Why Wait?: You could keep her on a basal-bolus regimen or you could try a different option¹

Struggles to manage 5 or more injections/day^*

BMI of 34
Uses 201 – 300 units of insulin/day
Uncontrolled A1C
Tried diet & exercise and other diabetes meds

^* Hypothetical patient profile

Indication for Humulin^® R U-500

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.

Select Important Safety Information

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.

Humulin R U-500 is the only insulin studied in a randomized clinical trial of patients requiring >200 units/day¹

Trial Objective

The Humulin R U-500 Initiation Trial was a 24-week, open-label, randomized study conducted in the United States and Puerto Rico. This study compared 2 treatment regimens (TID versus BID) for U-500 insulin for replacement of high-dose U-100 insulin.

Almost 70% of patients in the U-500 Initiation Trial transitioned to Humulin R U-500 insulin monotherapy from high-dose basal-bolus therapy.

Approximately 70% of patients were on a total daily dose of 201-300 units of insulin at the start of the U-500 Initiation Trial.

The trial included a 4-week lead-in period followed by a 12-week intensive dose titration period and subsequent 12-week maintenance phase using R U-500 either TID or BID 30 minutes before meals and dosing titration algorithms based on 4-times-daily self-monitored plasma glucose (SMPG) values. Initial dosing proportions were 40:30:30 (breakfast:lunch:dinner) and 60:40 (breakfast:dinner) for the TID and BID regimens, respectively.

Trial Participants

Had uncontrolled type 2 diabetes with A1C ≥7.5% and ≤12.0% (mean 8.7%)
Were taking >200 and ≤600 units/day of U-100 insulin with or without oral antidiabetes drugs (mean 287.5 units/day)
Injected U-100 insulin 2-10 times a day pretrial (median: 5)
Had a BMI ≥25 kg/m² (mean 41.9 kg/m²)
Were 18-75 years of age (mean 55.4 years; ≥65 years = 20.3%)
Had type 2 diabetes for approximately 15 years

Trial Summary

In this trial, initiation and titration of U-500 using either algorithm improved glycemic control from baseline with 2 or 3 injections in patients with type 2 diabetes previously uncontrolled on high-dose/high-volume U-100 insulin.¹

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.
Wysham C, Hood RC, Warren ML, et al. Effect of total daily dose on efficacy, dosing, and safety of 2 dose titration regimens of human regular U-500 insulin in severely insulin-resistant patients with type 2 diabetes. Endocr Pract. 2016;22(6):653-665.

Demonstrated efficacy as insulin monotherapy injected 2 or 3 times a day¹

Demonstrated efficacy as insulin monotherapy when injected 2 or 3 times/day1. This line graph presents the primary end point of similar reductions in A1C between a 3-times daily (n = 162) and 2-times daily (n = 161) dosing regimen for Humulin R U-500. The mean A1C at baseline for all patients was 8.7%. At 24 weeks, patients in the 3-times-daily arm of the study had a least squares mean change in A1C of -1.1% (A1C of 7.5%) and patients in the 2-times-daily arm had a least squares mean change in A1C of -1.2% (A1C of 7.4%). The difference in least squares mean A1C change from baseline between treatment groups was -0.10%. The 95% confidence interval (-0.33% to 0.12%) fell within the range established by the noninferiority margin of 0.4%, demonstrating clinical equivalence of the 2 treatment regimens. All efficacy analyses were conducted using the full analysis set defined as all randomized patients receiving at least 1 dose of study drug at baseline.

LS = least squares; MMRM = mixed-model repeated measures; TID = three times a day; BID = two times a day. The difference in least squares mean (LSM) A1C change from baseline between treatment groups (BID vs TID) was -0.10%. The 95% CI (-0.33% to 0.12%) fell within the range established by the noninferiority margin (0.4%), demonstrating clinical equivalence of the 2 treatment regimens.

Mean A1C at baseline for both groups was 8.7%
Mean A1C at endpoint was 7.5% for TID and 7.4% for BID

All efficacy analyses were conducted using the full analysis set defined as all randomized patients receiving at least one dose of study drug at baseline.

Study conducted with U-100 insulin syringes and Humulin R U-500 vials.

The Humulin R U-500 Initiation Trial was a 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 efficacious.¹

Select Safety Information for Humulin R U-500

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 a U-500 insulin syringe.

Humulin R U-500 helped the majority of patients reach glycemic targets¹

Percentage of Patients Reaching Glycemic Targets at Endpoint1,^*
Mean A1C at Baseline (TID and BID): 8.7%

Humulin R U-500 graph of patients reaching glycemic targets — This bar graph presents the percentage of patients reaching glycemic targets at end point (24 weeks for those not at target at randomization). The mean A1C for patients at baseline (TID and BID) was 8.7%. The percentages of patients at target at baseline were approximately 1.9% (A1C less than 7.0%), approximately 9.9% (A1C less than 7.5%), and approximately 24.8% (A1C less than 8.0%).
Percentage of patients reaching glycemic target at endpoint: approximately 70% of patients taking Humulin R U-500 3 times daily and 69% of patients taking Humulin R U-500 2 times daily achieved an A1C less than 8.0%. Approximately 55% of patients taking Humulin R U-500 3 times daily and 47% of patients taking Humulin R U-500 2 times daily achieved an A1C less than 7.5%. Approximately 29% of patients taking Humulin R U-500 3 times daily and 31% of patients taking Humulin R U-500 2 times daily achieved an A1C less than 7.0%. NOTE: There was no statistically significant difference in the percent-to-target results achieved between 3-times-daily and 2-times-daily dosing regimens. All efficacy analyses were conducted using the full analysis set defined as all randomized patients receiving at least 1 dose of study drug at baseline.

NOTE: There was no statistically significant difference in percent-to-target results achieved between TID and BID dosing.

All efficacy analyses were conducted using the full analysis set defined as all randomized patients receiving at least one dose of study drug at baseline.

Approximately 70% of patients reached A1C <8.0%.

^*At 24 weeks for those not at target at randomization. Patients at target (%) at baseline: 24.8% (<8.0%), 9.9% (<7.5%), and 1.9% (<7.0%).

Hypoglycemia rates and incidence

Rates and Incidence of Hypoglycemia in the Humulin R U-500 Initiation Trial

	TID (n = 162)	BID (n = 161)
Severe hypoglycemia Incidence, n (%) 30-day event rate^a	3 (1.9) 0.004 ± 0.028	6 (3.7) 0.009 ± 0.053
Nocturnal <50 mg/dL Incidence, n (%) 30-day event rate^a	59 (36.4) 0.17 ± 0.03	79 (49.1) 0.20 ± 0.04
Nocturnal ≤70 mg/dL Incidence, n (%) 30-day event rate^a	126 (77.8) 0.92 ± 0.11	130 (80.8) 1.20 ± 0.13
Documented symptomatic <50 mg/dL Incidence, n (%) 30-day event rate^a	91 (56.2) 0.44 ± 0.07	103 (64.0) 0.54 ± 0.09
Documented symptomatic ≤70 mg/dL Incidence, n (%) 30-day event rate^a	149 (92.0) 3.46 ± 0.33	145 (90.1) 4.30 ± 0.40

^aEvents/patients/30 days.

Rates are geometric least squares means ± SE (documented symptomatic and nocturnal) or means ± SD (severe)

NOTE: During this trial, hypoglycemia was categorized as documented symptomatic, nocturnal, or severe hypoglycemia. Documented symptomatic hypoglycemia was defined as signs or symptoms associated with hypoglycemia and plasma glucose ≤70 mg/dL or <50 mg/dL. Nocturnal hypoglycemia was defined as documented symptomatic hypoglycemia and plasma glucose ≤70 mg/dL or <50 mg/dL occurring between bedtime and waking. By definition, severe hypoglycemia required assistance from another person for treatment and was accompanied by neurologic/cognitive impairment. Incidence is reported as the number of patients with at least one hypoglycemic episode.

All hypoglycemia analyses were performed using the full analysis set defined as all randomized patients receiving at least 1 dose of study drug.

Leading endocrinologists discuss experience with high-dose patients

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.

Why Wait?: You could keep her on a basal-bolus regimen or you could try a different option1

Humulin R U-500 is the only insulin studied in a randomized clinical trial of patients requiring >200 units/day1