Semglee

Description

Semglee contains insulin glargine as a sterile solution for subcutaneous use. Insulin glargine is a recombinant human long-acting insulin analog [see CLINICAL PHARMACOLOGY]. Semglee is produced by recombinant DNA technology utilizing a recombinant yeast strain, Pichia pastoris, as the production organism. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Chemically, insulin glargine is 21^A-Gly-30^Ba-L-Arg-30^Bb-L-Arg-human insulin and has the empirical formula C₂₆₇H₄₀₄N₇₂O₇₈S₆ and a molecular weight of 6063. Insulin glargine has the following structural formula:

Semglee consists of insulin glargine dissolved in a clear, colorless, sterile solution. Each milliliter contains 100 units (3.64 mg) insulin glargine.

The 10 mL Semglee vial contains the following inactive ingredients per mL: 30 mcg zinc, 20 mg glycerol 85%, 20 mcg polysorbate-20, 2.7 mg m-Cresol and water for injection.

The 3 mL Semglee prefilled pen contains the following inactive ingredients per mL: 30 mcg zinc, 20 mg glycerol 85%, 2.7 mg m-Cresol and water for injection.

The pH is adjusted by addition of aqueous solutions of hydrochloric acid and sodium hydroxide. Semglee has a pH of approximately 4.

Indications

SEMGLEE is indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus.

Limitations Of Use

SEMGLEE is not recommended for the treatment of diabetic ketoacidosis.

Dosage And Administration

Important Administration Instructions

• Administer SEMGLEE subcutaneously once daily at any time of day but at the same time every day.
• Prior to initiation of SEMGLEE, train patients on proper use and injection technique.
• Patient should follow the Instructions for Use to correctly administer SEMGLEE.
• Administer SEMGLEE 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 [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].
• During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see WARNINGS AND PRECAUTIONS].
• Visually inspect SEMGLEE 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.
• The SEMGLEE prefilled pen dials in 1-unit increments.
• Use SEMGLEE prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
• Refrigerate unused (unopened) SEMGLEE vials and prefilled pens.
• Do not administer intravenously or via an insulin pump.
• Do not dilute or mix SEMGLEE with any other insulin or solution.
• The SEMGLEE prefilled pen is for single patient use only [see WARNINGS AND PRECAUTIONS].

General Dosing Instructions

• Individualize and adjust the dosage of SEMGLEE based on the individual’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 [see WARNINGS AND PRECAUTIONS].

Initiation Of SEMGLEE Therapy

Type 1 Diabetes

• In patients with type 1 diabetes, SEMGLEE must be used concomitantly with shortacting insulin. The recommended starting dose of SEMGLEE in patients with type 1 diabetes should be approximately one-third of the total daily insulin requirements. Shortacting, premeal insulin should be used to satisfy the remainder of the daily insulin requirements.

Type 2 Diabetes

• The recommended starting dose 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. One may need to adjust the amount and timing of short- or rapid-acting insulins and dosages of any oral antidiabetic drugs.

Changing To SEMGLEE From Other Insulin Therapies

• If changing patients from once-daily insulin glargine, 300 units/mL, to once-daily SEMGLEE, the recommended initial SEMGLEE dose is 80% of the insulin glargine, 300 units/mL dose that is being discontinued. This dose reduction will lower the likelihood of hypoglycemia [see WARNINGS AND PRECAUTIONS].
• If changing from a treatment regimen with an intermediate or long-acting insulin to a regimen with SEMGLEE, a change in the dose of the basal insulin may be required and the amount and timing of the shorter-acting insulins and doses of any oral antidiabetic drugs may need to be adjusted.
• If changing patients from once-daily NPH insulin to once-daily SEMGLEE, the recommended initial SEMGLEE dose is the same as the dose of NPH that is being discontinued.
• If changing patients from twice-daily NPH insulin to once-daily SEMGLEE, the recommended initial SEMGLEE dosage is 80% of the total NPH dose that is being discontinued. This dosage reduction will lower the likelihood of hypoglycemia [see WARNINGS AND PRECAUTIONS].

How Supplied

Dosage Forms And Strengths

Injection: 100 units per mL (U-100) clear and colorless solution available as:

• 10 mL multiple-dose vial
• 3 mL single-patient-use prefilled pen

Storage And Handling

SEMGLEE (insulin glargine-yfgn) injection is supplied as a clear and colorless solution 100 units/mL (U-100) available as:

The SEMGLEE prefilled pen dials in 1-unit increments.

Needles are not included in the packs.

BD® Ultra-Fine needles are compatible with this pen.

Storage

Dispense in the original sealed carton with the enclosed Instructions for Use.

SEMGLEE should not be stored in the freezer and should not be allowed to freeze. Discard SEMGLEE if it has been frozen. Protect SEMGLEE from direct heat and light.

Storage conditions are summarized in the following table:

Manufactured by: Mylan Pharmaceuticals Inc. Morgantown, West Virginia 26505 U.S.A. U.S. License No. 2210. Revised: Jul 2021

Side Effects

The following adverse reactions are discussed elsewhere:

• Hypoglycemia [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity and allergic reactions [see WARNINGS AND PRECAUTIONS]
• Hypokalemia [see WARNINGS AND PRECAUTIONS]

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 2327 patients with type 1 diabetes to insulin glargine or NPH. The type 1 diabetes population had the following characteristics: Mean age was 38.5 years. Fifty four percent were male, 96.9% were Caucasian, 1.8% were Black or African American and 2.7% were Hispanic. The mean BMI was 25.1 kg/m².

The data in Table 2 reflect the exposure of 1563 patients with type 2 diabetes to insulin glargine or NPH. The type 2 diabetes population had the following characteristics: Mean age was 59.3 years. Fifty eight percent were male, 86.7% were Caucasian, 7.8% were Black or African American and 9% were Hispanic. The mean BMI was 29.2 kg/m².

The frequencies of adverse events during insulin glargine clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.

Table 1: Adverse Events in Pooled Clinical Trials up to 28 Weeks Duration in Adults with Type 1 Diabetes (adverse events with frequency ≥ 5%)

Table 2: Adverse Events in Pooled Clinical Trials up to 1 Year Duration in Adults with Type 2 Diabetes (adverse events with frequency ≥ 5%)

Table 3: Adverse Events in a 5 Year Trial of Adults with Type 2 Diabetes (adverse events with frequency ≥ 10%)

Table 4: Adverse Events in a 28-Week Clinical Trial of Children and Adolescents with Type 1 Diabetes (adverse events with frequency ≥ 5%)

Severe Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulins, including insulin glargine products [see WARNINGS AND PRECAUTIONS]. Tables 5, and 6, and 7 summarize the incidence of severe hypoglycemia in the insulin glargine individual clinical trials. 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 trial and ≤ 36 mg/dL in the ORIGIN trial) or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration.

Percentages of insulin glargine-treated adult patients experiencing severe symptomatic hypoglycemia in the insulin glargine clinical trials [see Clinical Studies] were comparable to percentages of NPH-treated patients for all treatment regimens (see Tables 5 and 6). In the pediatric phase 3 clinical trial, children and adolescents with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to the adult trials with type 1 diabetes.

Table 5: Severe Symptomatic Hypoglycemia in Patients with Type 1 Diabetes

Table 6: Severe Symptomatic Hypoglycemia in Patients with Type 2 Diabetes

Table 7 displays the proportion of patients experiencing severe symptomatic hypoglycemia in the insulin glargine and Standard Care groups in the ORIGIN Trial [see Clinical Studies].

Table 7: Severe Symptomatic Hypoglycemia in the ORIGIN Trial

Peripheral Edema

Some patients taking insulin glargine products have experienced sodium retention and edema, particularly if previously poor metabolic control is 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 [see DOSAGE AND ADMINISTRATION].

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 some insulin therapies including insulin glargine products and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

Allergic Reactions

Local Allergy: As with any insulin therapy, patients taking insulin glargine products may experience 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 Allergy

Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any 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 phase 3 clinical trials 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 other insulins, particularly rapid-acting insulins, have been accidentally administered instead of insulin glargine products [see Patient Counseling Information]. To avoid medication errors between SEMGLEE and other insulins, patients should be instructed to always verify the insulin label before each injection.

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

Drug Interactions

Table 8 includes clinically significant drug interactions with SEMGLEE.

Table 8: Clinically Significant Drug Interactions with SEMGLEE

WarningS

Included as part of the PRECAUTIONS section.

Precautions

Never Share A SEMGLEE Prefilled Pen, Syringe, Or Needle Between Patients

SEMGLEE prefilled pens must never be shared between patients, even if the needle is changed. Patients using SEMGLEE vials must never re-use or share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.

Hyperglycemia Or Hypoglycemia With Changes In Insulin Regimen

Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see WARNINGS AND PRECAUTIONS] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to unaffected area) has been reported to result in hypoglycemia [see ADVERSE REACTIONS].

Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant oral and antidiabetic products may be needed.

Hypoglycemia

Hypoglycemia is the most common adverse reaction associated with insulins, including insulin glargine products. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).

Hypoglycemia can happen suddenly, and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see DRUG INTERACTIONS], or in patients who experience recurrent hypoglycemia.

Risk Factors For Hypoglycemia

The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of insulin glargine products may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see CLINICAL PHARMACOLOGY].

Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to coadministered medication [see DRUG INTERACTIONS]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use In Specific Populations].

Risk Mitigation Strategies For Hypoglycemia

Patients and caregivers must be educated to recognize and manage hypoglycemia. Selfmonitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

The long-acting effect of insulin glargine products may delay recovery from hypoglycemia.

Medication Errors

Accidental mix-ups among insulin products, particularly between long-acting insulins and rapidacting insulins, have been reported. To avoid medication errors between SEMGLEE and other insulins, instruct patients to always check the insulin label before each injection [see ADVERSE REACTIONS].

Hypersensitivity And Allergic

Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including insulin glargine products. If hypersensitivity reactions occur, discontinue SEMGLEE; treat per standard of care and monitor until symptoms and signs resolve [see ADVERSE REACTIONS]. SEMGLEE is contraindicated in patients who have had hypersensitivity reactions to insulin glargine products or one of the excipients in SEMGLEE [see CONTRAINDICATIONS].

Hypokalemia

All insulins, including insulin glargine products, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia, if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).

Fluid Retention And Heart Failure With Concomitant Use Of PPAR-gamma Agonists

Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)- gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin including SEMGLEE, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

Never Share A SEMGLEE Prefilled Pen Or Syringe Between Patients

Advise patients that they must never share a SEMGLEE prefilled pen with another person, even if the needle is changed. Advise patients using SEMGLEE vials not to re-use or share needles or syringes with another person. Sharing carries a risk for transmission of blood-borne pathogens [see WARNINGS AND PRECAUTIONS].

Hyperglycemia Or Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia. Inform patients that the ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see WARNINGS AND PRECAUTIONS].

Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see WARNINGS AND PRECAUTIONS].

Medications Errors

Instruct patients to always check the insulin label before each injection [see WARNINGS AND PRECAUTIONS].

Administration

Advise patients that SEMGLEE must NOT be diluted or mixed with any other insulin or solution and that SEMGLEE must only be used if the solution is clear and colorless with no particles visible [see DOSAGE AND ADMINISTRATION].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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 dose 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 of insulin glargine 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.

Use In Specific Populations

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 dose 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).

The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with an HbA1c >7 and has been reported to be as high as 20% to 25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. 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.

Clinical Considerations

Disease-Associated Maternal And/Or Embryo-Fetal Risk

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 macrosomiarelated 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 dose 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 dose 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.

Lactation

Risk Summary

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.

Pediatric Use

The safety and effectiveness of insulin glargine products have been established in pediatric patients (age 6 to 15 years) with type 1 diabetes [see Clinical Studies]. The safety and effectiveness of insulin glargine products in pediatric patients younger than 6 years of age with type 1 diabetes and pediatric patients with type 2 diabetes have not been established.

The dosage recommendation when changing to SEMGLEE in pediatric patients (age 6 to 15 years) with type 1 diabetes is the same as that described for adults [see DOSAGE AND ADMINISTRATION, Clinical Studies]. As in adults, the dosage of SEMGLEE must be individualized in pediatric patients (age 6 to 15 years) with type 1 diabetes based on metabolic needs and frequent monitoring of blood glucose.

In the pediatric clinical trial, pediatric patients (age 6 to 15 years) with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia compared to the adults in trials with type 1 diabetes [see ADVERSE REACTIONS].

Geriatric Use

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% were ≥ 65 years of age and 2% were ≥ 75 years of age. The only difference in safety or effectiveness in the subpopulation of patients ≥ 65 years of age compared to the entire study population was a higher incidence of cardiovascular events typically seen in an older population in the insulin glargine and NPH treatment groups.

Nevertheless, caution should be exercised when SEMGLEE is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of insulin glargine products has not been studied. Frequent glucose monitoring and dose adjustment may be necessary for SEMGLEE in patients with hepatic impairment [see WARNINGS AND PRECAUTIONS].

Renal Impairment

The effect of renal 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 renal failure. Frequent glucose monitoring and dose adjustment may be necessary for SEMGLEE in patients with renal impairment [see WARNINGS AND PRECAUTIONS].

Obesity

In controlled clinical trials, subgroup analyses based on BMI did not show differences in safety and efficacy between insulin glargine and NPH.

Overdose

Excess insulin administration may cause hypoglycemia and hypokalemia [see WARNINGS AND PRECAUTIONS]. Mild episodes of hypoglycemia can usually be treated with oral carbohydrates. Adjustments in drug dosage, meal patterns, or exercise may be needed.

More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon 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.

Contraindications

SEMGLEE is contraindicated:

• during episodes of hypoglycemia [see WARNINGS AND PRECAUTIONS].
• in patients with hypersensitivity to insulin glargine products or any of the excipients in SEMGLEE [see WARNINGS AND PRECAUTIONS].

Clinical Pharmacology

Mechanism Of Action

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.

Pharmacodynamics

In clinical studies, the glucose-lowering effect on a molar basis (i.e., 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 the injection. The median time between injection and the end of pharmacological effect was 14.5 hours (range: 9.5 to 19.3 hours) for NPH insulin, and 24 hours (range: 10.8 to > 24.0 hours) (24 hours was the end of the observation period) for insulin glargine.

Figure 1: Activity Profile 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 was similar. The time course of action of insulins, including insulin glargine products, may vary between individuals and within the same individual.

Pharmacokinetics

Absorption And Bioavailability

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 And Elimination

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 (21A-Gly-insulin) and M2 (21^A-Gly-des- 30^B-Thr-insulin). Unchanged drug and these degradation products are also present in the circulation.

Special Populations

Age, Race, And Gender

Effect of age, race, and gender on the pharmacokinetics of insulin glargine products has not been evaluated. However, in controlled clinical trials in adults (n = 3890) and a controlled clinical trial in pediatric patients (n = 349), subgroup analyses based on age, race, and gender did not show differences in safety and efficacy between insulin glargine and NPH insulin [see Clinical Studies].

Obesity

Effect of Body Mass Index (BMI) on the pharmacokinetics of insulin glargine products has not been evaluated.

Clinical Studies

Overview Of 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.

Clinical Studies In Adult and Pediatric Patients With Type 1 Diabetes

In two clinical studies (Studies A and B), 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 39.2 years. The majority of patients were White (99%) and 55.7% were male. The mean BMI was approximately 24.9 kg/m². The mean duration of diabetes was 15.5 years.

In Study B, the average age was 38.5 years. The majority of patients were White (95.3%) and 50.6% were male. The mean BMI was approximately 25.8 kg/m². The mean duration of diabetes was 17.4 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 39.2 years. The majority of patients were White (96.9%) and 50.6% were male. The mean BMI was approximately 25.6 kg/m². The mean duration of diabetes was 18.5 years.

In these 3 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].

Table 9: Type 1 Diabetes Mellitus – Adult

Type 1 Diabetes – Pediatric (see Table 10)

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. Insulin glargine was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 11.7 years. The majority of patients were White (96.8%) and 51.9% were male. The mean was approximately 18.9 kg/m². The mean duration of diabetes was 4.8 years. Similar effects on HbA1c (Table 10) were observed in both treatment groups [see ADVERSE REACTIONS].

Table 10: Type 1 Diabetes Mellitus – Pediatric

Clinical Studies In Adults with Type 2 Diabetes

In a randomized, controlled clinical study (Study E) (n = 570), 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 59.5 years. The majority of patients were White (92.8%) and 53.7% were male. The mean BMI was approximately 29.1 kg/m². The mean duration of diabetes was 10.3 years. Insulin glargine administered once daily at bedtime was as effective as NPH insulin administered once daily at bedtime in reducing HbA1c and fasting glucose (Table 11). The rate of severe symptomatic hypoglycemia was similar in insulin glargine and NPH insulin treated patients [see ADVERSE REACTIONS].

In a randomized, controlled clinical study (Study F), in 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 59.3 years. The majority of patients were White (80.7%) and 60% were male. The mean BMI was approximately 30.5 kg/m². The mean duration of diabetes was 13.7 years. Insulin glargine had similar effectiveness as either once- or twice-daily NPH insulin in reducing HbA1c and fasting glucose (Table 11) with a similar incidence of hypoglycemia [see ADVERSE REACTIONS].

In a randomized, controlled clinical study (Study G), 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 dose 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 dose that was 80% of the total previous NPH insulin dose. 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 doses to a target fasting plasma glucose ≤ 100 mg/dL. After the insulin glargine or NPH insulin dose was adjusted, other anti-diabetic agents, including premeal insulin were to be adjusted or added. The average age was 55.1 years. The majority of patients were White (85.3%) and 53.9% were male. The mean BMI was approximately 34.3 kg/m². The mean duration of diabetes was 10.8 years. The insulin glargine group had a smaller mean reduction from baseline in HbA1c compared to the NPH insulin group, which may be explained by the lower daily basal insulin doses in the insulin glargine group (Table 11). The incidences of severe symptomatic hypoglycemia were similar between groups [see ADVERSE REACTIONS].

Table 11: Type 2 Diabetes Mellitus – Adult

Insulin Glargine Timing Of Daily Dosing (see Table 12)

The safety and efficacy of insulin glargine administered pre-breakfast, pre-dinner, or at bedtime were evaluated in a randomized, controlled clinical study in patients with type 1 diabetes (study H, n = 378). Patients were also treated with insulin lispro at mealtime. The average age was 40.9 years. All patients were White (100%) and 53.7% were male. The mean BMI was approximately 25.3 kg/m². The mean duration of diabetes was 17.3 years. Insulin glargine administered at different times of the day 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 injection of insulin glargine regardless of time of administration.

In this study, 5% of patients in the insulin glargine-breakfast arm discontinued treatment because of lack of efficacy. No patients in the other two arms discontinued for this reason. The safety and efficacy of 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 60.8 years. The majority of patients were White (96.6%) and 53.7% were male. The mean BMI was approximately 28.7 kg/m². The mean duration of diabetes was 10.1 years. Insulin glargine given before breakfast was at least as effective in lowering HbA1c as insulin glargine given at bedtime or NPH insulin given at bedtime (see Table 12).

Table 12: Insulin Glargine Timing of Daily Dosing in Type 1 (Study H) and Type 2 (Study I) Diabetes Mellitus

Five-Year Trial Evaluating The Progression Of Retinopathy

Retinopathy was evaluated in the insulin glargine clinical studies by analysis of reported retinal adverse events and fundus photography. The numbers of retinal adverse events reported for insulin glargine and NPH insulin treatment groups were similar for patients with type 1 and type 2 diabetes.

Insulin glargine was compared to NPH insulin in a 5-year randomized clinical trial 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 8.4%. 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 (panretinal 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.

Table 13: Number (%) of Patients with 3 or More Step Progression on ETDRS Scale at Endpoint

The Origin Study

The Outcome Reduction with Initial Glargine Intervention trial (i.e., ORIGIN) was an openlabel, randomized, 2-by-2, factorial design study. One intervention in ORIGIN compared the effect of insulin glargine to standard care on major adverse cardiovascular outcomes in 12,537 participants ≥ 50 years of age with abnormal glucose levels (i.e., impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) or early type 2 diabetes mellitus and established cardiovascular (i.e., CV) disease or CV risk factors at baseline.

The objective of the trial was to demonstrate that use of insulin glargine could significantly lower the risk of major cardiovascular outcomes compared to standard care. Two coprimary composite cardiovascular endpoints were used in ORIGIN. The first coprimary endpoint was the time to first occurrence of a major adverse cardiovascular event defined as the composite of CV death, nonfatal myocardial infarction and nonfatal stroke. The second coprimary endpoint was the time to the first occurrence of CV death or nonfatal myocardial infarction or nonfatal stroke or revascularization procedure or hospitalization for heart failure.

Participants were randomized to either insulin glargine (N = 6264) titrated to a goal fasting plasma glucose of ≤ 95 mg/dL or to standard care (N = 6273). Anthropometric and disease characteristics were balanced at baseline. The mean age was 64 years and 8% of participants were 75 years of age or older. The majority of participants 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 participants 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 6.5% (1.0). Fifty-nine percent of participants had had a prior cardiovascular event and 39% had documented coronary artery disease or other cardiovascular risk factors.

Vital status was available for 99.9% and 99.8% of participants randomized to insulin glargine and standard care respectively at end of trial. The median duration of follow-up was 6.2 years (range: 8 days to 7.9 years). The mean HbA1c (SD) at the end of the trial was 6.5% (1.1) and 6.8% (1.2) in the insulin glargine and standard care group respectively. The median dose of insulin glargine at end of trial was 0.45 U/kg. 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 cardiovascular outcomes was similar between groups (see Table 14). All-cause mortality was also similar between groups.

Table 14: Cardiovascular Outcomes in ORIGIN – Time to First Event Analyses

In the ORIGIN trial, 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 – Time to First Event Analyses