT-test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters). In a combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which was approximately 50 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day) maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. Consequently, a reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin.
CLINICAL STUDIES
The safety and effectiveness of insulin glargine given once-daily at bedtime was compared to that of once-daily and twice-daily NPH insulin in open-label, randomized, active-controlled, parallel studies of 2,327 adult patients and 349 pediatric patients with type 1 diabetes mellitus and 1,563 adult patients with type 2 diabetes mellitus (see Tables 9-11). In general, the reduction in glycated hemoglobin (HbA1c) with insulin glargine was similar to that with NPH insulin. Adult Patients with Type 1 Diabetes In two clinical studies (Studies A and B), adult patients with type 1 diabetes (Study A, n = 585, Study B n = 534) were randomized to 28 weeks of basal-bolus treatment with insulin glargine or NPH insulin. Regular human insulin was administered before each meal. Insulin glargine was administered at bedtime. NPH insulin was administered either as once daily at bedtime or in the morning and at bedtime when used twice daily. In Study A, the average age was 39 years. The majority of patients were White (99%) and 56% were male. The mean BMI was approximately 24. The mean duration of diabetes was 16 years. In Study B, the average age was 39 years. The majority of patients were White (95%) and 51% were male. The mean BMI was approximately 25. The mean duration of diabetes was 17 years. In another clinical study (Study C), patients with type 1 diabetes (n = 619) were randomized to 16 weeks of basal-bolus treatment with insulin glargine or NPH insulin. Insulin lispro was used before each meal. Insulin glargine was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 39 years. The majority of patients were White (97%) and 51% were male. The mean duration of diabetes was 19 years. In these 3 adult studies, insulin glargine and NPH insulin had similar effects on HbA1c (Table 9) with a similar overall rate of severe symptomatic hypoglycemia [see Adverse Reactions (6. 1) Table 9: Type 1 Diabetes Mellitus en dash Adults Treatment duration Treatment in combination with Study A 28 weeks Regular insulin Study B 28 weeks Regular insulin Study C 16 weeks Insulin lispro Insulin Glargine NPH Insulin Glargine NPH Insulin Glargine NPH Number of subjects treated 292 293 264 270 310 309 HbA1c Baseline HbA1c 8. 7 Adjusted mean change at study end +0. 1 Treatment Difference (95% CI) +0. 1) Basal insulin dose Baseline mean 21 23 29 29 28 28 Mean change from baseline -2 0 -4 +2 -5 +1 Total insulin dose Baseline mean 48 52 50 51 50 50 Mean change from baseline -1 0 0 +4 -3 0 Fasting blood glucose (mg/dL) Baseline mean 167 166 166 175 175 173 Adj. mean change from baseline -21 -16 -20 -17 -29 -12 Body weight (kg) Baseline mean 73. 6 Mean change from baseline 0. 5 Pediatric Patients with Type 1 Diabetes In a randomized, controlled clinical study (Study D), pediatric patients (age range 6 to 15 years) with type 1 diabetes (n = 349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal. The average age was 11. The majority of patients were White (97%) and 52% were male. The mean BMI was approximately 18. 9 kg/m 2 [see Adverse Reactions (6. 1) Table 10: Type 1 Diabetes Mellitus en dash Pediatric Patients Treatment duration Treatment in combination with Study D 28 weeks Regular insulin Insulin Glargine + Regular insulin NPH+ Regular insulin Number of subjects treated 174 175 HbA1c Baseline mean 8. 8 Change from baseline (adjusted mean) +0. 3 Difference from NPH (adjusted mean) 0. 0 (95% CI) (-0. 3) Basal insulin dose Baseline mean 19 19 Mean change from baseline -1 +2 Total insulin dose Baseline mean 43 43 Mean change from baseline +2 +3 Fasting blood glucose (mg/dL) Baseline mean 194 191 Mean change from baseline -23 -12 Body weight (kg) Baseline mean 45. 6 Mean change from baseline 2. 5 In a randomized, controlled clinical study (Study E) in 570 adults with type 2 diabetes, insulin glargine was evaluated for 52 weeks in combination with oral anti-diabetic medications (a sulfonylurea, metformin, acarbose, or combinations of these drugs). The average age was 60 years old. The majority of patients were White (93%) and 54% were male. The mean BMI was approximately 29. 1 kg/m 2 [see Adverse Reactions (6. 1) In a randomized, controlled clinical study (Study F), in adult patients with type 2 diabetes not using oral antidiabetic medications (n = 518), a basal-bolus regimen of insulin glargine once daily at bedtime or NPH insulin administered once or twice daily was evaluated for 28 weeks. Regular human insulin was used before meals, as needed. The average age was 59 years. The majority of patients were White (81%) and 60% were male. The mean BMI was approximately 30. 5 kg/m 2 [see Adverse Reactions (6. 1) In a randomized, controlled clinical study (Study G), adult patients with type 2 diabetes were randomized to 5 years of treatment with once-daily insulin glargine or twice-daily NPH insulin. For patients not previously treated with insulin, the starting dosage of insulin glargine or NPH insulin was 10 units daily. Patients who were already treated with NPH insulin either continued on the same total daily NPH insulin dose or started insulin glargine at a dosage that was 80% of the total previous NPH insulin dosage. The primary endpoint for this study was a comparison of the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. HbA1c change from baseline was a secondary endpoint. Similar glycemic control in the 2 treatment groups was desired in order to not confound the interpretation of the retinal data. Patients or study personnel used an algorithm to adjust the insulin glargine and NPH insulin dosages to a target fasting plasma glucose <= 100 mg/dL. After the insulin glargine or NPH insulin dosage was adjusted, other anti-diabetic agents, including premeal insulin were to be adjusted or added. The average age was 55 years. The majority of patients were White (85%) and 54% were male. The mean BMI was approximately 34. 3 kg/m 2 [see Adverse Reactions (6. 1) Table 11: Type 2 Diabetes Mellitus en dash Adults Treatment duration Treatment in combination with Study E 52 weeks Oral agents Study F 28 weeks Regular insulin Study G 5 years Regular insulin Insulin Glargine NPH Insulin Glargine NPH Insulin Glargine NPH Number of subjects treated 289 281 259 259 513 504 HbA1c 9. 4) Basal insulin dose In Study G, the baseline dose of basal or total insulin was the first available on-treatment dose prescribed during the study (on visit month 1. 5 39 44 +12 +9 -1 +7 +23 +30 Total insulin dose 14 15 64 67 48 53 +12 +9 +10 +13 +41 +40 Fasting blood glucose (mg/dL) 179 180 164 166 190 180 -49 -46 -24 -22 -45 -44 Body weight (kg) 83. 8 Different Timing of Insulin Glargine Administration in Diabetes Type 1 and Diabetes Type 2 The safety and efficacy of once daily insulin glargine administered either at pre-breakfast, pre-dinner, or at bedtime were evaluated in a randomized, controlled clinical study in adult patients with type 1 diabetes (Study H, n = 378). Patients were also treated with insulin lispro at mealtime. The average age was 41 years. All patients were White (100%) and 54% were male. Insulin glargine administered at pre-breakfast or at pre-dinner (both once daily) resulted in similar reductions in HbA1c compared to that with bedtime administration (see Table 12). In these patients, data are available from 8-point home glucose monitoring. The maximum mean blood glucose was observed just prior to insulin glargine injection regardless of time of administration. In this study, 5% of patients in the insulin glargine-breakfast group discontinued treatment because of lack of efficacy. No patients in the other two groups (pre-dinner, bedtime) discontinued for this reason. The safety and efficacy of once daily insulin glargine administered pre-breakfast or at bedtime were also evaluated in a randomized, active-controlled clinical study (Study I, n = 697) in patients with type 2 diabetes not adequately controlled on oral anti-diabetic therapy. All patients in this study also received glimepiride 3 mg daily. The average age was 61 years. The majority of patients were White (97%) and 54% were male. The mean BMI was approximately 28. 7 kg/m 2 Table 12: Study of Different Times of Once Daily Insulin Glargine Dosing in Type 1 (Study H) and Type 2 (Study I) Diabetes Mellitus Treatment duration Treatment in combination with Study H 24 weeks Insulin lispro Study I 24 weeks Glimepiride Insulin Glargine Before Breakfast Insulin Glargine Before Dinner Insulin Glargine Bedtime Insulin Glargine Before Breakfast Insulin Glargine Bedtime NPH Bedtime Number of subjects treated Intent-to-treat 112 124 128 234 226 227 HbA1c Baseline mean 7. 1 Mean change from baseline -0. 8 Basal insulin dose (Units) Baseline mean 22 23 21 19 20 19 Mean change from baseline 5 2 2 11 18 18 Total insulin dose (Units) - - - NA Not applicable NA NA Baseline mean 52 52 49 - - - Mean change from baseline 2 3 2 - - - Body weight (kg) 77. 7 82 81 Mean change from baseline 0. 9 Progression of Retinopathy Evaluation in Adults with Diabetes Type 1 and Diabetes Type 2 Insulin glargine was compared to NPH insulin in a 5-year randomized clinical study that evaluated the progression of retinopathy as assessed with fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS). Patients had type 2 diabetes (mean age 55 years) with no (86%) or mild (14%) retinopathy at baseline. Mean baseline HbA1c was 8. The primary outcome was progression by 3 or more steps on the ETDRS scale at study endpoint. Patients with pre-specified post-baseline eye procedures (pan-retinal photocoagulation for proliferative or severe nonproliferative diabetic retinopathy, local photocoagulation for new vessels, and vitrectomy for diabetic retinopathy) were also considered as 3-step progressors regardless of actual change in ETDRS score from baseline. Retinopathy graders were blinded to treatment group assignment. The results for the primary endpoint are shown in Table 13 for both the per-protocol and intent-to-treat populations, and indicate similarity of insulin glargine to NPH in the progression of diabetic retinopathy as assessed by this outcome. In this study, the numbers of retinal adverse events reported for insulin glargine and NPH insulin treatment groups were similar for adult patients with type 1 and type 2 diabetes. Table 13: Number (%) of Patients with 3 or More Step Progression on ETDRS Scale at Endpoint Insulin Glargine (%) NPH (%) Difference Difference = Insulin Glargine en dash NPH Using a generalized linear model (SAS GENMOD) with treatment and baseline HbA1c strata (cutoff 9. 0%) as the classified independent variables, and with binomial distribution and identity link function (SE) 95% CI for difference Per-protocol 53/374 (14. 2%) 57/363 (15. 1% Intent-to-Treat 63/502 (12. 5%) 71/487 (14. 1% The ORIGIN Study of Major Cardiovascular Outcomes in Patients with Established CV Disease or CV Risk Factor The Outcome Reduction with Initial Glargine Intervention study (i. , ORIGIN) was an open-label, randomized, 2-by-2, factorial design study. One intervention in ORIGIN compared the effect of insulin glargine to standard care on major adverse cardiovascular (CV) outcomes in 12,537 adults >= 50 years of age with: The objective of the study was to demonstrate that insulin glargine use could significantly lower the risk of major CV outcomes compared to standard care. There were two coprimary composite CV endpoints: Patients were randomized to either insulin glargine (N = 6,264) titrated to a goal fasting plasma glucose of <= 95 mg/dL or to standard care (N = 6,273). Anthropometric and disease characteristics were balanced at baseline. The mean age was 64 years and 8% of patients were 75 years of age or older. The majority of patients were male (65%). Fifty nine percent were Caucasian, 25% were Latin, 10% were Asian and 3% were Black. The median baseline BMI was 29 kg/m2. Approximately 12% of patients had abnormal glucose levels (IGT and/or IFG) at baseline and 88% had type 2 diabetes. For patients with type 2 diabetes, 59% were treated with a single oral antidiabetic drug, 23% had known diabetes but were on no antidiabetic drug and 6% were newly diagnosed during the screening procedure. The mean HbA1c (SD) at baseline was 6. Fifty-nine percent of the patients had had a prior CV event and 39% had documented coronary artery disease or other CV risk factors. Vital status was available for 99. 8% of patients randomized to insulin glargine and standard care respectively at end of study. The median duration of follow-up was 6. 2 years (range: 8 days to 7. The mean HbA1c (SD) at the end of the study was 6. 2) in the insulin glargine and standard care group respectively. The median dose of insulin glargine at end of study was 0. Eighty-one percent of patients randomized to insulin glargine were using insulin glargine at end of the study. The mean change in body weight from baseline to the last treatment visit was 2. 2 kg greater in the insulin glargine group than in the standard care group. Overall, the incidence of major adverse CV outcomes was similar between groups (see Table 14). All-cause mortality was also similar between groups. Table 14: Cardiovascular Outcomes in ORIGIN in Patients with Established CV Disease or CV Risk Factors en dash Time to First Event Analyses Insulin Glargine N = 6,264 Standard Care N = 6,273 Insulin Glargine vs Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Coprimary endpoints CV death, nonfatal myocardial infarction, or nonfatal stroke 1041 (2. 11) CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure or revascularization procedure 1792 (5. 11) Components of coprimary endpoints CV death 580 576 1. 13) Myocardial Infarction (fatal or nonfatal) 336 326 1. 19) Stroke (fatal or nonfatal) 331 319 1. 21) Revascularizations 908 860 1. 16) Hospitalization for heart failure 310 343 0. 05) In the ORIGIN study, the overall incidence of cancer (all types combined) or death from cancer (Table 15) was similar between treatment groups. Table 15: Cancer Outcomes in ORIGIN en dash Time to First Event Analyses Insulin Glargine N = 6,264 Standard Care N = 6,273 Insulin Glargine vs Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Cancer endpoints Any cancer event (new or recurrent) 559 (1. 11) New cancer events 524 (1. 09) Death due to Cancer 189 (0.
PATIENT INFORMATION
SEMGLEEregistered (Sehm-GLEE) Do not share your syringes with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. What is SEMGLEE? SEMGLEE is a long-acting man-made-insulin used to control high blood sugar in adults and children with diabetes mellitus. SEMGLEE is not for use to treat diabetic ketoacidosis. Who should not use SEMGLEE? Do not use SEMGLEE if you: What should I tell my healthcare provider before using SEMLGEE? Before using SEMGLEE, tell your healthcare provider about all your medical conditions including if you: . Tell your healthcare provider about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements. Before you start using SEMGLEE, talk to your healthcare provider about low blood sugar and how to manage it. How should I use SEMGLEE? Instructions for Use . Do not Do not Change (rotate) injection sites within the area you chose with each dose o Do not o Do not o Do not Do not Check your blood sugar levels. Keep SEMGLEE and all medicines out of the reach of children. Your dose of SEMGLEE may need to change because of: What should I avoid while using SEMGLEE? While using SEMGLEE do not: What are the possible side effects of SEMGLEE and other insulins? SEMGLEE may cause serious side effects that can lead to death, including: low blood sugar (hypoglycemia). o severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of a severe allergic reaction: o low potassium in your blood (hypokalemia). heart failure. o Get emergency medical help if you have: The most common side effects of SEMGLEE include: These are not all the possible side effects of SEMGLEE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 General information about the safe and effective use of SEMGLEE. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not Do not This Patient Information leaflet summarizes the most important information about SEMGLEE. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about SEMGLEE that is written for healthcare professionals. What are the ingredients in SEMGLEE? Active ingredient: 10 mL vial inactive ingredients: For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). Manufactured for: Manufactured by: This Patient Information has been approved by the U.S. Food and Drug Administration. MA:B:PIV:INGLIJK:RX7
PATIENT INFORMATION
SEMGLEEregistered (Sehm-GLEE) Do not share your SEMGLEE pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. What is SEMGLEE? SEMGLEE is a long-acting man-made insulin used to control high blood sugar in adults and children with diabetes mellitus. SEMGLEE is not for use to treat diabetic ketoacidosis. Who should not use SEMGLEE? Do not use SEMGLEE if you: What should I tell my healthcare provider before using SEMLGEE? Before using SEMGLEE, tell your healthcare provider about all your medical conditions including if you: . Tell your healthcare provider about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements. Before you start using SEMGLEE, talk to your healthcare provider about low blood sugar and how to manage it. How should I use SEMGLEE? Do not Do not Do not Step 3 Instructions for Use Change (rotate) your injection sites within area you chose with each dose o Do not o Do not o Do not Do not Check your blood sugar levels. Keep SEMGLEE and all medicines out of the reach of children. Your dose of SEMGLEE may need to change because of: What should I avoid while using SEMGLEE? While using SEMGLEE do not: What are the possible side effects of SEMGLEE and other insulins? SEMGLEE may cause serious side effects that can lead to death, including: low blood sugar (hypoglycemia). o severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of a severe allergic reaction: o low potassium in your blood (hypokalemia). heart failure. o Get emergency medical help if you have: The most common side effects of SEMGLEE include: These are not all the possible side effects of SEMGLEE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 General information about the safe and effective use of SEMGLEE. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not Do not This Patient Information leaflet summarizes the most important information about SEMGLEE. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about SEMGLEE that is written for healthcare professionals. What are the ingredients in SEMGLEE? Active ingredient: 3 mL prefilled pen inactive ingredients: For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). Manufactured for: Manufactured by: This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 05/2023 Manufactured by: Mylan Pharmaceuticals Inc. Manufactured for: Mylan Specialty L.P. Product of Malaysia SEMGLEE is a registered trademark of Mylan Pharmaceuticals Inc., a Viatris Company. MA:B:PIP:INGLIJK:RX7

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