ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed elsewhere in the labeling:Hypoglycemia [see Warnings and Precautions (5.3)] Medication Errors [see Warnings and Precautions (5.4)] Hypersensitivity Reactions [see Warnings and Precautions (5.5)] Hypokalemia [see Warnings and Precautions (5.6)] Hypoglycemia [see Warnings and Precautions (5.3)] Medication Errors [see Warnings and Precautions (5.4)] Hypersensitivity Reactions [see Warnings and Precautions (5.5)] Hypokalemia [see Warnings and Precautions (5.6)] Adverse reactions observed with HUMALOG Mix75/25 include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, weight gain, edema, pruritus, and rash. (6)To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Adverse Reactions from Clinical Studies or Postmarketing ReportsThe following adverse reactions have been identified during post-marketing use of HUMALOG Mix75/25. Because some of these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. Adverse reactions associated with insulin initiation and glucose control intensificationIntensification or rapid improvement in glucose control has been associated with transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. Over the long-term, improved glycemic control decreases the risk of diabetic retinopathy and neuropathy.Hypersensitivity reactionsSevere, life-threatening, generalized allergy, including anaphylaxis.HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in HUMALOG Mix75/25.HypokalemiaHUMALOG Mix75/25 can cause shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia.Injection site reactionsHUMALOG Mix75/25 can cause local injection site reactions including redness, swelling, or itching at the site of injection. These reactions usually resolve in few days to few weeks, but in some occasions, may require discontinuation. Localized reactions and generalized myalgias have been reported with the use of meta-cresol, which is an excipient in HUMALOG Mix75/25.LipodystrophyAdministration of insulin subcutaneously, including HUMALOG Mix75/25, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) [see Dosage and Administration (2.1)] in some patients.Localized cutaneous amyloidosisLocalized 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 sudden change to an unaffected injection site.Medication ErrorsMedication errors in which other insulins have been accidentally substituted for HUMALOG Mix75/25 have been identified during postapproval use.Peripheral EdemaInsulin, including HUMALOG Mix75/25, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.Weight gainWeight gain can occur with insulin therapy, including HUMALOG Mix75/25, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria.ImmunogenicityAs with all therapeutic peptides, insulin administration may cause anti-insulin antibodies to form. The incidence of antibody formation with HUMALOG Mix75/25 is unknown.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.1)11/2019Warnings and Precautions (5.2)11/2019.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. The effect of renal impairment on the pharmacokinetics of HUMALOG Mix75/25 has not been studied. Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent HUMALOG Mix75/25 dose adjustment and more frequent glucose monitoring [see Warnings and Precautions (5.3)].

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: November 2019Patient InformationHUMALOG(R)(HU-ma-log) Mix75/25(TM)(insulin lispro protamine and insulin lispro injectable suspension)for subcutaneous useDo not share your HUMALOG Mix75/25 KwikPen, needles or syringes with other people, even if the needle has been changed. You may give other people serious infection or get serious infection from them.What is HUMALOG Mix75/25HUMALOG Mix75/25 is man-made insulin that is used to control high blood sugar in people with diabetes mellitus.It is not known if HUMALOG Mix75/25 is safe and effective in children under 18 years of age.Who should not take HUMALOG Mix75/25Do not take HUMALOG Mix75/25 if you:are having an episode of low blood sugar (hypoglycemia).have an allergy to HUMALOG Mix75/25 or any of the ingredients in HUMALOG Mix75/25. See the end of this Patient Information leaflet for complete list of ingredients in Humalog Mix75/25.What should tell my healthcare provider before taking Humalog Mix75/25Before taking HUMALOG Mix75/25, tell your healthcare provider about all of your medical conditions, including if you:have liver or kidney problems.take any other medicines, especially ones called TZDs (thiazolidinediones).have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with HUMALOG Mix75/25.are pregnant or plan to become pregnant. Talk with your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.are breastfeeding or plan to breastfeed. Talk with your healthcare provider about the best way to feed your baby while taking HUMALOG Mix75/25. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Before you start taking HUMALOG Mix75/25, talk to your healthcare provider about low blood sugar and how to manage it. How should take HUMALOG Mix75/25Read the Instructions for Use that comes with your HUMALOG Mix75/25.Take HUMALOG Mix75/25 exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much HUMALOG Mix75/25 to take and when to take it.HUMALOG Mix75/25 starts acting fast. Inject HUMALOG Mix75/25 within 15 minutes before you eat meal.Know the type, strength, and amount of insulin you take. Do not change the type or amount of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin.Check your insulin label each time you give your injection to make sure you are taking the correct insulin.Inject HUMALOG Mix75/25 under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs or upper arms. Do not inject HUMALOG Mix75/25 into your vein (intravenously) or muscle (intramuscularly) or use in an insulin infusion pump. Change (rotate) your injection sites within the area you choose with 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 use the exact same spot for each injection.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 mix HUMALOG Mix75/25 with other insulins or liquids.Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels. Keep HUMALOG Mix75/25 and all medicines out of the reach of children.Your dose of HUMALOG Mix75/25 may need to change because of a:change in physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.What should avoid while taking HUMALOG Mix75/25While taking HUMALOG Mix75/25 do not:drive or operate heavy machinery until you know how HUMALOG Mix75/25 affects you.drink alcohol or take prescription or over-the-counter medicines that contain alcohol.What are the possible side effects of HUMALOG Mix75/25HUMALOG Mix75/25 may cause serious side effects that can lead to death, including:low blood sugar (hypoglycemia). Signs and symptoms of low blood sugar may include: dizziness or light-headednesssweatingconfusionheadacheblurred visionslurred speechshakinessfast heartbeatanxiety, irritability or mood changeshungerYour healthcare provider may prescribe glucagon emergency kit so that someone else can give you glucagon if your blood sugar becomes too low (severe hypoglycemia) and you are unable to take sugar by mouth. severe allergic reaction (whole body reaction). Get medical help right away, if you have any of these signs or symptoms of severe allergic reaction: rash over your whole bodytrouble breathinga fast heartbeatsweatinglow potassium in your blood (hypokalemia).heart failure. Taking certain diabetes pills called thiazolidinediones or TZDs with HUMALOG Mix75/25 may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with HUMALOG Mix75/25. Your healthcare provider should monitor you closely while you are taking TZDs with HUMALOG Mix75/25. Tell your healthcare provider if you have any new or worse symptoms of heart failure including: shortness of breathswelling of your ankles or feetsudden weight gainTreatment with TZDs and HUMALOG Mix75/25 may need to be adjusted or stopped by your healthcare provider if you have new or worse heart failure. Get emergency medical help if you have: trouble breathingshortness of breathfast heartbeatswelling of your face, tongue, or throatsweatingextreme drowsinessdizzinessconfusionThe most common side effects of HUMALOG Mix75/25 include:low blood sugar (hypoglycemia)reactions at your injection siteskin thickening or pits at the injection site (lipodystrophy)weight gainswelling in your hands or feetitchingrashThese are not all the possible side effects of HUMALOG Mix75/25. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of HUMALOG Mix75/25.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not take HUMALOG Mix75/25 for condition for which it was not prescribed. Do not give HUMALOG Mix75/25 to other people, even if they have the same symptoms that you have. It may harm them.This Patient Information leaflet summarizes the most important information about HUMALOG Mix75/25. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about HUMALOG Mix75/25 that is written for health professionals.What are the ingredients in HUMALOG Mix75/25Active ingredients: insulin lispro Inactive ingredients: protamine sulfate, glycerin, dibasic sodium phosphate, metacresol, zinc oxide (zinc ion), phenol and water for injection.Humalog(R), Humalog(R) Mix75/25(TM) and Humalog(R) Mix75/25(TM) KwikPen(R) are trademarks of Eli Lilly and Company. Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright (C) 1999, 2019, Eli Lilly and Company. All rights reserved.For more information, go to www.humalog.com or call 1-800-545-5979.LOG7525-0003-PPI-20191115. HUMALOG Mix75/25 is man-made insulin that is used to control high blood sugar in people with diabetes mellitus.. It is not known if HUMALOG Mix75/25 is safe and effective in children under 18 years of age.. are having an episode of low blood sugar (hypoglycemia).. have an allergy to HUMALOG Mix75/25 or any of the ingredients in HUMALOG Mix75/25. See the end of this Patient Information leaflet for complete list of ingredients in Humalog Mix75/25.. have liver or kidney problems.. take any other medicines, especially ones called TZDs (thiazolidinediones).. have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with HUMALOG Mix75/25.. are pregnant or plan to become pregnant. Talk with your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.. are breastfeeding or plan to breastfeed. Talk with your healthcare provider about the best way to feed your baby while taking HUMALOG Mix75/25. Read the Instructions for Use that comes with your HUMALOG Mix75/25.. Take HUMALOG Mix75/25 exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much HUMALOG Mix75/25 to take and when to take it.. HUMALOG Mix75/25 starts acting fast. Inject HUMALOG Mix75/25 within 15 minutes before you eat meal.. Know the type, strength, and amount of insulin you take. Do not change the type or amount of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin.. Check your insulin label each time you give your injection to make sure you are taking the correct insulin.. Inject HUMALOG Mix75/25 under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs or upper arms. Do not inject HUMALOG Mix75/25 into your vein (intravenously) or muscle (intramuscularly) or use in an insulin infusion pump. Change (rotate) your injection sites within the area you choose with 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 use the exact same spot for each injection.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 use the exact same spot for each injection.. 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 mix HUMALOG Mix75/25 with other insulins or liquids.. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels. change in physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.. drive or operate heavy machinery until you know how HUMALOG Mix75/25 affects you.. drink alcohol or take prescription or over-the-counter medicines that contain alcohol.. low blood sugar (hypoglycemia). Signs and symptoms of low blood sugar may include: dizziness or light-headedness. sweating. confusion. headache. blurred vision. slurred speech. shakiness. fast heartbeat. anxiety, irritability or mood changes. hunger. severe allergic reaction (whole body reaction). Get medical help right away, if you have any of these signs or symptoms of severe allergic reaction:. rash over your whole body. trouble breathing. fast heartbeat. sweating. low potassium in your blood (hypokalemia).. heart failure. Taking certain diabetes pills called thiazolidinediones or TZDs with HUMALOG Mix75/25 may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with HUMALOG Mix75/25. Your healthcare provider should monitor you closely while you are taking TZDs with HUMALOG Mix75/25. Tell your healthcare provider if you have any new or worse symptoms of heart failure including: shortness of breath. swelling of your ankles or feet. sudden weight gain. trouble breathing. shortness of breath. fast heartbeat. swelling of your face, tongue, or throat. sweating. extreme drowsiness. dizziness. confusion. low blood sugar (hypoglycemia). reactions at your injection site. skin thickening or pits at the injection site (lipodystrophy). weight gain. swelling in your hands or feet. itching. rash.

SPL UNCLASSIFIED SECTION.

Limitations of Use:The proportions of rapid-acting and intermediate-acting insulins in HUMALOG Mix75/25 are fixed and do not allow for basal versus prandial dose adjustments.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Standard 2-year carcinogenicity studies in animals have not been performed with HUMALOG Mix75/25. In Fischer 344 rats, 12-month repeat-dose toxicity study was conducted with insulin lispro (a component of HUMALOG Mix75/25) at subcutaneous doses of 20 and 200 units/kg/day (approximately and 32 times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area). Insulin lispro did not produce important target organ toxicity including mammary tumors at any dose.Insulin lispro was not mutagenic in the following genetic toxicity assays: bacterial mutation, unscheduled DNA synthesis, mouse lymphoma, chromosomal aberration and micronucleus assays.Male fertility was not compromised when male rats given subcutaneous insulin lispro injections of and 20 units/kg/day (0.8 and times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area) for months were mated with untreated female rats. In combined fertility, perinatal, and postnatal study in male and female rats given 1, 5, and 20 units/kg/day subcutaneously (0.2, 0.8, and times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The primary activity of insulin, including HUMALOG Mix75/25, is the regulation of glucose metabolism. Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.. 12.2 Pharmacodynamics. In glucose clamp study performed in 30 healthy subjects, the onset of action and glucose-lowering activity of HUMALOG, HUMALOG(R) Mix50/50(TM), HUMALOG Mix75/25, and insulin lispro protamine suspension (ILPS) were compared (see Figure 1). Graphs of mean glucose infusion rate versus time showed distinct insulin activity profile for each formulation. The rapid onset of glucose-lowering activity characteristic of HUMALOG was maintained in HUMALOG Mix75/25. The median maximum pharmacologic effect of HUMALOG Mix75/25 after administration of 0.3 unit/kg dose to healthy subjects occurred at approximately hours (range: 1-6 hours); glucose lowering activity was detectable for median of 22 hours (range: 13 to 22 hours), which was the end of the clamp.In separate glucose clamp studies performed in healthy subjects, pharmacodynamics of HUMALOG Mix75/25 and HUMULIN(R) 70/30 were assessed and are presented in Figure 2. HUMALOG Mix75/25 has duration of activity similar to that of HUMULIN 70/30. Figures and should be considered only as representative examples since the time course of action of insulin and insulin analogs, may vary in different individuals or within the same individual.Figure 1: Mean Insulin Activity Versus Time Profiles After Injection of 0.3 units/kg of HUMALOG, HUMALOG Mix50/50, HUMALOG Mix75/25, or Insulin Lispro Protamine Suspension (ILPS) in 30 Healthy Subjects.Figure 2: Mean Insulin Activity Versus Time Profiles After Injection of 0.3 units/kg of HUMALOG Mix75/25 or HUMULIN 70/30 in Healthy Subjects.. Figure 1. Figure 2. 12.3 Pharmacokinetics. Absorption -- HUMALOG Mix75/25 has two phases of absorption. The early phase represents insulin lispro and its distinct characteristics of rapid onset. The late phase represents the prolonged absorption of insulin lispro protamine suspension.In 31 healthy subjects given subcutaneous doses (0.3 unit/kg) of HUMALOG Mix75/25, the median peak serum concentration was 60 minutes (range: 30 minutes to hours) after dosing. Identical results were found in patients with type diabetes. The rapid absorption characteristics of HUMALOG are maintained with HUMALOG Mix75/25. HUMALOG Mix75/25 has more rapid absorption than HUMULIN 70/30, which has been confirmed in patients with type diabetes.. Metabolism -- Human metabolism studies of HUMALOG Mix75/25 have not been conducted. However, studies in animals indicate that the metabolism of HUMALOG, the rapid-acting component of HUMALOG Mix75/25, is identical to that of regular human insulin.. Elimination -- Because of the absorption-rate limited kinetics of insulin mixtures, true half-life cannot be accurately estimated from the terminal slope of the concentration versus time curve.. Specific PopulationsThe effects of age, race, obesity, pregnancy, smoking, or renal or hepatic impairment on the pharmacokinetics of HUMALOG Mix75/25 have not been studied.. Gender -- Pharmacokinetic and pharmacodynamic comparisons between men and women administered HUMALOG Mix75/25 showed no gender differences.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. HUMALOG Mix75/25 is contraindicated:during episodes of hypoglycemia [see Warnings and Precautions (5.3)] in patients who have had hypersensitivity reactions to HUMALOG Mix75/25 or to any of its excipients. [see Warnings and Precautions (5.5)] during episodes of hypoglycemia [see Warnings and Precautions (5.3)] in patients who have had hypersensitivity reactions to HUMALOG Mix75/25 or to any of its excipients. [see Warnings and Precautions (5.5)] Do not use during episodes of hypoglycemia. (4)Do not use in patients with hypersensitivity to HUMALOG Mix75/25 or any of its excipients. (4). Do not use during episodes of hypoglycemia. (4). Do not use in patients with hypersensitivity to HUMALOG Mix75/25 or any of its excipients. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. HUMALOG Mix75/25 (insulin lispro protamine and insulin lispro injectable suspension) is mixture of 75% insulin lispro protamine, an intermediate-acting human insulin analog, and 25% insulin lispro, rapid-acting human insulin analog. Insulin lispro is produced by recombinant DNA technology utilizing non-pathogenic laboratory strain of Escherichia coli. Insulin lispro differs from human insulin in that the amino acid proline at position B28 is replaced by lysine and the lysine in position B29 is replaced by proline. Chemically, it is Lys(B28), Pro(B29) human insulin analog and has the empirical formula C257H383N65O77S6 and molecular weight of 5808, both identical to that of human insulin. Insulin lispro protamine suspension is suspension of crystals produced from combining insulin lispro and protamine sulfate under appropriate conditions for crystal formation.Insulin lispro has the following primary structure:HUMALOG Mix75/25 vials and KwikPens contain white and cloudy, sterile suspension of insulin lispro protamine suspension mixed with soluble insulin lispro for use as an injection.Each milliliter of HUMALOG Mix75/25 injection contains insulin lispro 100 units, 0.28 mg protamine sulfate, 16 mg glycerin, 3.78 mg dibasic sodium phosphate, 1.76 mg Metacresol, zinc oxide content adjusted to provide 0.025 mg zinc ion, 0.715 mg phenol, and Water for Injection. The pH is 7.0 to 7.8. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.. Primary Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. See Full Prescribing Information for important administration instructions. (2.1)Inject subcutaneously in abdominal wall, thigh, upper arm, or buttocks and rotate injection sites to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. (2.1)Individualize and adjust dosage based on metabolic needs, blood glucose monitoring results and glycemic control goal. (2.2)Inject HUMALOG Mix75/25 subcutaneously within 15 minutes before meal. (2.2)Do not administer HUMALOG Mix75/25 intravenously or by continuous subcutaneous insulin infusion pump. (2.1)HUMALOG Mix75/25 is typically dosed twice daily (with each dose intended to cover meals or meal and snack). (2.2). See Full Prescribing Information for important administration instructions. (2.1). Inject subcutaneously in abdominal wall, thigh, upper arm, or buttocks and rotate injection sites to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. (2.1). Individualize and adjust dosage based on metabolic needs, blood glucose monitoring results and glycemic control goal. (2.2). Inject HUMALOG Mix75/25 subcutaneously within 15 minutes before meal. (2.2). Do not administer HUMALOG Mix75/25 intravenously or by continuous subcutaneous insulin infusion pump. (2.1). HUMALOG Mix75/25 is typically dosed twice daily (with each dose intended to cover meals or meal and snack). (2.2). 2.1 Important Administration Instructions. Always check insulin labels before administration [see Warnings and Precautions (5.4)].HUMALOG Mix75/25 is suspension that must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.To resuspend vial, carefully invert the vial at least 10 times until the suspension appears uniformly white and cloudy. Inject immediately.To resuspend KwikPen, gently roll the KwikPen at least 10 times and then carefully invert the Kwikpen at least 10 times until the suspension appears uniformly white and cloudy. Inject immediately.Inspect HUMALOG Mix75/25 visually before use. Do not use if discoloration or particulate matter is seen.Administer HUMALOG Mix75/25 by subcutaneous injection into the abdominal wall, thigh, upper arm, or buttocks.Rotate the injection site 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 patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].The HUMALOG Mix75/25 KwikPen dials in unit increments.Use HUMALOG Mix75/25 KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose.Do not administer HUMALOG Mix75/25 intravenously, intramuscularly or by continuous subcutaneous insulin infusion pump.Do not mix HUMALOG Mix75/25 with any other insulins or diluents.. Always check insulin labels before administration [see Warnings and Precautions (5.4)].. HUMALOG Mix75/25 is suspension that must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.. To resuspend vial, carefully invert the vial at least 10 times until the suspension appears uniformly white and cloudy. Inject immediately.. To resuspend KwikPen, gently roll the KwikPen at least 10 times and then carefully invert the Kwikpen at least 10 times until the suspension appears uniformly white and cloudy. Inject immediately.. Inspect HUMALOG Mix75/25 visually before use. Do not use if discoloration or particulate matter is seen.. Administer HUMALOG Mix75/25 by subcutaneous injection into the abdominal wall, thigh, upper arm, or buttocks.. Rotate the injection site 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 patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].. The HUMALOG Mix75/25 KwikPen dials in unit increments.. Use HUMALOG Mix75/25 KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose.. Do not administer HUMALOG Mix75/25 intravenously, intramuscularly or by continuous subcutaneous insulin infusion pump.. Do not mix HUMALOG Mix75/25 with any other insulins or diluents.. 2.2 Dosage Information. Individualize and adjust the dosage of HUMALOG Mix75/25 based on the individuals metabolic needs, blood glucose monitoring results and glycemic control goal.Inject HUMALOG Mix75/25 subcutaneously within 15 minutes before meal.HUMALOG Mix75/25 is typically dosed twice-daily (with each dose intended to cover meals or meal and snack)Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions (5.2, 5.3) and Use in Specific Populations (8.6, 8.7)].Dosage adjustment may be needed when switching from another insulin to HUMALOG Mix75/25.. Individualize and adjust the dosage of HUMALOG Mix75/25 based on the individuals metabolic needs, blood glucose monitoring results and glycemic control goal.. Inject HUMALOG Mix75/25 subcutaneously within 15 minutes before meal.. HUMALOG Mix75/25 is typically dosed twice-daily (with each dose intended to cover meals or meal and snack). Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions (5.2, 5.3) and Use in Specific Populations (8.6, 8.7)].. Dosage adjustment may be needed when switching from another insulin to HUMALOG Mix75/25.. 2.3 Dosage Adjustment Due to Drug Interactions. Dosage adjustment may be needed when HUMALOG Mix75/25 is coadministered with certain drugs [see Drug Interactions (7)].. Dosage adjustment may be needed when HUMALOG Mix75/25 is coadministered with certain drugs [see Drug Interactions (7)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. HUMALOG Mix75/25 injectable suspension 100 units per mL (U-100) is 75% insulin lispro protamine and 25% insulin lispro, white and cloudy suspension available as:10 mL multiple-dose vial3 mL single-patient-use KwikPen (prefilled). 10 mL multiple-dose vial. mL single-patient-use KwikPen (prefilled). Injectable suspension: HUMALOG Mix75/25 is 100 units per mL (U-100), 75% insulin lispro protamine and 25% insulin lispro available as: (3)10 mL multiple-dose vial3 mL single-patient-use KwikPen(R) (prefilled). 10 mL multiple-dose vial. mL single-patient-use KwikPen(R) (prefilled).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table 1: Clinically Significant Drug Interactions with HUMALOG Mix75/25Drugs that May Increase the Risk of HypoglycemiaDrugs: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.Intervention:Dose adjustment and increased frequency of glucose monitoring may be required when HUMALOG Mix75/25 is co-administered with these drugs.Drugs that May Decrease the Blood Glucose Lowering Effect of HUMALOG Mix75/25Drugs: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.Intervention:Dose adjustment and increased frequency of glucose monitoring may be required when HUMALOG Mix75/25 is co-administered with these drugs.Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of HUMALOG Mix75/25Drugs:Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.Intervention:Dose adjustment and increased frequency of glucose monitoring may be required when HUMALOG Mix75/25 is co-administered with these drugs.Drugs that May Blunt Signs and Symptoms of HypoglycemiaDrugs:Beta-blockers, clonidine, guanethidine, and reserpine.Intervention:Increased frequency of glucose monitoring may be required when HUMALOG Mix75/25 is co-administered with these 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. (7)Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics, 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. (7)Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine. (7)Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine. (7). 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. (7). Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics, 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. (7). Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine. (7). Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine. (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of Humalog Mix75/25 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics of HUMALOG Mix75/25 has not been studied. Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent HUMALOG Mix75/25 dose adjustment and more frequent glucose monitoring [see Warnings and Precautions (5.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. HUMALOG Mix75/25 injectable suspension 100 units per mL (U-100) is 75% insulin lispro protamine and 25% insulin lispro, white and cloudy suspension available as:10 mL multiple-dose vialNDC 0002-7511-013 mL single-patient-use KwikPen (prefilled)NDC 0002-8797-59HUMALOG Mix75/25 KwikPens must never be shared between patients, even if the needle is changed. Patients using HUMALOG Mix75/25 vials must never share needles or syringes with another person. Always use new disposable syringe or needle for each injection to prevent contamination.The HUMALOG Mix75/25 KwikPen dials in unit increments.. 16.2 Storage and Handling. Dispense in the original sealed carton with the enclosed Instructions for Use.Do not use after the expiration date. Protect from direct heat and light. Do not freeze. See storage table below:Not In-Use (Unopened)Refrigerated (36 to 46F [2 to 8C])Not In Use (unopened) Room Temperature (Below 86F [30C])In-Use (Opened)Room Temperature, (Below 86F [30C])10 mL multiple-dose vialUntil expiration date28 days28 days, refrigerated/room temperature3 mL single-patient-use KwikPenUntil expiration date10 days10 days, room temperature.Do not refrigerate.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. HUMALOG Mix75/25 is indicated to improve glycemic control in patients with diabetes mellitus.. HUMALOG(R) Mix75/25(TM) is mixture of insulin lispro protamine, an intermediate-acting human insulin analog, and insulin lispro, rapid-acting human insulin analog indicated to improve glycemic control in patients with diabetes mellitus. (1)Limitations of Use:The proportions of rapid-acting and intermediate-acting insulins are fixed and do not allow for basal versus prandial dose adjustments. (1). Limitations of Use:The proportions of rapid-acting and intermediate-acting insulins in HUMALOG Mix75/25 are fixed and do not allow for basal versus prandial dose adjustments.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).. Never Share HUMALOG Mix75/25 KwikPen or Syringe Between PatientsAdvise patients using Humalog Mix75/25 vials or Humalog Mix75/25 KwikPen not to share needles, syringes, or KwikPen with another person. Sharing poses risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].. Hyperglycemia or HypoglycemiaInform patients that hypoglycemia is the most common adverse reaction with insulin. Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of HUMALOG Mix75/25 therapy. Instruct patients on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. Instruct patients on the management of hypoglycemia [see Warnings and Precautions (5.3)]. Inform patients that their ability to concentrate and react may be impaired as result of hypoglycemia. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.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 ErrorsInstruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions (5.4)].. Hypersensitivity ReactionsAdvise patients that hypersensitivity reactions have occurred with HUMALOG Mix75/25. Inform patients on the symptoms of hypersensitivity reactions and to seek medical attention if they occur [see Warnings and Precautions (5.5)].Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright (C) 1999, 2019, Eli Lilly and Company. All rights reserved.LOG7525-0005-USPI-20191115.

INSTRUCTIONS FOR USE SECTION.

Instructions for UseHUMALOG(R)(HU-ma-log) Mix75/25(TM)(insulin lispro protamine and insulin lispro injectable suspension)for subcutaneous use10 mL multiple-dose vial (100 units/mL)Read this Instructions for Use before you start taking HUMALOG Mix75/25 and each time you get new vial. 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 needles or syringes with other people, even if the needle has been changed. You may give other people serious infection or get serious infection from them.Supplies needed to give your injectiona multiple-dose HUMALOG Mix75/25 viala U-100 insulin syringe and needle2 alcohol swabsgauze1 sharps container for throwing away used needles and syringes. See Disposing of used needles and syringes at the end of these instructions.VialSyringePreparing your HUMALOG Mix75/25 doseWash your hands with soap and water.Check the HUMALOG Mix75/25 label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.HUMALOG Mix75/25 is easier to mix when it is at room temperature.After mixing HUMALOG Mix75/25, inject your dose right away. If you wait to inject your dose, the insulin will need to be mixed again.Always use new syringe and needle for each injection to help prevent infections and blocked needles. Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.Step 1:Gently roll the vial between the palms of your hands at least 10 times.Step 2:Gently move the vial up and down (invert) at least 10 times. Mixing is important to make sure you get the right dose. Humalog Mix75/25 should look white and cloudy after mixing. Do not use it if it looks clear or contains any lumps or particles.Step 3:If you are using new vial, pull off the plastic Protective Cap, but do not remove the Rubber Stopper.Step 4:Wipe the Rubber Stopper with an alcohol swab.Step 5:Remove the Needle Shield from the syringe by pulling the Needle Shield straight off. Hold the syringe with the needle pointing up. Pull down on the Plunger until the Plunger Tip reaches the line for the number of units for your prescribed dose.(Example Dose: 20 units shown)Step 6:Push the needle through the Rubber Stopper of the vial.Step 7:Push the Plunger all the way in. This puts air into the vial.Step 8:Turn the vial and syringe upside down and slowly pull the Plunger down until the Plunger Tip is few units past the line for your prescribed dose.(Example Dose: 20 units Plunger Tip is shown at 24 units)If there are air bubbles, tap the syringe gently few times to let any air bubbles rise to the top.Step 9:Slowly push the Plunger up until the Plunger Tip reaches the line for your prescribed dose.Check the syringe to make sure that you have the right dose.(Example Dose: 20 units shown)Step 10:Pull the syringe out of the Rubber Stopper of the vial.Giving your HUMALOG Mix75/25 InjectionInject your insulin exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you should pinch the skin before injecting.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.Step 11:Choose your injection site.HUMALOG Mix75/25 is injected under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs or upper arms.Wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose.Step 12:Insert the needle into your skin.Step 13:Push down on the Plunger to inject your dose.The needle should stay in your skin for at least seconds to make sure you have injected all of your insulin dose.Step 14:Pull the needle out of your skin.If you see blood after you take the needle out of your skin, press the injection site with piece of gauze or an alcohol swab. Do not rub the area.Do not recap the needle. Recapping the needle can lead to needle stick injury.Disposing of used needles and syringesPut your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.If you do not have FDA-cleared sharps disposal container, you may use household container that is:-made of heavy-duty plastic,-can be closed with 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 FDAs 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.How should store HUMALOG Mix75/25All unopened vials:Store all unopened vials in the refrigerator at 36F to 46F (2C to 8C).Do not freeze. Do not use if HUMALOG Mix75/25 has been frozen.Keep away from heat and out of direct light.Unopened vials can be used until the expiration date on the carton and label, if they have been stored in the refrigerator.Unopened vials should be thrown away after 28 days, if they are stored at room temperature.After vials have been opened:Store opened vials in the refrigerator or at room temperature below 86F (30C) for up to 28 days.Keep vials away from heat and out of direct light.Throw away all opened vials after 28 days of use, even if there is insulin left in the vial.Keep HUMALOG Mix75/25 vials, syringes, needles, and all medicines out of the reach of children.If you have any questions or problems with your HUMALOG, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider for help. For more information on HUMALOG and insulin, go to www.humalog.com.Scan this code to launch the humalog.com websiteThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Humalog(R) and Humalog(R) Mix75/25(TM) are registered trademarks of Eli Lilly and Company.Revised: 11/2019Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright (C) 1999, 2019, Eli Lilly and Company. All rights reserved.LOG7525VL-0002-IFU-20191115. multiple-dose HUMALOG Mix75/25 vial. U-100 insulin syringe and needle. alcohol swabs. gauze. sharps container for throwing away used needles and syringes. See Disposing of used needles and syringes at the end of these instructions.. Wash your hands with soap and water.. Check the HUMALOG Mix75/25 label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.. HUMALOG Mix75/25 is easier to mix when it is at room temperature.. After mixing HUMALOG Mix75/25, inject your dose right away. If you wait to inject your dose, the insulin will need to be mixed again.. Always use new syringe and needle for each injection to help prevent infections and blocked needles. Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.. Inject your insulin exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you should pinch the skin before injecting.. 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.. If you see blood after you take the needle out of your skin, press the injection site with piece of gauze or an alcohol swab. Do not rub the area.. Do not recap the needle. Recapping the needle can lead to needle stick injury.. Put your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.. If you do not have FDA-cleared sharps disposal container, you may use household container that is:-made of heavy-duty plastic,-can be closed with 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. -made of heavy-duty plastic,. -can be closed with 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 FDAs 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.. Store all unopened vials in the refrigerator at 36F to 46F (2C to 8C).. Do not freeze. Do not use if HUMALOG Mix75/25 has been frozen.. Keep away from heat and out of direct light.. Unopened vials can be used until the expiration date on the carton and label, if they have been stored in the refrigerator.. Unopened vials should be thrown away after 28 days, if they are stored at room temperature.. Store opened vials in the refrigerator or at room temperature below 86F (30C) for up to 28 days.. Keep vials away from heat and out of direct light.. Throw away all opened vials after 28 days of use, even if there is insulin left in the vial.. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of HUMALOG Mix75/25 in human milk, the effects on the breastfed infant, or the effect on milk production. One small published study reported that exogenous insulin was present in human milk. However, there is insufficient information to determine the effects of HUMALOG Mix75/25 on the breastfed infant and no available information on the effects of HUMALOG Mix75/25 on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for insulin, any potential adverse effects on the breastfed child from HUMALOG Mix75/25 or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The primary activity of insulin, including HUMALOG Mix75/25, is the regulation of glucose metabolism. Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Standard 2-year carcinogenicity studies in animals have not been performed with HUMALOG Mix75/25. In Fischer 344 rats, 12-month repeat-dose toxicity study was conducted with insulin lispro (a component of HUMALOG Mix75/25) at subcutaneous doses of 20 and 200 units/kg/day (approximately and 32 times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area). Insulin lispro did not produce important target organ toxicity including mammary tumors at any dose.Insulin lispro was not mutagenic in the following genetic toxicity assays: bacterial mutation, unscheduled DNA synthesis, mouse lymphoma, chromosomal aberration and micronucleus assays.Male fertility was not compromised when male rats given subcutaneous insulin lispro injections of and 20 units/kg/day (0.8 and times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area) for months were mated with untreated female rats. In combined fertility, perinatal, and postnatal study in male and female rats given 1, 5, and 20 units/kg/day subcutaneously (0.2, 0.8, and times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular or subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately [see Warnings and Precautions (5.3, 5.6)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE CARTON HUMALOG Mix75/25 10 mL vial 1ctNDC 0002-7511-0110 mL100 units per mLHumalog(R) Mix75/25TM insulin lispro protamineand insulin lispro injectable suspensionFor subcutaneous use only.Rx onlyU-100www.humalog.comLilly. PACKAGE CARTON HUMALOG Mix75/25 10 mL vial 1ct.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of HUMALOG Mix75/25 in patients less than 18 years of age has not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. In glucose clamp study performed in 30 healthy subjects, the onset of action and glucose-lowering activity of HUMALOG, HUMALOG(R) Mix50/50(TM), HUMALOG Mix75/25, and insulin lispro protamine suspension (ILPS) were compared (see Figure 1). Graphs of mean glucose infusion rate versus time showed distinct insulin activity profile for each formulation. The rapid onset of glucose-lowering activity characteristic of HUMALOG was maintained in HUMALOG Mix75/25. The median maximum pharmacologic effect of HUMALOG Mix75/25 after administration of 0.3 unit/kg dose to healthy subjects occurred at approximately hours (range: 1-6 hours); glucose lowering activity was detectable for median of 22 hours (range: 13 to 22 hours), which was the end of the clamp.In separate glucose clamp studies performed in healthy subjects, pharmacodynamics of HUMALOG Mix75/25 and HUMULIN(R) 70/30 were assessed and are presented in Figure 2. HUMALOG Mix75/25 has duration of activity similar to that of HUMULIN 70/30. Figures and should be considered only as representative examples since the time course of action of insulin and insulin analogs, may vary in different individuals or within the same individual.Figure 1: Mean Insulin Activity Versus Time Profiles After Injection of 0.3 units/kg of HUMALOG, HUMALOG Mix50/50, HUMALOG Mix75/25, or Insulin Lispro Protamine Suspension (ILPS) in 30 Healthy Subjects.Figure 2: Mean Insulin Activity Versus Time Profiles After Injection of 0.3 units/kg of HUMALOG Mix75/25 or HUMULIN 70/30 in Healthy Subjects.. Figure 1. Figure 2.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption -- HUMALOG Mix75/25 has two phases of absorption. The early phase represents insulin lispro and its distinct characteristics of rapid onset. The late phase represents the prolonged absorption of insulin lispro protamine suspension.In 31 healthy subjects given subcutaneous doses (0.3 unit/kg) of HUMALOG Mix75/25, the median peak serum concentration was 60 minutes (range: 30 minutes to hours) after dosing. Identical results were found in patients with type diabetes. The rapid absorption characteristics of HUMALOG are maintained with HUMALOG Mix75/25. HUMALOG Mix75/25 has more rapid absorption than HUMULIN 70/30, which has been confirmed in patients with type diabetes.. Metabolism -- Human metabolism studies of HUMALOG Mix75/25 have not been conducted. However, studies in animals indicate that the metabolism of HUMALOG, the rapid-acting component of HUMALOG Mix75/25, is identical to that of regular human insulin.. Elimination -- Because of the absorption-rate limited kinetics of insulin mixtures, true half-life cannot be accurately estimated from the terminal slope of the concentration versus time curve.. Specific PopulationsThe effects of age, race, obesity, pregnancy, smoking, or renal or hepatic impairment on the pharmacokinetics of HUMALOG Mix75/25 have not been studied.. Gender -- Pharmacokinetic and pharmacodynamic comparisons between men and women administered HUMALOG Mix75/25 showed no gender differences.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe limited available data with HUMALOG Mix75/25 in pregnant women are insufficient to inform drug-associated risk of adverse developmental outcomes. Published studies with insulin lispro used during pregnancy have not reported an association between insulin lispro and the induction of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Pregnant rats and rabbits were exposed to insulin lispro in animal reproduction studies during organogenesis. No adverse effects on embryo/fetal viability or morphology were observed in offspring of rats exposed to insulin lispro at dose approximately times the human subcutaneous dose of unit insulin lispro/kg/day. No adverse effects on embryo/fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.2 times the human subcutaneous dose of unit/kg/day (see Data). The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.. Data. Human DataPublished data from retrospective studies and meta-analyses do not report an association with insulin lispro and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin lispro is used during pregnancy. However, these studies cannot definitely establish or exclude the absence of any risk because of methodological limitations including small sample size, selection bias, confounding by unmeasured factors, and some lacking comparator groups.. Animal DataAnimal reproduction studies have not been performed with HUMALOG Mix75/25. However, subcutaneous reproduction and teratology studies have been conducted with insulin lispro (a component of HUMALOG Mix75/25). In combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 1, 5, and 20 units/kg/day (0.2, 0.8, and times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area, respectively) from weeks prior to cohabitation through Gestation Day 19. There were no adverse effects on female fertility, implantation, or fetal viability and morphology. However, fetal growth retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal weight and an increased incidence of fetal runts/litter.In an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1, 0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.2 times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation days through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Dispense in the original sealed carton with the enclosed Instructions for Use.Do not use after the expiration date. Protect from direct heat and light. Do not freeze. See storage table below:Not In-Use (Unopened)Refrigerated (36 to 46F [2 to 8C])Not In Use (unopened) Room Temperature (Below 86F [30C])In-Use (Opened)Room Temperature, (Below 86F [30C])10 mL multiple-dose vialUntil expiration date28 days28 days, refrigerated/room temperature3 mL single-patient-use KwikPenUntil expiration date10 days10 days, room temperature.Do not refrigerate.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThe limited available data with HUMALOG Mix75/25 in pregnant women are insufficient to inform drug-associated risk of adverse developmental outcomes. Published studies with insulin lispro used during pregnancy have not reported an association between insulin lispro and the induction of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Pregnant rats and rabbits were exposed to insulin lispro in animal reproduction studies during organogenesis. No adverse effects on embryo/fetal viability or morphology were observed in offspring of rats exposed to insulin lispro at dose approximately times the human subcutaneous dose of unit insulin lispro/kg/day. No adverse effects on embryo/fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.2 times the human subcutaneous dose of unit/kg/day (see Data). The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.. Data. Human DataPublished data from retrospective studies and meta-analyses do not report an association with insulin lispro and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin lispro is used during pregnancy. However, these studies cannot definitely establish or exclude the absence of any risk because of methodological limitations including small sample size, selection bias, confounding by unmeasured factors, and some lacking comparator groups.. Animal DataAnimal reproduction studies have not been performed with HUMALOG Mix75/25. However, subcutaneous reproduction and teratology studies have been conducted with insulin lispro (a component of HUMALOG Mix75/25). In combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 1, 5, and 20 units/kg/day (0.2, 0.8, and times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area, respectively) from weeks prior to cohabitation through Gestation Day 19. There were no adverse effects on female fertility, implantation, or fetal viability and morphology. However, fetal growth retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal weight and an increased incidence of fetal runts/litter.In an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1, 0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.2 times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation days through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose.. 8.2 Lactation. Risk SummaryThere are no data on the presence of HUMALOG Mix75/25 in human milk, the effects on the breastfed infant, or the effect on milk production. One small published study reported that exogenous insulin was present in human milk. However, there is insufficient information to determine the effects of HUMALOG Mix75/25 on the breastfed infant and no available information on the effects of HUMALOG Mix75/25 on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for insulin, any potential adverse effects on the breastfed child from HUMALOG Mix75/25 or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness of HUMALOG Mix75/25 in patients less than 18 years of age has not been established.. 8.5 Geriatric Use. Clinical studies of Humalog Mix75/25 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3)]. 8.6 Renal Impairment. The effect of renal impairment on the pharmacokinetics of HUMALOG Mix75/25 has not been studied. Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent HUMALOG Mix75/25 dose adjustment and more frequent glucose monitoring [see Warnings and Precautions (5.3)].. 8.7 Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics of HUMALOG Mix75/25 has not been studied. Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent HUMALOG Mix75/25 dose adjustment and more frequent glucose monitoring [see Warnings and Precautions (5.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Never share HUMALOG Mix75/25 KwikPen or syringe between patients, even if the needle is changed. (5.1)Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Make changes to patients 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 blood glucose monitoring with changes to insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness. (5.3)Hypoglycemia Due to Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. (5.4)Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue HUMALOG Mix75/25, monitor and treat if indicated. (5.5)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 reductions or discontinuation if heart failure occurs. (5.7). Never share HUMALOG Mix75/25 KwikPen or syringe between patients, even if the needle is changed. (5.1). Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Make changes to patients 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 blood glucose monitoring with changes to insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness. (5.3). Hypoglycemia Due to Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. (5.4). Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue HUMALOG Mix75/25, monitor and treat if indicated. (5.5). 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 reductions or discontinuation if heart failure occurs. (5.7). 5.1 Never Share HUMALOG Mix75/25 KwikPen or Syringe Between Patients. HUMALOG Mix75/25 KwikPens must never be shared between patients, even if the needle is changed. Patients using HUMALOG Mix75/25 vials must never share needles or syringes with another person. Sharing poses risk for transmission of blood-borne pathogens.. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen. Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6)].Make any changes to patients 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 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.. 5.3 Hypoglycemia. Hypoglycemia is the most common adverse reaction associated with all insulin therapies, including HUMALOG Mix75/25. Severe hypoglycemia can cause seizures, may lead to unconsciousness, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual 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 individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or in patients who experience recurrent hypoglycemia.. Risk Factors for HypoglycemiaThe 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 insulin preparations, the glucose lowering effect time course of HUMALOG Mix75/25 may vary in different individuals or at different times in the same individual 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 co-administered medication [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)].. Risk Mitigation Strategies for HypoglycemiaPatients 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.. 5.4 Hypoglycemia Due to Medication Errors. Accidental mix-ups between HUMALOG Mix75/25 and other insulin products have been reported. To avoid medication errors between HUMALOG Mix75/25 and other insulins, instruct patients to always check the insulin label before each injection.. 5.5 Hypersensitivity Reactions. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including HUMALOG Mix75/25. If hypersensitivity reactions occur, discontinue HUMALOG Mix75/25; treat per standard of care and monitor until symptoms and signs resolve. HUMALOG Mix75/25 is contraindicated in patients who have had hypersensitivity reactions to HUMALOG Mix75/25 or any of its excipients [see Contraindications (4)].. 5.6 Hypokalemia. All insulin products, including HUMALOG Mix75/25, cause shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).. 5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists. Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including HUMALOG Mix75/25, and 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.