These Highlights Do Not Include All The Information Needed To Use Rezvoglar Safely And Effectively. See Full Prescribing Information For Rezvoglar.

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 insulins, the glucose lowering effect time course of insulin glargine products may vary in different patients or at different times in the same patient and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology (12.2)]. 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 concomitant drugs [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].

This Patient Information has been approved by the U.S. Food and Drug Administration.

REZ-0002-PPI-20221116

INSTRUCTIONS FOR USE

REZVOGLAR^TM KwikPen^® (REHZ-voh-glahr)

(insulin glargine-aglr)

injection, for subcutaneous use

3 mL Single-Patient-Use PREFILLED-PEN: 100 units/mL (U-100)

Read these Instructions for Use before you start taking the REZVOGLAR KwikPen (“Pen”) and each time you get a new REZVOGLAR KwikPen. 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 REZVOGLAR KwikPen 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 REZVOGLAR KwikPen prefilled pen without help from a person trained to use REZVOGLAR KwikPen prefilled pen.

REZVOGLAR KwikPen is a disposable prefilled pen used to inject REZVOGLAR. Each REZVOGLAR KwikPen 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, but you may not notice that it moves. The plunger will only move to the end of the cartridge when 300 units of REZVOGLAR have been given.

Important Information You Need to Know Before Injecting REZVOGLAR

• Do not use your Pen if it is damaged or if you are not sure that it is working properly.
• Do not use a syringe to remove REZVOGLAR from your Pen.
• Do not reuse Needles. If you do, you might get the wrong dose of REZVOGLAR and/or increase the chance of getting an infection.
• Always perform a safety test (prime the REZVOGLAR KwikPen) (see Step 3).
• Always carry a spare Pen and spare Needles in case of loss or damage.
• Change (rotate) your injection sites within the area you choose for each dose (see “Places to inject”).

Learn to Inject

• Talk with your healthcare provider about how to inject before using your Pen.
• Ask for help if you have problems handling the Pen, for example if you have problems with your sight.
• Read all these instructions before using your Pen. If you do not follow all these instructions, you may get too much or too little insulin.

Need Help?

If you have any questions about your Pen or about diabetes, ask your healthcare provider, or go to www.rezvoglar.com or call Eli Lilly and Company at 1-800-545-5979.

Extra Items You Will Need

• a new sterile Pen Needle (see Step 2).
• an alcohol swab.
• a puncture-resistant container for used Needles and Pens (See "Throwing your Pen away").

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.
• Do not try to change your dose while injecting.

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. The REZVOGLAR KwikPen is light grey with a light grey Dose Knob that has a green ring on the end. The label on the Pen is light grey with green color bars.

• Make sure you have the correct insulin.

• Do not use your Pen after the expiration date.

1B Pull off the Pen Cap.

1C Check that the insulin is clear.

• Do not use the Pen if the insulin looks cloudy, colored or contains particles.

1D Wipe the Rubber Seal with an alcohol swab.

If you have other injector pens:

• Making sure you have the correct medicine is especially important if you have other injector pens.

Step 2: Attach a new Needle

• Do not re-use Needles. Always use a new sterile Needle for each injection. This helps stop blocked Needles, contamination, and infection.

Only use Needles that are compatible with REZVOGLAR KwikPen. Becton, Dickinson and Company (BD) Pen Needles are recommended. These are sold separately. Contact your healthcare provider for further information.

2A Take a new Needle and peel off the Paper Tab.

2B Keep the Needle straight and screw it onto the Pen until fixed. Do not over-tighten.

2C Pull off the Outer Needle Shield. Keep this for later.

2D Pull off the Inner Needle Shield and throw away.

Handling Needles

• Take care when handling Needles to prevent needle-stick injury and cross-infection.

Step 3: Do a safety test (Prime your REZVOGLAR KwikPen)

Always do a safety test (prime) before each injection to:

• Check your Pen and the Needle to make sure they are working properly.
• Make sure that you get the correct REZVOGLAR dose.

3A Select 2 units by turning the Dose Knob until the Dose Indicator is at the 2 mark.

3B Press the Dose Knob all the way in.

When insulin comes out of the Needle tip, your Pen is working correctly:

If no insulin appears:

• You may need to repeat this step up to 4 times before seeing insulin.
• If no insulin comes out after the fourth time, the Needle may be blocked. If this happens:
  • change the Needle (see Step 6 and Step 2),
  • then repeat the safety test (prime) (Step 3).
• Do not use your Pen if there is still no insulin coming out of the Needle tip. Use a new Pen.
• Do not use a syringe to remove insulin from your Pen.

If you see air bubbles:

• You may see air bubbles in the insulin. This is normal, they will not harm you.

Step 4: Select the dose

Do not select a dose or press the Dose Knob without a Needle attached. This may damage your Pen.

4A Make sure a Needle is attached and the dose is set to "0".

4B Turn the Dose Knob until the Dose Indicator lines up with your dose.

• If you turn past your dose, you can turn back down.
• The Dose Knob clicks as you turn it. Do not dial your dose by counting the clicks because you may dial the wrong dose.
• If there are not enough units left in your Pen for your dose, the Dose Indicator will stop at the number of units left.
• If you cannot select your full prescribed dose, use a new Pen or inject the remaining units and use a new Pen to complete your dose.

How to read the Dose Window

Even numbers are shown in line with Dose Indicator.

(Example: 12 units shown in the Dose Window)

Odd numbers, after the number 1, are shown as a line between even numbers.

(Example: 25 units shown in the Dose Window)

Units of REZVOGLAR in your Pen:

• Your Pen contains a total of 300 units of REZVOGLAR. You can select doses from 1 to 80 in steps of 1 unit. Each Pen contains more than 1 dose.
• You can see roughly how many units of insulin are left by looking at where the Plunger is on the insulin scale.

Step 5: Injecting Your REZVOGLAR Dose

If you find it hard to press the Dose Knob 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 picture above.

5B Push the Needle into the skin as shown by your healthcare provider.

Do not touch the Dose Knob yet.

5C Place your thumb on the Dose Knob. Then press all the way in and hold.

5D Keep the Dose Knob held in and when you see "0" in the Dose Window, slowly count to 5.

• This will make sure you get your full dose.
• Do not try to inject your insulin by turning the Dose Knob. You will not receive your insulin by turning the Dose Knob.

5E After holding and slowly counting to 5, release the Dose Knob. Then remove the Needle from your skin.

• If you do not see “0” in the Dose Window, you did not receive your full dose. Do not redial. Insert the needle into your skin and finish your injection.
• If you still do not think you received the full amount you dialed for your injection, do not start over or repeat the injection. Monitor your blood glucose and call your healthcare provider for further instructions.

If you find it hard to press the Dose Knob in:

• Change the Needle (see Step 6 and Step 2) then do a safety test (prime the Pen) (see Step 3).
• If you still find it hard to press in, get a new Pen.
• Do not use a syringe to remove insulin from your Pen.

Step 6: Remove the Needle

• Take care when handling Needles to prevent needle-stick injury and cross-infection.
• Do not put the Inner Needle Shield back on.

6A Leave the Outer Needle Shield on a flat surface. Using one hand, scoop the Outer Needle Shield straight onto the Needle. When the tip is covered, lift the Needle and Pen. Then push firmly on.

6B Grip and squeeze the widest part of the Outer Needle Shield. Turn your Pen several times with your other hand to remove the Needle.

• Try again if the Needle does not come off the first time.

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 put the Pen back in the refrigerator.

Storing the REZVOGLAR KwikPen

Before first use

• Keep new Pens in the refrigerator between 36°F to 46°F (2°C to 8°C).
• Do not freeze. Do not use REZVOGLAR if it has been frozen.
• Unused Pens may be used until the expiration date printed on the Label, if the Pen has been kept in the refrigerator.

After first use

• Keep your Pen at room temperature below 86°F (30°C).
• Keep your Pen away from heat or light.
• Store your Pen with the Pen Cap on.
• Do not put your Pen back in the refrigerator.
• Do not store your Pen with the Needle attached.
• Keep out of the reach of children.
• Only use your Pen for up to 28 days after its first use. Throw away the REZVOGLAR KwikPen you are using after 28 days, even if it still has insulin left in it.

Caring for Your REZVOGLAR KwikPen

Handle your Pen with care

• Do not drop your Pen or knock it against hard surfaces.
• If you think that your Pen may be damaged, do not try to fix it. Use a new one.

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.

Throwing your Pen away

• The used REZVOGLAR KwikPen may be thrown away in your household trash after you have removed the Needle.
• Put the used Needle in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the used Needles in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
  • made of a heavy-duty plastic,
  • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
  • upright and stable during use,
  • leak-resistant, and
  • properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used Needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.
• Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Eli Lilly and Company

Indianapolis, IN 46285, USA

US License Number 1891

Copyright © 2021, 2022, Eli Lilly and Company. All rights reserved.

REZVOGLAR^TM and REZVOGLAR^TM KwikPen^® are trademarks of Eli Lilly and Company.

Instructions for Use revised: Nov 2022

REZKP-0002-IFU-20221116

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.

Insulin glargine-aglr is a long-acting human insulin analog produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Insulin glargine-aglr 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. Insulin glargine-aglr has a molecular weight of 6063 Da.

REZVOGLAR (insulin glargine-aglr) injection is a sterile, clear and colorless solution for subcutaneous use in a 3 mL single-patient use prefilled pen (REZVOGLAR KwikPen).

Prefilled Pen (REZVOGLAR KwikPen): Each mL contains 100 units of insulin glargine-aglr and the inactive ingredients: glycerin (17 mg), metacresol (2.7 mg), zinc oxide (content adjusted to provide 30 mcg zinc ion), and Water for Injection, USP.

The pH is adjusted by addition of aqueous solutions of hydrochloric acid 10% and/or sodium hydroxide 10%. REZVOGLAR has a pH of approximately 4.

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).

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.

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 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.

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.

REZVOGLAR is contraindicated:

• during episodes of hypoglycemia [see Warnings and Precautions (5.3)].
• in patients with hypersensitivity to insulin glargine products or any of the excipients in REZVOGLAR [see Warnings and Precautions (5.5)].

The following adverse reactions are discussed elsewhere:

• Hypoglycemia [see Warnings and Precautions (5.3)].
• Hypoglycemia Due to Medication Errors [see Warnings and Precautions (5.4)].
• Hypersensitivity Reactions [see Warnings and Precautions (5.5)].
• Hypokalemia [see Warnings and Precautions (5.6)].

Table 8 includes clinically significant drug interactions with REZVOGLAR.

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)].

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.

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)].

REZVOGLAR™ is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus.

Limitations of Use

REZVOGLAR is not recommended for the treatment of diabetic ketoacidosis.

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.

• Never share a REZVOGLAR KwikPen prefilled pen between patients, even if the needle is changed. (5.1)
• Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to a patient's insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. (5.2)
• Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, concomitant drugs, meal pattern, physical activity; and in patients with renal or hepatic impairment and hypoglycemia unawareness. (5.3, 6.1)
• Hypoglycemia due to medication errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. (5.4, 6.3)
• Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue REZVOGLAR. Monitor and treat if indicated. (5.5, 6.1)
• Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. (5.6)
• Fluid retention and heart failure with concomitant use of thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation of TZD if heart failure occurs. (5.7)

• Individualize dosage based on metabolic needs, blood glucose monitoring, glycemic control, type of diabetes, and prior insulin use. (2.1, 2.2, 2.3, 2.4)
• Administer subcutaneously into the abdominal area, thigh, or deltoid once daily at any time of day, but at the same time every day. (2.1)
• Do not dilute or mix with any other insulin or solution. (2.1)
• Rotate injection sites to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. (2.1)
• See Full Prescribing Information for the recommended starting dosage in patients with type 2 diabetes and how to change to REZVOGLAR from other insulins (2.3, 2.4)
• Closely monitor glucose when switching to REZVOGLAR and during initial weeks thereafter. (2.4)

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

• 3 mL single-patient-use REZVOGLAR KwikPen prefilled pen.

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.

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.

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 in Studies A, B, C, and D [see Clinical Studies (14.2)]. The type 1 diabetes population had the following characteristics: Mean age was 39 years. Fifty-four percent were male, 97% were Caucasian, 2% were Black or African American and 3% 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 in Studies E, F, and G [see Clinical Studies (14.3)]. The type 2 diabetes population had the following characteristics: Mean age was 59 years. Fifty-eight percent were male, 87% were Caucasian, 8% were Black or African American and 9% were Hispanic. The mean BMI was 29.2 kg/m².

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).

• 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.

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.

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

Never Share a REZVOGLAR KwikPen Prefilled Pen Between Patients

Advise patients that they must never share a REZVOGLAR KwikPen with another person, even if the needle is changed. Sharing carries a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].

Hyperglycemia or Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia (e.g., impaired ability to concentrate and react). 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 (5.3)].

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 (5.2)].

Hypoglycemia Due to Medication Errors

Instruct patients to always check the insulin label before each injection to reduce the risk of a medication error [see Warnings and Precautions (5.4)].

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions have occurred with insulin glargine products. Inform patients about the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)].

Literature issued: Nov 2022

Manufactured by:

Eli Lilly and Company, Indianapolis, IN 46285, USA

US License Number 1891

Copyright © 2021, 2022, Eli Lilly and Company. All rights reserved.

REZ-0002-USPI-20221116

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.

Product: 50090-6439

NDC: 50090-6439-0 3 mL in a SYRINGE / 5 in a CARTON

• 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.

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)].

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)].

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.

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.

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.

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.

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)].

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).

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.

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 insulins, the glucose lowering effect time course of insulin glargine products may vary in different patients or at different times in the same patient and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology (12.2)]. 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 concomitant drugs [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].

This Patient Information has been approved by the U.S. Food and Drug Administration.

REZ-0002-PPI-20221116

INSTRUCTIONS FOR USE

REZVOGLAR^TM KwikPen^® (REHZ-voh-glahr)

(insulin glargine-aglr)

injection, for subcutaneous use

3 mL Single-Patient-Use PREFILLED-PEN: 100 units/mL (U-100)

Read these Instructions for Use before you start taking the REZVOGLAR KwikPen (“Pen”) and each time you get a new REZVOGLAR KwikPen. 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 REZVOGLAR KwikPen 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 REZVOGLAR KwikPen prefilled pen without help from a person trained to use REZVOGLAR KwikPen prefilled pen.

REZVOGLAR KwikPen is a disposable prefilled pen used to inject REZVOGLAR. Each REZVOGLAR KwikPen 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, but you may not notice that it moves. The plunger will only move to the end of the cartridge when 300 units of REZVOGLAR have been given.

Important Information You Need to Know Before Injecting REZVOGLAR

• Do not use your Pen if it is damaged or if you are not sure that it is working properly.
• Do not use a syringe to remove REZVOGLAR from your Pen.
• Do not reuse Needles. If you do, you might get the wrong dose of REZVOGLAR and/or increase the chance of getting an infection.
• Always perform a safety test (prime the REZVOGLAR KwikPen) (see Step 3).
• Always carry a spare Pen and spare Needles in case of loss or damage.
• Change (rotate) your injection sites within the area you choose for each dose (see “Places to inject”).

Learn to Inject

• Talk with your healthcare provider about how to inject before using your Pen.
• Ask for help if you have problems handling the Pen, for example if you have problems with your sight.
• Read all these instructions before using your Pen. If you do not follow all these instructions, you may get too much or too little insulin.

Need Help?

If you have any questions about your Pen or about diabetes, ask your healthcare provider, or go to www.rezvoglar.com or call Eli Lilly and Company at 1-800-545-5979.

Extra Items You Will Need

• a new sterile Pen Needle (see Step 2).
• an alcohol swab.
• a puncture-resistant container for used Needles and Pens (See "Throwing your Pen away").

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.
• Do not try to change your dose while injecting.

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. The REZVOGLAR KwikPen is light grey with a light grey Dose Knob that has a green ring on the end. The label on the Pen is light grey with green color bars.

• Make sure you have the correct insulin.

• Do not use your Pen after the expiration date.

1B Pull off the Pen Cap.

1C Check that the insulin is clear.

• Do not use the Pen if the insulin looks cloudy, colored or contains particles.

1D Wipe the Rubber Seal with an alcohol swab.

If you have other injector pens:

• Making sure you have the correct medicine is especially important if you have other injector pens.

Step 2: Attach a new Needle

• Do not re-use Needles. Always use a new sterile Needle for each injection. This helps stop blocked Needles, contamination, and infection.

Only use Needles that are compatible with REZVOGLAR KwikPen. Becton, Dickinson and Company (BD) Pen Needles are recommended. These are sold separately. Contact your healthcare provider for further information.

2A Take a new Needle and peel off the Paper Tab.

2B Keep the Needle straight and screw it onto the Pen until fixed. Do not over-tighten.

2C Pull off the Outer Needle Shield. Keep this for later.

2D Pull off the Inner Needle Shield and throw away.

Handling Needles

• Take care when handling Needles to prevent needle-stick injury and cross-infection.

Step 3: Do a safety test (Prime your REZVOGLAR KwikPen)

Always do a safety test (prime) before each injection to:

• Check your Pen and the Needle to make sure they are working properly.
• Make sure that you get the correct REZVOGLAR dose.

3A Select 2 units by turning the Dose Knob until the Dose Indicator is at the 2 mark.

3B Press the Dose Knob all the way in.

When insulin comes out of the Needle tip, your Pen is working correctly:

If no insulin appears:

• You may need to repeat this step up to 4 times before seeing insulin.
• If no insulin comes out after the fourth time, the Needle may be blocked. If this happens:
  • change the Needle (see Step 6 and Step 2),
  • then repeat the safety test (prime) (Step 3).
• Do not use your Pen if there is still no insulin coming out of the Needle tip. Use a new Pen.
• Do not use a syringe to remove insulin from your Pen.

If you see air bubbles:

• You may see air bubbles in the insulin. This is normal, they will not harm you.

Step 4: Select the dose

Do not select a dose or press the Dose Knob without a Needle attached. This may damage your Pen.

4A Make sure a Needle is attached and the dose is set to "0".

4B Turn the Dose Knob until the Dose Indicator lines up with your dose.

• If you turn past your dose, you can turn back down.
• The Dose Knob clicks as you turn it. Do not dial your dose by counting the clicks because you may dial the wrong dose.
• If there are not enough units left in your Pen for your dose, the Dose Indicator will stop at the number of units left.
• If you cannot select your full prescribed dose, use a new Pen or inject the remaining units and use a new Pen to complete your dose.

How to read the Dose Window

Even numbers are shown in line with Dose Indicator.

(Example: 12 units shown in the Dose Window)

Odd numbers, after the number 1, are shown as a line between even numbers.

(Example: 25 units shown in the Dose Window)

Units of REZVOGLAR in your Pen:

• Your Pen contains a total of 300 units of REZVOGLAR. You can select doses from 1 to 80 in steps of 1 unit. Each Pen contains more than 1 dose.
• You can see roughly how many units of insulin are left by looking at where the Plunger is on the insulin scale.

Step 5: Injecting Your REZVOGLAR Dose

If you find it hard to press the Dose Knob 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 picture above.

5B Push the Needle into the skin as shown by your healthcare provider.

Do not touch the Dose Knob yet.

5C Place your thumb on the Dose Knob. Then press all the way in and hold.

5D Keep the Dose Knob held in and when you see "0" in the Dose Window, slowly count to 5.

• This will make sure you get your full dose.
• Do not try to inject your insulin by turning the Dose Knob. You will not receive your insulin by turning the Dose Knob.

5E After holding and slowly counting to 5, release the Dose Knob. Then remove the Needle from your skin.

• If you do not see “0” in the Dose Window, you did not receive your full dose. Do not redial. Insert the needle into your skin and finish your injection.
• If you still do not think you received the full amount you dialed for your injection, do not start over or repeat the injection. Monitor your blood glucose and call your healthcare provider for further instructions.

If you find it hard to press the Dose Knob in:

• Change the Needle (see Step 6 and Step 2) then do a safety test (prime the Pen) (see Step 3).
• If you still find it hard to press in, get a new Pen.
• Do not use a syringe to remove insulin from your Pen.

Step 6: Remove the Needle

• Take care when handling Needles to prevent needle-stick injury and cross-infection.
• Do not put the Inner Needle Shield back on.

6A Leave the Outer Needle Shield on a flat surface. Using one hand, scoop the Outer Needle Shield straight onto the Needle. When the tip is covered, lift the Needle and Pen. Then push firmly on.

6B Grip and squeeze the widest part of the Outer Needle Shield. Turn your Pen several times with your other hand to remove the Needle.

• Try again if the Needle does not come off the first time.

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 put the Pen back in the refrigerator.

Storing the REZVOGLAR KwikPen

Before first use

• Keep new Pens in the refrigerator between 36°F to 46°F (2°C to 8°C).
• Do not freeze. Do not use REZVOGLAR if it has been frozen.
• Unused Pens may be used until the expiration date printed on the Label, if the Pen has been kept in the refrigerator.

After first use

• Keep your Pen at room temperature below 86°F (30°C).
• Keep your Pen away from heat or light.
• Store your Pen with the Pen Cap on.
• Do not put your Pen back in the refrigerator.
• Do not store your Pen with the Needle attached.
• Keep out of the reach of children.
• Only use your Pen for up to 28 days after its first use. Throw away the REZVOGLAR KwikPen you are using after 28 days, even if it still has insulin left in it.

Caring for Your REZVOGLAR KwikPen

Handle your Pen with care

• Do not drop your Pen or knock it against hard surfaces.
• If you think that your Pen may be damaged, do not try to fix it. Use a new one.

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.

Throwing your Pen away

• The used REZVOGLAR KwikPen may be thrown away in your household trash after you have removed the Needle.
• Put the used Needle in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the used Needles in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
  • made of a heavy-duty plastic,
  • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
  • upright and stable during use,
  • leak-resistant, and
  • properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used Needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.
• Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Eli Lilly and Company

Indianapolis, IN 46285, USA

US License Number 1891

Copyright © 2021, 2022, Eli Lilly and Company. All rights reserved.

REZVOGLAR^TM and REZVOGLAR^TM KwikPen^® are trademarks of Eli Lilly and Company.

Instructions for Use revised: Nov 2022

REZKP-0002-IFU-20221116

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.

Insulin glargine-aglr is a long-acting human insulin analog produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Insulin glargine-aglr 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. Insulin glargine-aglr has a molecular weight of 6063 Da.

REZVOGLAR (insulin glargine-aglr) injection is a sterile, clear and colorless solution for subcutaneous use in a 3 mL single-patient use prefilled pen (REZVOGLAR KwikPen).

Prefilled Pen (REZVOGLAR KwikPen): Each mL contains 100 units of insulin glargine-aglr and the inactive ingredients: glycerin (17 mg), metacresol (2.7 mg), zinc oxide (content adjusted to provide 30 mcg zinc ion), and Water for Injection, USP.

The pH is adjusted by addition of aqueous solutions of hydrochloric acid 10% and/or sodium hydroxide 10%. REZVOGLAR has a pH of approximately 4.

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).

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.

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 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.

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.

REZVOGLAR is contraindicated:

• during episodes of hypoglycemia [see Warnings and Precautions (5.3)].
• in patients with hypersensitivity to insulin glargine products or any of the excipients in REZVOGLAR [see Warnings and Precautions (5.5)].

The following adverse reactions are discussed elsewhere:

• Hypoglycemia [see Warnings and Precautions (5.3)].
• Hypoglycemia Due to Medication Errors [see Warnings and Precautions (5.4)].
• Hypersensitivity Reactions [see Warnings and Precautions (5.5)].
• Hypokalemia [see Warnings and Precautions (5.6)].

Table 8 includes clinically significant drug interactions with REZVOGLAR.

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)].

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.

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)].

REZVOGLAR™ is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus.

Limitations of Use

REZVOGLAR is not recommended for the treatment of diabetic ketoacidosis.

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.

• Never share a REZVOGLAR KwikPen prefilled pen between patients, even if the needle is changed. (5.1)
• Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to a patient's insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. (5.2)
• Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, concomitant drugs, meal pattern, physical activity; and in patients with renal or hepatic impairment and hypoglycemia unawareness. (5.3, 6.1)
• Hypoglycemia due to medication errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. (5.4, 6.3)
• Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue REZVOGLAR. Monitor and treat if indicated. (5.5, 6.1)
• Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. (5.6)
• Fluid retention and heart failure with concomitant use of thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation of TZD if heart failure occurs. (5.7)

• Individualize dosage based on metabolic needs, blood glucose monitoring, glycemic control, type of diabetes, and prior insulin use. (2.1, 2.2, 2.3, 2.4)
• Administer subcutaneously into the abdominal area, thigh, or deltoid once daily at any time of day, but at the same time every day. (2.1)
• Do not dilute or mix with any other insulin or solution. (2.1)
• Rotate injection sites to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. (2.1)
• See Full Prescribing Information for the recommended starting dosage in patients with type 2 diabetes and how to change to REZVOGLAR from other insulins (2.3, 2.4)
• Closely monitor glucose when switching to REZVOGLAR and during initial weeks thereafter. (2.4)

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

• 3 mL single-patient-use REZVOGLAR KwikPen prefilled pen.

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.

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.

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 in Studies A, B, C, and D [see Clinical Studies (14.2)]. The type 1 diabetes population had the following characteristics: Mean age was 39 years. Fifty-four percent were male, 97% were Caucasian, 2% were Black or African American and 3% 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 in Studies E, F, and G [see Clinical Studies (14.3)]. The type 2 diabetes population had the following characteristics: Mean age was 59 years. Fifty-eight percent were male, 87% were Caucasian, 8% were Black or African American and 9% were Hispanic. The mean BMI was 29.2 kg/m².

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).

• 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.

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.

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

Never Share a REZVOGLAR KwikPen Prefilled Pen Between Patients

Advise patients that they must never share a REZVOGLAR KwikPen with another person, even if the needle is changed. Sharing carries a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].

Hyperglycemia or Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia (e.g., impaired ability to concentrate and react). 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 (5.3)].

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 (5.2)].

Hypoglycemia Due to Medication Errors

Instruct patients to always check the insulin label before each injection to reduce the risk of a medication error [see Warnings and Precautions (5.4)].

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions have occurred with insulin glargine products. Inform patients about the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)].

Literature issued: Nov 2022

Manufactured by:

Eli Lilly and Company, Indianapolis, IN 46285, USA

US License Number 1891

Copyright © 2021, 2022, Eli Lilly and Company. All rights reserved.

REZ-0002-USPI-20221116

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.

Product: 50090-6439

NDC: 50090-6439-0 3 mL in a SYRINGE / 5 in a CARTON

• 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.

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)].

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)].

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.

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.

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.

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.

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)].

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).

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.