Humulin R U-500 human insulin monotherapy delivers a dual action, providing the properties of both basal and mealtime coverage when dosed as directed

Fast-acting insulin starts working within 15 minutes after injection, peaks in about 1 to 2 hours after injection, and lasts between 2 to 4 hours after injection. Short-acting insulin starts working approximately 30 minutes after injection, peaks 2 to 3 hours after injection, and lasts for approximately 3 to 6 hours after injection. Intermediate-acting insulin starts working between 2 and 4 hours after injection, peaks 4 to 12 hours after injection, and lasts 12 to 18 hours after injection. Long-acting insulin starts working several hours after injection, has no peak, and tends to lower glucose levels up to 24 hours.

Select Safety Information for Humulin R U-500

Contraindications
Humulin^® R U-500 is contraindicated during episodes of hypoglycemia and in patients hypersensitive to Humulin R U-500 or any of its excipients.

Hyperglycemia or Hypoglycemia With Changes in Insulin Regimen

Changes in insulin strength, manufacturer, type, injection site, or method of administration may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Any changes in insulin regimen should be made cautiously and only under close medical supervision, and the frequency of blood glucose monitoring should be increased. Due to reports of hypoglycemia and hyperglycemia, advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to the unaffected areas and to closely monitor blood glucose. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.

U-500 insulin monotherapy may reduce the injection burden^*1,2

At study entry (Hood et al, 2015), patients requiring more than 200 units of insulin daily injected their insulin an average of 35 times per week or 1825 or more times per year. Patients switching to a U-500 two-times- or three-times-daily regimen injected their insulin 14 to 21 times per week or 730 to 1095 times per year.

In patients who need more than 200 units a day, U-500 is usually injected 2 or 3 times per day, compared with a median of 5^b times for other insulin regimens.^3,c

^*Compared to U-100 insulin. For patients taking >200 units of insulin per day.

^aUsually injected 2 or 3 times per day.

^bBased on a median of 5 injections per day, range 2 to 10.

^cOther insulin regimens included at study entry were: basal/bolus, pre-mixed insulin, basal only, and others.

Data on file, Lilly USA, LLC. HI20130603A
Data on file, Lilly Research Laboratories. HI20130221A
Humulin R U-500. Prescribing Information. Lilly USA, LLC.

Two syringes are depicted, showing the different volume of liquid needed to inject an equal amount of insulin between Humulin R U-500 insulin and U-100 insulins. The U-500 dose is shown as being 80% less volume than the U-100 dose.

Lower the daily insulin volume

80% less liquid volume than U-100 insulin delivers the same number of daily units.

Demonstrated in the Humulin R U-500 Initiation Trial A clinical framework for transitioning patients from U-100 insulin to U-500⁴

Clinical framework for transitioning patients from u-100 to u-500 — STEP 1: Determine Starting Dose³

If the patient's A1C is less than or equal to 8% or the patient's mean self-monitored plasma glucose is less than 183 mg/dL within the past 7 days, start at 80% of the final U-100 total daily dose (after calculating total daily dose, round down to the nearest increment of 5). If the patient's A1C is greater than 8% or the patient's mean self-monitored plasma glucose is equal to or greater than 183 mg/dL within the past 7 days, start at 100% of the final U-100 total daily dose (again, after calculating TDD, round down to the nearest increment of 5).

STEP 2: Determine Dose Proportions³

For the 3-times-daily regimen, 40% of the total daily dose is administered before breakfast, 30% is administered before lunch, and 30% is administered before dinner. For the 2-times-daily regimen, 60% is administered before breakfast and 40% is administered before dinner.

How starting doses were determined in the U-500 Initiation Trial:

If A1C was >8% at Week -4 and mean self-monitored plasma glucose (SMPG) ≥183 mg/dL in the 7 days before Week 0, then the starting total daily dose (TDD) of U-500 was 100% of the final U-100 TDD
If A1C was ≤8% at Week -4 or mean SMPG <183 mg/dL in the 7 days before Week 0, then the starting TDD of U-500 was 80% of the final U-100 TDD (20% reduction)

Study Design

24-week, open-label, randomized trial to compare the efficacy and safety of 2 dosing regimens (TID, n=162 vs BID, n=163) for U-500 insulin replacing high-dose U-100 insulin (>200 units per day) with or without oral antihyperglycemic drugs in adult patients with uncontrolled type 2 diabetes. These regimens were found to be equivalent for A1C reduction over 24 weeks, and both were found to be efficacious⁴.

Hood RC, Arakaki RF, Wysham C, et al. Two treatment approaches for human regular U-500 insulin in patients with type 2 diabetes not achieving adequate glycemic control on high-dose U-100 insulin therapy with or without oral agents: a randomized, titration-to-target clinical trial. Endocr Pract. 2015;21(7):782-793. Erratum, 2016;22(7):905.

Titration

Treat-to-target dosing algorithms titrated TID or BID regimens to achieve fasting and pre-meal SMPG 71-130 mg/dL
Both doses of the BID regimen were titrated; only 2 of 3 TID doses were titrated (those most needing adjustment)
Dose reductions were prioritized over dose increases for hypoglycemia
U-500 dosing was recommended 30 minutes before meals using a U-100 insulin syringe
Patients checked their blood glucose before each meal and at bedtime daily, and at 3 AM if they had increased their dose in the last 48 hours

Select Important Safety Information for Humulin R U-500

Hypoglycemia

Hypoglycemia is the most common adverse reaction associated with insulin, including Humulin R U-500. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death.
Increase monitoring with changes to insulin dosage, co-administered glucose-lowering medications, meal patterns, physical activity, and in patients with renal or hepatic impairment or hypoglycemia unawareness. To minimize risk of hypoglycemia, do not administer Humulin R U-500 intravenously, intramuscularly, or in an insulin pump or dilute or mix with other products, including other insulins.
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

An effective treat-to-target dosing algorithm with 2 or 3 injections of U-500 per day⁴

TID Initial Dose Proportions: 40:30:30⁴

INSULIN DOSE TO ADJUST	PLASMA-EQUIVALENT GLUCOSE VALUE^a	SMPG (mg/dL)	DOSE TITRATION^b
		≤70^c	-10%
PRE-BREAKFAST	MEDIAN^d PRE-LUNCH SMPG	71-130	No change in dose
PRE-LUNCH	MEDIAN^d PRE-DINNER SMPG	131-180	+5%
PRE-DINNER	MEDIAN^d PRE-BREAKFAST SMPG	181-220	+10%
		>220	+15%

BID Initial Dose Proportions: 60:40⁴

INSULIN DOSE TO ADJUST	PLASMA-EQUIVALENT GLUCOSE VALUE^a	SMPG (mg/dL)	DOSE TITRATION^b
		≤70^c	-10%
PRE-BREAKFAST	MEDIAN^d PRE-DINNER SMPG	71-130	No change in dose
		131-180	+5%
PRE-DINNER	MEDIAN^d PRE-BREAKFAST SMPG	181-220	+10%
		>220	+15%

^aPatients should check their blood glucose daily before each meal, at bedtime, and at 3 AM if they have increased their dose in the last 48 hours.

^bUsed conventional rounding to nearest 5-unit increment.

^c10% dose reduction if any pre-mealtime median, bedtime median, or single 3 AM SMPG ≤70 mg/dL.

^dMedian of 3 most recent daily self-monitored plasma glucose (SMPG) readings.

Hood RC, Arakaki RF, Wysham C, et al. Two treatment approaches for human regular U-500 insulin in patients with type 2 diabetes not achieving adequate glycemic control on high-dose U-100 insulin therapy with or without oral agents: a randomized, titration-to-target clinical trial. Endocr Pract. 2015;21(7):782-793. Erratum, 2016;22(7):905.

IMPORTANT SAFETY INFORMATION

Humulin R U-500 is contraindicated during episodes of hypoglycemia and in patients hypersensitive to Humulin R U-500 or any of its excipients.

Hyperglycemia, Hypoglycemia, or Death Due to Dosing Errors With Vial Presentation can be life-threatening. Overdose has occurred as a result of dispensing, prescribing, or administration errors. Attention to details at all levels is required to prevent these errors.

Patients should be prescribed U-500 syringes for use with Humulin R U-500 vials. Do not use any other type of syringe to administer Humulin R U-500.
If using the Humulin R U-500 KwikPen^®, patients should be counseled to dial and dose the prescribed number of units of insulin.
Do NOT perform dose conversion when using the Humulin R U-500 KwikPen or U-500 insulin syringe.

DO NOT transfer Humulin R U-500 from the KwikPen into any syringe for administration. Overdose and severe hypoglycemia can occur.

Never share a KwikPen or U-500 syringe between patients, even if the needle is changed, to avoid risk of transmission of blood-borne pathogens.

Hyperglycemia or Hypoglycemia With Changes in Insulin Regimen

Changes in insulin strength, manufacturer, type, injection site, or method of administration may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Any changes in insulin regimen should be made cautiously and only under close medical supervision, and the frequency of blood glucose monitoring should be increased. Due to reports of hypoglycemia and hyperglycemia, advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to the unaffected areas and to closely monitor blood glucose. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.

Hypoglycemia

Hypoglycemia is the most common adverse reaction associated with insulins, including Humulin R U-500. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death.
Increase monitoring with changes to insulin dosage, co-administered glucose-lowering medications, meal patterns, physical activity, and in patients with renal or hepatic impairment or hypoglycemia unawareness. To minimize risk of hypoglycemia, do not administer Humulin R U-500 intravenously or dilute or mix with other products, including other insulins.
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

Hypersensitivity Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including Humulin R U-500. If hypersensitivity reactions occur, discontinue Humulin R U-500; treat per standard of care and monitor until symptoms and signs resolve.

Hypokalemia

May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated.

Fluid Retention and Heart Failure With Concomitant Use of Thiazolidinediones (TZDs)

Thiazolidinediones (TZDs) can cause dose-related fluid retention when used in combination with insulin. Observe for signs and symptoms of heart failure and consider reduction or discontinuation if heart failure occurs.

Adverse Reactions

Other adverse reactions include allergic reactions, lipodystrophy, injection site reactions, pruritus, and rash.

Drug Interactions

The following drugs may alter glucose metabolism and may necessitate insulin dose adjustment:

Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics.
Drugs that may decrease the blood glucose lowering effect of Humulin R U-500: atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
Drugs that may increase or decrease the blood glucose lowering effect of Humulin R U-500: alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

Increased frequency of glucose monitoring may be required when Humulin R U-500 is co-administered with the following drugs:

Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics.
Drugs that may decrease the blood glucose lowering effect of Humulin R U-500: atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
Drugs that may increase or decrease the blood glucose lowering effect of Humulin R U-500: alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Drugs that may blunt signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine.

HM U500 HCP ISI 02FEB2023

INDICATION

Humulin R U-500 is a concentrated human insulin indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day.

Limitations of Use: The safety and efficacy of Humulin R U-500 used in combination with other insulins, or when delivered by continuous subcutaneous infusion, has not been determined.