2.1 Important Administration Instructions

• Always check insulin labels before administration [see Warnings and Precautions (5.4)].
• Visually inspect REZVOGLAR KwikPen prefilled pens for particulate matter and discoloration prior to administration. Only use if the solution is clear and colorless with no visible particles.
• Administer REZVOGLAR 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 (5.2), and Adverse Reactions (6)].
• During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].
• Do not administer intravenously or via an insulin pump.
• Do not dilute or mix REZVOGLAR with any other insulin or solution.
• The REZVOGLAR KwikPen prefilled pen dials in 1-unit increments.
• Use REZVOGLAR KwikPen prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.

2.2 General Dosing Instructions

• Administer REZVOGLAR subcutaneously once daily at any time of day but at the same time every day.
• Individualize and adjust the dosage of REZVOGLAR based on the patient's metabolic needs, blood glucose monitoring results and glycemic control goal.
• Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), during acute illness, or changes in renal or hepatic function. Dosage adjustments should only be made under medical supervision with appropriate glucose monitoring [see Warnings and Precautions (5.2)].
• In patients with type 1 diabetes, REZVOGLAR must be used concomitantly with short-acting insulin.

2.3 Initiation of REZVOGLAR Therapy

Recommended Starting Dosage in Patients with Type 1 Diabetes

The recommended starting dosage of REZVOGLAR 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 REZVOGLAR 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.

2.4 Switching to REZVOGLAR from Other Insulin Therapies

Dosage adjustments are recommended to lower the risk of hypoglycemia when switching patients to REZVOGLAR from other insulin therapies [see Warnings and Precautions (5.3)]. When switching from:

• Once-daily insulin glargine, 300 units/mL, to once-daily REZVOGLAR (100 units/mL), the recommended starting REZVOGLAR dosage is 80% of the insulin glargine, 300 units/mL dosage that is being discontinued.
• Once-daily NPH insulin to once-daily REZVOGLAR, the recommended starting REZVOGLAR dosage is the same as the dosage of NPH that is being discontinued.
• Twice-daily NPH insulin to once-daily REZVOGLAR, the recommended starting REZVOGLAR dosage is 80% of the total NPH dosage that is being discontinued.

5.1 Never Share a REZVOGLAR KwikPen Prefilled Pen Between Patients

REZVOGLAR KwikPen prefilled pens must never be shared between patients, even if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens.

5.2 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 (5.3)] 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 (6)].

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.

5.3 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 the patient 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 patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, using drugs that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or who experience recurrent hypoglycemia.

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

5.4 Hypoglycemia Due to Medication Errors

Accidental mix-ups among insulin products have been reported. To avoid medication errors between REZVOGLAR and other insulins, instruct patients to always check the insulin label before each injection [see Adverse Reactions (6.3)].

5.5 Hypersensitivity Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including insulin glargine products [see Adverse Reactions (6.1)]. If hypersensitivity reactions occur, discontinue REZVOGLAR; treat per standard of care and monitor until symptoms and signs resolve. REZVOGLAR is contraindicated in patients who have had hypersensitivity reactions to insulin glargine products or one of the excipients in REZVOGLAR.

5.6 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).

5.7 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, when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including REZVOGLAR, 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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

The data in Table 1 reflect the exposure of 2,327 patients with type 1 diabetes to insulin glargine or NPH in Studies A, B, C, and D [see Clinical Studies (14.2)]. The type 1 diabetes population had the following characteristics: the mean age was 39 years, 54% were male, and mean body mass index (BMI) was 25.1 kg/m2. Ninety-seven percent were White, 2% were Black or African American and less than 1% were Asian. Approximately 3% of the patients in studies B and C were Hispanic.

The data in Table 2 reflect the exposure of 1,563 patients with type 2 diabetes to insulin glargine or NPH in Studies E, F, and G [see Clinical Studies (14.3)]. The type 2 diabetes population had the following characteristics: the mean age was 59 years, 58% were male, and mean BMI was 29.2 kg/m2. Eighty-seven percent were White, 8% were Black or African American and 3% were Asian. Approximately 9% of patients in Study F were Hispanic.

The frequencies of adverse reactions during insulin glargine clinical studies in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below (Tables 1, 2, 3, and 4).

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other insulin glargine products may be misleading. All insulin products can elicit the formation of insulin antibodies. The presence of such insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In clinical studies of insulin glargine, increases in titers of antibodies to insulin were observed in NPH insulin and insulin glargine treatment groups with similar incidences.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of insulin glargine products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Medication errors have been reported in which rapid-acting insulins and other insulins, have been accidentally administered instead of insulin glargine products.

Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of REZVOGLAR to improve glycemic control in pediatric patients with diabetes mellitus have been established. Use of REZVOGLAR 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)].

8.5 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% (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 REZVOGLAR 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.

8.6 Renal Impairment

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 REZVOGLAR in patients with kidney impairment [see Warnings and Precautions (5.3)].

8.7 Hepatic Impairment

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 REZVOGLAR in patients with hepatic impairment [see Warnings and Precautions (5.3)].

12.1 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.

12.2 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 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: 9.5 to 19.3 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.

12.3 Pharmacokinetics

13.1 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 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 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.

14.1 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.

14.2 Clinical Studies in Adult and Pediatric Patients with Type 1 Diabetes

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 24.9 kg/m2. 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 25.8 kg/m2. 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 BMI was approximately 25.6 kg/m2. 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)].

14.3 Clinical Studies in Adults with Type 2 Diabetes

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 antidiabetic 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/m2. The mean duration of diabetes was 10 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 (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/m2. The mean duration of diabetes was 14 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 (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 antidiabetic 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/m2. The mean duration of diabetes was 11 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 (6.1)].

14.4 Additional Clinical Studies in Adults with Diabetes Type 1 and Type 2

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. The mean BMI was approximately 25.3 kg/m2. The mean duration of diabetes was 17 years.

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 antidiabetic 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/m2. The mean duration of diabetes was 10 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).

16.1 How Supplied

REZVOGLAR (insulin glargine-aglr) injection is supplied as a clear and colorless solution containing 100 units/mL (U-100) available as follows:

Additional Information about REZVOGLAR KwikPen:

• The REZVOGLAR KwikPen prefilled pen dials in 1 unit increments.
• Needles are not included in the packs.

This device is recommended for use with Becton, Dickinson & Company's insulin pen needles which are sold separately.

16.2 Storage

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

Store unused REZVOGLAR in a refrigerator between 36°F and 46°F (2°C and 8°C). Do not freeze. Discard REZVOGLAR if it has been frozen. Protect REZVOGLAR from direct heat and light.

Storage conditions are summarized in the following table: