Humalog® Mixes
Humalog Mix75/25 and Humalog Mix50/50 are mixtures of insulin lispro protamine, an intermediate-acting human insulin analog, and insulin lispro, a rapid-acting human insulin analog indicated to improve glycemic control in patients with diabetes mellitus.
The proportions of rapid-acting and intermediate-acting insulins in Humalog Mix75/25 and Humalog Mix50/50 are fixed and do not allow for basal versus prandial dose adjustments.
Select Important Safety Information
Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, and Humalog Mix50/50 are contraindicated during episodes of hypoglycemia and in patients who are hypersensitive to these insulins or any of their excipients.
Efficacy of Humalog Mix75/25
In three studies of adult patients with type 2 diabetes:
Humalog Mix75/25 provided improved glucose control.1,2,3
When added to metformin, Humalog Mix75/25 improved A1C1,2
- Two open-label, randomized, crossover trials compared the glycemic response of Humalog Mix75/25 BID + metformin with that of glargine QD + metformin1,2
See PAIR-IN and PAIR-PI study design and methods below.
Humalog Mix75/25 improved fasting blood glucose (FBG) and postprandial glucose (PPG) control3
-
A randomized, double-blind study with 3-way crossover compared Human Insulin 70/30, Humalog Mix75/25, and Humalog®
Mix50/50™ after a standardized breakfast meal3
See study design and methods below.
Select Important Safety Information
Never share a Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, or Humalog Mix50/50 prefilled pen, cartridge, reusable pen compatible with Lilly 3 mL cartridges, or syringe between patients as it poses a risk for transmission of blood-borne pathogens.
PAIR-IN: Design and methods1
- Humalog Mix75/25 BID plus metformin versus glargine QD plus metformin
- Open-label, randomized, crossover trial, 16 weeks on each treatment
- 105 insulin-naive patients with type 2 diabetes
- Mean age 55 years
- All randomized patients included in safety analysis
- 67 patients included in efficacy analysis (29 patients excluded because they may have received expired study drug)
- Baseline A1C: 8.7%
Primary endpoint
- Change in A1C over 16 weeks
Note: PAIR-IN average (standard deviation) daily dose of insulin was 0.62 (0.37) U/kg for Humalog Mix75/25 vs 0.57 (0.37) U/kg for glargine (P<.001).
PAIR-PI: Design and methods2
- Humalog Mix75/25 BID plus metformin versus glargine QD plus metformin
- Inadequately controlled patients with type 2 diabetes on once- or twice-daily insulin alone or in combination with oral agents
- 97 patients
- Open-label, randomized, crossover trial
Note: PAIR-PI average (standard deviation) daily dose of insulin was 0.42 (0.20) U/kg for Humalog Mix75/25 vs 0.36 (0.18) U/kg for glargine (P<.001).
MET=metformin
Select Important Safety Information
Changes in insulin regimen (e.g. insulin strength, manufacturer, type, injection site, or method of administration) may affect glycemic control and predispose patients to hypoglycemia and hyperglycemia. Make changes cautiously with increased frequency of blood glucose monitoring.
See PAIR-IN: Study Design and Methods above
See PAIR-PI: Study Design and Methods above
Select Important Safety Information
Severe hypoglycemia may be life threatening and can cause seizures or death. Hypoglycemia is the most common adverse effect of Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, and Humalog Mix50/50 therapy. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia.
Humalog Mix75/25 improved fasting3 and postprandial4 glucose control
Design and methods
- Comparison of insulin formulations: Human Insulin 70/30, Humalog Mix75/25, and Humalog Mix50/50 after a standardized breakfast meal
- Study was randomized and double-blind, with 3-way crossover of the premixed insulins in patients with type 2 diabetes. A control group of subjects without diabetes underwent the standardized test meal with no insulin treatment
- After the test breakfast, glucose was measured for 4 hours
- 22 patients received a single dose of Human Insulin 70/30 before breakfast; 22 received Humalog Mix75/25; and 23 received Humalog Mix50/50. Ten subjects without diabetes received no insulin. One patient who received Human Insulin 70/30 before the test meal, followed by the usual dose of insulin lispro before lunch, reported symptoms of hypoglycemia that resolved with oral carbohydrate
Note: Mean (SD) dose of insulin was 44.1 (18.2) U/day for Human Insulin 70/30; 44.1 (18.2) U/day for Humalog Mix75/25; and 43.8 (17.8) U/day for Humalog Mix50/50. Standard test breakfast: 500 kcal; 50% carbohydrate, 34% fat, 16% protein. Each regimen resulted in 2-hour postprandial glucose significantly different from all other regimens (pairwise comparison).
Select Important Safety Information
Instruct patients to always check the insulin label before each injection to avoid medication errors. Do NOT transfer Humalog U-200 from the Humalog KwikPen to a syringe as overdose and severe hypoglycemia can occur.
Efficacy of Humalog Mix50/50
Humalog Mix50/50 improved postprandial glucose control3,5,6
A randomized, double-blind study compared Human Insulin 70/30, Humalog Mix75/25, and Humalog Mix50/50 after a standardized breakfast meal in patients with type 2 diabetes.3 Humalog Mix50/50 improved postprandial glucose control.3,5,6
Design and methods3
Comparison of insulin formulations: Human Insulin 70/30, Humalog Mix75/25, and Humalog Mix50/50 after a standardized breakfast meal
Study was randomized and double-blind, with 3-way crossover of the premixed insulins in patients with type 2 diabetes. A control group of subjects without diabetes underwent the standardized test meal with no insulin treatment
All patients previously used insulin (excluding insulin glargine) for at least one month prior to the study
After the test breakfast, glucose was measured for 4 hours
22 patients received a single dose of Human Insulin 70/30 before breakfast; 22 received Humalog Mix75/25; and 23 received Humalog Mix50/50. Ten subjects without diabetes received no insulin. One patient who received Human Insulin 70/30 before the test meal, followed by the usual dose of insulin lispro before lunch, reported symptoms of hypoglycemia that resolved with oral carbohydrate
Humalog Mix50/50 provided improved postprandial control for patients after a standardized breakfast meal3
*Each regimen resulted in 2-hour postprandial glucose significantly different from all other regimens (pairwise comparison).
Note: Mean (SD) dose of insulin was 44.1 (18.2) U/day for Human Insulin 70/30; 44.1 (18.2) U/day for Humalog Mix75/25; and 43.8 (17.8) U/day for Humalog Mix50/50. Standard test breakfast: 500 kcal; 50% carbohydrate, 34% fat, 16% protein.
Select Important Safety Information
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, and Humalog Mix50/50. If hypersensitivity reactions occur, discontinue the insulin and treat per standard of care until signs and symptoms resolve.
Dosing for Humalog mixes
The following dosing options for patients with type 2 diabetes starting premixed insulin are based on Hirsch et al.7 Dosing guidelines should be individualized for each patient.
Recommended dose
- Start 10 units predinner
- Add subsequent prebreakfast dose based on patient's needs, or
- Start 10 units prebreakfast and predinner
Titration
- Prebreakfast dose: Adjust based on predinner/evening glucose values
- Predinner dose: Adjust based on prebreakfast/morning glucose values
- Do not increase dose if hypoglycemia (<70 mg/dL) or symptoms are present
Titration schedule for once-daily or twice-daily insulin regimens7
Some Important Dosing Information
Dosage regimens of insulin will vary among patients and should be determined by the healthcare provider familiar with the patient's metabolic needs, eating habits, and other lifestyle variables.
In addition, the dose must be individualized and adjusted for each patient, based on metabolic needs, blood glucose monitoring results and glycemic control goals.
References: 1. Malone JK, Kerr LF, Campaigne BN, Sachson RA, Holcombe JH; Lispro Mixture-Glargine Study Group. Combined therapy with insulin lispro Mix75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy [published correction appears in Clin Ther. 2005;27(7):1112]. Clin Ther. 2004;26(12):2034-2044. 2. Malone JK, Bai S, Campaigne BN, Reviriego J, Augendre-Ferrante B. Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with Type 2 diabetes. Diabet Med. 2005;22(4):374-381. 3. Schwartz S, Zagar AJ, Althouse SK, Pinaire JA, Holcombe JH. A single-center, randomized, double-blind, three-way crossover study examining postchallenge glucose responses to human insulin 70/30 and insulin lispro fixed mixtures 75/25 and 50/50 in patients with Type 2 diabetes mellitus. Clin Ther. 2006;28(10):1649-1657. 4. Koivisto VA, Tuominen JA, Ebeling P. Lispro Mix25 insulin as premeal therapy in type 2 diabetic patients. Diabetes Care. 1999;22(3):459-462. 5. Kazda C, Hülstrunk H, Helsberg K, Langer F, Forst T, Hanefeld M. Prandial insulin substitution with insulin lispro or insulin lispro mid mixture vs. basal therapy with insulin glargine: a randomized controlled trial in patients with type 2 diabetes beginning insulin therapy. J Diabetes Complications. 2006;20(3):145-152. 6. Roach P, Trautmann M, Arora V, Sun B, Anderson JH Jr. Improved postprandial blood glucose control and reduced nocturnal hypoglycemia during treatment with two novel insulin lispro-protamine formulations, insulin lispro mix25 and insulin lispro mix50. Clin Ther. 1999;23:523-534. 7. Hirsch IB, Bergenstal RM, Parkin CG, Wright E Jr, Buse JB. A real-world approach to insulin therapy in primary care practice. Clin Diabetes. 2005;23(2):78-86.
Indication for Humalog Brand of Insulins and Lilly's Non-Branded Insulin Lispro Products
Humalog and Insulin Lispro Injection are rapid-acting insulin analogs indicated to improve glycemic control in adults and children with diabetes mellitus. Humalog Mix75/25 and Humalog Mix50/50, and Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 are mixtures of intermediate-acting and rapid-acting insulin analogs indicated to improve glycemic control in patients with diabetes mellitus.
Limitations of Use: The proportions of rapid-acting and intermediate-acting insulins in Humalog Mix75/25 and Humalog Mix50/50, and Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 are fixed and do not allow for basal versus prandial dose adjustments.
Important Safety Information for Humalog Brand of Insulins and Lilly’s Non-Branded Insulin Lispro Products
Contraindications
Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, and Humalog Mix50/50 are contraindicated during episodes of hypoglycemia and in patients who are hypersensitive to these insulins or any of their excipients.
Warnings and Precautions
Never share a Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, or Humalog Mix50/50 prefilled pen, cartridge, reusable pen compatible with Lilly 3 mL cartridges, or syringe between patients, even if the needle is changed. Patients using vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.
Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Changes in 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 under close medical supervision and the frequency of blood glucose monitoring should be increased. Due to reports of hyperglycemia and hypoglycemia, 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 blood glucose. For patients with type 2 diabetes, dosage adjustments of concomitant antidiabetic products may be needed.
Hypoglycemia: Severe hypoglycemia may be life threatening and can cause seizures or death. Hypoglycemia is the most common adverse reaction of Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, and Humalog Mix50/50. Monitor blood glucose and increase monitoring frequency with changes to insulin dosage, use with glucose-lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness.
Hypoglycemia Due to Medication Errors: Instruct patients to always check the insulin label before each injection to avoid medication errors. Humalog U-200 should not be transferred from the Humalog KwikPen to a syringe as overdose and severe hypoglycemia can occur.
Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, and Humalog Mix50/50. If hypersensitivity reactions occur, discontinue the use of insulin and treat per standard of care until signs and symptoms resolve.
Hypokalemia: Hypokalemia may be life threatening. Insulins, including Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, and Humalog Mix50/50, cause a shift in potassium from the extracellular to intracellular space possibly leading to hypokalemia, which, if untreated, may result in respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia (e.g., patients using potassium-lowering medications or medications sensitive to serum potassium concentrations).
Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists: Thiazolidinediones (TZDs), which are PPAR-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin, including Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, and Humalog Mix50/50. This may lead to or exacerbate heart failure. Observe patients for signs and symptoms of heart failure and consider discontinuation or dose reduction of the PPAR-gamma agonist.
Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction: Malfunction of the insulin pump device, infusion set, or insulin degradation can rapidly lead to hyperglycemia and ketoacidosis. Patients using subcutaneous insulin infusion pumps must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure.
Adverse Reactions
Adverse reactions associated with Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, and Humalog Mix50/50 include hypoglycemia, hypokalemia, allergic reactions, injection-site reactions, lipodystrophy, pruritus, rash, weight gain, and peripheral edema.
Drug Interactions
Some medications may alter glucose metabolism, insulin requirements, and the risk for hypoglycemia or hyperglycemia. Signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs. Particularly close monitoring may be required.
Please see links to Full Prescribing Information, Patient Information and Instructions for Use at the bottom of the page for more information.
HI BOI SP U100 75/25 HCP ISI 10JAN2020